Secrets – Pediatric: Infectious Diseases

Secrets – Pediatric: Infectious Diseases

ANTI-INFECTIVE THERAPY

KEY POINTS ANTI- INFECTIVE THERAPY
1. Formal allergy testing is frequently negative in patients who report a penicillin allergy.
2. Rashes seen with viral or bacterial illnesses may confound a history of antibiotic allergy.
3. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming a prevalent pathogen in the community, and empiric therapy for certain infections may be broadened to include MRSA coverage.
4. Antibiotic resistance is emerging in all types of organisms, risking the use of drugs that are safe and approved for use in the pediatric population.

1. What are the main features of penicillins?
Penicillins are among the earliest classes of antibiotics developed. They are derived from the fungus Penicillium, and share a core structural feature—a β-lactam ring—with other classes of antibiotics, such as cephalosporins and carbapenems. Penicillins interfere with the peptidoglycan cross-linking that is required to produce stable bacterial cell walls. They penetrate most tissue spaces well but do not cross the blood-brain barrier except in the case of inflamed meninges. However, they have a high therapeutic index, and thus doses can be escalated to increase tissue penetration. They are not active against organisms that are cell-wall deficient, such as Chlamydia and Mycoplasma species.
2. What are the different classes and spectra of activity of penicillins?
• Penicillins (penicillins G [intravenous] and V [oral]):
• These are natural penicillins that are derived directly from the Penicillium mold. These drugs are active against most nonpenicillinase producing gram-positive cocci and gram-positive anaerobic organisms.
• Penicillin G is the drug of choice for Treponema pallidum infection (syphilis) and Streptococcus agalactiae (also known as group B strep).
• Penicillins are also the treatment of choice for group A streptococcal pharyngitis and some anaerobic infections.
• Antistaphylococcal penicillins are also called penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin, and dicloxacillin [oral]):
• These have side chains attached to the penicillin lactam ring that inhibit their inactivation by antistaphylococcal penicillinases.
• They display excellent activity against sensitive strains of Staphylococcus aureus and should be used, whenever possible, instead of vancomycin, which has less staphylococcal activity.
• The bulky side chains also limit penetration of these drugs through the cell membrane, giving them a narrow spectrum of action.
• Aminopenicillins (ampicillin and amoxicillin):
• The spectrum is similar to that of penicillin but includes additional activity against aerobic gram- negative bacteria (i.e., Escherichia coli, Listeria, and Salmonella spp.).
• Many previously susceptible gram-negative organisms are now resistant to the aminopenicillins.
• Extended spectrum, also described as “Anti-pseudomonal penicillins” (piperacillin and ticarcillin):
• These have an expanded gram-negative spectrum and can be used to treat susceptible strains of Pseudomonas aeruginosa and Proteus spp.
• Combinations with β-lactamase inhibitors: The spectrum of certain penicillins can be increased by the addition of a β-lactamase inhibitor. β-Lactamases are a common basis for penicillin resistance in some bacteria. Available combinations include amoxicillin-clavulanate, ampicillin-sulbactam,

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piperacillin-tazobactam, and ticarcillin-clavulanate, which extend their activity to cover Haemophilus influenza, Bacteroides fragilis, and some Enterobacteriaceae.
3. In patients for whom the history lists “penicillin allergy,” how commonly is a true allergy present on testing? A true allergy is present on testing £10% of the time. In patients reporting a penicillin allergy, skin tests and radioallergosorbent tests are frequently negative ( 20% and 3%, respectively). Much of the confusion arises from the use of the term “allergic reaction” to describe a gamut of nonimmunologic adverse experiences that may be attributable to either the medication, the underlying disease process, or an interaction of the two.

Pichichero ME: A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients, Pediatrics 115:1048–1057, 2005.

4. If a 16-year-old male develops a pruritic, maculopapular rash 1 week after starting treatment with amoxicillin for an exudative pharyngitis, should he be designated as “amoxicillin allergic?”
No! As previously alluded to, the immune response that is mounted to a viral pathogen may alter the immune response to antimicrobials, creating an “allergic reaction” that is unique to the organism and drug at hand. The classic example of this is the development of a rash following treatment with amoxicillin in patients with Epstein-Barr virus (EBV). Recent reports have implicated the virus itself in addition to the interaction of the virus and the antimicrobial. In addition, many herpes viruses (such as EBV and human herpesvirus 6), as well as enteroviruses, will cause a maculopapular eruption as part of the viral syndrome. These patients are not allergic to penicillins. This should also be taken as further incentive to avoid prescribing antimicrobials for viral illnesses.
5. What are the similarities between penicillins and cephalosporins? Both cephalosporins and penicillin are derived from fungi: cephalosporins are from the fungus Acremonium (formerly Cephalosporium), and penicillin is from the Penicillium fungus. Furthermore, they both contain a β-lactam ring and interfere with bacterial cell wall synthesis by irreversibly inhibiting penicillin-binding protein peptidoglycan cross-linking.
6. How do the “generations” of cephalosporins differ from one another?
They are divided into four “generations” based on antimicrobial spectrum of action; in general, activity against gram-negative organisms increases with increasing generation, whereas activity against
gram-positive organisms decreases with each generation. Third- and fourth-generation cephalosporins have good penetration in the cerebrospinal fluid (CSF).
7. What are the differences among first-, second-, third-, and fourth-generation cephalosporins?
• First-generation cephalosporins (e.g., cefazolin, cephalexin, cefadroxil)
• Good activity against gram-positive organisms (especially Methicillin-susceptible S. aureus and streptococci spp.)
• Frequently used as prophylaxis for orthopedic, cardiovascular, head and neck, and many types of neurosurgical or general surgical procedures (i.e., herniorrhaphy)
• May have activity against some E. coli and Klebsiella species, but lack efficacy against
Haemophilus influenza
• May be considered as alternatives to penicillins for the treatment of group A streptococcal pharyngitis and group B streptococcal prophylaxis during labor.
• Second-generation cephalosporins (e.g., cefuroxime, cefotetan, cefoxitin)
• Increased spectrum of activity, including many gram-negative organisms
• Increased activity against B. fragilis
• Prophylaxis for intra-abdominal (e.g., cefotetan, cefoxitin)
• Treatment for nosocomial pneumonia
• No antipseudomonal activity
• Third-generation cephalosporins (e.g., ceftriaxone, cefotaxime, cefixime, cefdinir, ceftazidime)
• Broad spectrum, excellent activity against gram-negative bacteria
• Generally less activity against gram-positive organisms than earlier generations, such as
methicillin-susceptible S. aureus.

• Very high blood and CSF levels achievable in relation to minimal inhibitory concentration for bacterial strains
• Wide therapeutic index with generally minimal toxicity (similar to previous generations)
• Some offer single-daily dosing
• Ceftazidime: the first cephalosporin with antipseudomonal coverage
• More expensive
• Fourth-generation cephalosporins (e.g., cefepime)
• Broadest spectrum, with activity against most staphylococcal and streptococcal species (NOT methicillin-resistant S. aureus) and gram-negative organisms, including Pseudomonas spp.
• Crosses into the CSF
• No activity against anaerobic organisms

Harrison CJ, Bratcher D: Cephalosporins: a review, Pediatr REV 29:264–272, 2008.

8. Can cephalosporins be safely given to patients who are allergic to penicillin? Previous estimates of cross-sensitivity to cephalosporins among penicillin-allergic patients were thought to be 8% to 18%, but these rates have been criticized as inaccurate and excessive. Side-chain–specific antibodies appear to be key in the immune response to cephalosporins. The incidence of allergic cross- reactivity varies with the chemical side-chain similarity of the cephalosporin to penicillin or amoxicillin. For first-generation cephalosporins, the attributable increased risk is thought to be only 0.4%. For certain second- and third-generation cephalosporins (e.g., cefuroxime, cefpodoxime, and cefdinir), the risk is thought to be close to zero. No evidence supports an increase of anaphylaxis with cephalosporins among penicillin-allergic patients. The American Academy of Pediatrics (AAP) guidelines do endorse the use of selected second-generation and third-generation cephalosporins for penicillin-allergic patients as long as the penicillin reaction is not severe.

Pichichero M: A review of the evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients, Pediatrics 115:1048–1057, 2005.

9. What are the two primary mechanisms of resistance to β-lactam antibiotics?
• Penicillin-binding proteins (PBPs)
• PBPs are enzymes responsible for the cross-linking between glycan chains and are the target proteins for β-lactam antibiotics. Mutational alterations in PBPs can confer resistance by reducing binding of a β-lactam antibiotic to the active site. This mechanism can be overcome by a higher dose of the antibiotic.
• β-Lactamase
These are enzymes that hydrolyze the β-lactam ring of the antibiotic. The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer. Certain β-lactamase gene expression may be induced by exposure to β-lactams; for example, the genes encoding these β-lactamases are found in the chromosomes of organisms such as Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter (often labeled the “SPACE” organisms). This mechanism of resistance, in general, cannot be overcome simply by using a higher dose of drug.
10. What are the main features of carbapenems?
Carbapenems are β-lactam antibiotics that also bind PBPs, disrupting the growth and structural integrity of bacterial cell walls. They provide gram-positive as well as enhanced anaerobic and excellent gram-negative coverage as compared with other β-lactams. They are also resistant to most β-lactamases, including so-called extended-spectrum β-lactamases (ESBLs). They do not cover methicillin-resistant S. aureus (MRSA).
11. What is the role of “double antimicrobial coverage”?
Synergy is when the combination of two antibiotics has a greater killing effect than the sum of the two drugs given separately (i.e., the effect is superadditive: 2 + 2 5). In general, the use of two drugs has not been shown to be better than one drug that appropriately targets the causative organism and site of infection. One exception to this is in infective endocarditis, where the use of two or more drugs is recommended in most circumstances. Another role for the use of more than

one drug for a suspected causative organism is in an unstable patient for whom there is a high suspicion for an infection with an antibiotic-resistant organism. Empiric therapy with more than one drug to cover “gaps” in sensitivities is often appropriate. Therapy can then be narrowed if an organism is isolated or as the patient improves.
12. What are the “ESKAPE” organisms?
The bacteria Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii,
P. aeruginosa, and Enterobacter species are sometimes referred to as the “ESKAPE” organisms, which emphasizes that they are major causes of nosocomial (and increasingly community-acquired) infections and have developed mechanisms to “escape” the effects of many antimicrobials. In addition to MRSA, vancomycin-resistant E. faecium (VRE), Acinetobacter species, multidrug-resistant (MDR) P. aeruginosa, carbapenem-resistant Klebsiella species, and E.coli are emerging as significant pathogens in both the United States and other parts of the world.

Boucher HW, Talbot GH, Bradley JS, et al: Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 48:1–12, 2009.

13. How can the emergence of antibiotic-resistant pathogens be minimized?
• Appropriate hand hygiene, contact isolation, and environmental decontamination to reduce the transmission of resistant organisms to other patients
• Use of the most potent, narrowest spectrum antibiotic possible for an appropriate length of time
• Minimization of the empiric use of broad-spectrum antibiotics
• Avoidance of antibiotic treatment of illnesses that are likely viral
• Awareness of local antibiotic resistance patterns
14. What is the distinction between community-associated methicillin-resistant
S. aureus (CA-MRSA) and hospital acquired methicillin-resistant S. aureus
(HA-MRSA)?
MRSA was first reported in 1961, and was described for the next three decades as primarily a nosocomial pathogen. A report describing the deaths of four previously healthy children in the Midwestern
United States in 1998 brought to attention the issue of MRSA infections in the general population, and CA-MRSA was recognized as a distinct clinical entity.
The most commonly accepted definition of CA-MRSA, as put forth by the Centers for Disease Control and Prevention (CDC), is the diagnosis of MRSA in the outpatient setting or within 48 hours of hospital admission and a lack of risk factors for chronic medical conditions. However, the source of the infection, the antibiotic phenotype, and the genotype of the organism have all been ways to differentiate CA-MRSA from HA-MRSA. Practically, these definitions and distinctions are becoming less relevant as the epidemiology of MRSA and its resistance patterns change and expand. In many locations, strains historically classified as CA-MRSA now cause a majority of nosocomial disease. As molecular typing methods advance, it is likely that the terms CA-MRSA and HA-MRSA will become obsolete and be replaced with more descriptive terms for both the local and global strains of MRSA.

Mediavilla J, Chen L, Mathema B, Kreiswirth BN: Global epidemiology of community-associated methicillin resistant
Staphylococcus aureus (CA-MRSA), Curr Opin Microbiol 15:588–595, 2012. Chua K, Laurent F, Coombs G, Grayson ML, et al: Antimicrobial resistance: Not community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)! A clinician’s guide to community MRSA – its evolving antimicrobial resistance and implications for therapy, Clin Infect Dis 52:99–114, 2011.

15. Why is the D-test done?
The D-test is done with MRSA isolates that are susceptible to clindamycin and resistant to erythromycin to evaluate whether that isolate might have resistance not constitutively expressed (i.e., always produced) but inducible by exposure to macrolides. If patients with this type of MRSA are begun on clindamycin, they may have a higher likelihood of treatment failure or recrudescence. The test involves placing antibiotic disks for erythromycin and clindamycin in close proximity on the agar plate. A flattening of the clindamycin zone of bacterial growth adjacent to the erythromycin disk produces a “D” appearance and indicates the MRSA isolate has inducible resistance to clindamycin (Fig. 10-1).

Figure 10-1. D-test showing flattened zone of clindamycin near the erythromycin disk, demonstrating erythromycin-induced clindamycin resistance. (From Mohapatra TM, Shrestha B, Pokhrel BM: ConstitutIVE and inducible clindamycin resistance in Staphylococcus aureus and their association with methicillin-resistant S. aureus (MRSA), Int J Antimicrob Agents 33:188, 2009.)

16. Is mupirocin useful in the eradication of S. aureus in colonized children?
Colonization of the nasal mucosa or skin is common in children. About 15% to 40% of healthy children are carriers of methicillin-sensitive S. aureus (MSSA). MRSA nasal carriage ranges from 1% to 24% in various studies involving day care, emergency room visits, or hospitalized children. The use of mupirocin applied twice to three times daily for 1 to 21 days was shown in some adult studies to significantly but variably decrease colonization and recurrent invasive disease. However, eradication
is difficult and typically involves additional measures such as chlorhexidine baths, stringent cleaning of the home environment, and often decolonization of the family as well. Unfortunately, recolonization is common. Protracted use of mupirocin leads readily to increased rates of mupirocin resistance in both MSSA and MRSA isolates. Thus, mupirocin is not recommended for routine use in otherwise healthy children to decrease colonization. In certain special circumstances, such as patients with frequent skin and soft tissue infections and underlying medical conditions (e.g., severe eczema, acquired or congenital immunodeficiencies), decolonization may be warranted.

Marimuthu K, Harbarth S: Screening for methicillin-resistant Staphylococcus aureus.. . all doors closed? Curr Opin Infect Dis 27:356–362, 2014.
Abad CL, Pulia MS, Safdar N: Does the nose know? An update on MRSA decolonization strategies, Curr Infect Dis Rep
15:455–464, 2013.
Liu C, Bayer A, Cosgrove SE, et al: Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary, Clin Infect Dis 52: 285–292, 2011.

17. What is the “red man syndrome” and which antibiotic is it associated with? The red man syndrome is a frequent occurrence with the rapid infusion of vancomycin (although there are reports of red man syndrome from ciprofloxacin, rifampin, and amphotericin b) and is characterized by flushing of the neck, face, and thorax. Patients commonly complain of diffuse burning, itching, and dizziness and can develop fever and paresthesias around the mouth. Histamine release from degranulation of mast cells underlies this reaction; however, it is not mediated by IgE and therefore does not represent
a true hypersensitivity reaction. Generally, the reaction appears in the first 10 minutes of administration and can be avoided by slowing the rate of drug infusion. Administration of an H1-receptor antagonist (e.g., diphenhydramine) before vancomycin is given is also effective for preventing this reaction.
18. How should infections with vancomycin-resistant enterococci be managed? Resistance to vancomycin has been observed in Enterococcus faecium and, less commonly, Enterococcus faecalis. These infections are acquired nosocomially, which reflects the fact that the organism can survive

on inanimate surfaces (including medical equipment) for weeks. They occur more commonly with prolonged use of antibiotics. Basic tenets of anti-infective therapy apply: foreign bodies should be removed, infected fluid collections should be drained, and patients should be placed on contact isolation to prevent spread. The oxazolidinone antibiotic linezolid (Zyvox) has shown some effectiveness, but the data are limited. Combination streptogramin agent quinupristin-dalfopristin (Synercid) is approved for individuals 16 years of age, and dosing guidelines for children 12 years of age are available. It is noteworthy that quinupristin-dalfopristin has activity against E. faecium but not E. faecalis, and it has many drug interactions, which limits its use in certain situations. Daptomycin and newer cephalosporins, including ceftaroline, have direct or synergistic activity against these organisms as well, but there is less experience with their use in pediatric populations.

Patel R, Gallagher JC: Vancomycin-resistant enterococcal bacteremia pharmacotherapy, Ann Pharmacother
49:69–85, 2015.
Zirakzadeh A, Patel R: Vancomycin-resistant enterococci: colonization, infection, detection, and treatment, Mayo Clin Proc 81:529–536, 2006.

19. Is vancomycin still effective against all staphylococci?
Within a few years of the emergence of VRE, isolates of S. aureus with reduced susceptibility and resistance to vancomycin were reported. In some of these isolates, acquisition of resistance genes from VRE has been demonstrated; in others, lower levels of resistance are conferred by a variety of mutations in a small number of staphylococcal regulatory genes. Fortunately, these isolates have retained susceptibility to a variety of other antibiotics. However, some recent reports indicate that methicillin-resistant, vancomycin-“heteroresistant” coagulase-negative staphylococci, mainly Staphylococcus capitis, could emerge as a significant pathogen in the neonatal intensive care unit (NICU). This is especially concerning because there are fewer safe and effective therapeutic options in this population. Appropriate use of vancomycin is key to preventing misuse and overuse and to limiting the likelihood of further emergence of vancomycin resistance.

Howden B, Peleg AY, Stinear TP: The evolution of vancomycin intermediate Staphylococcus aureus (VISA) and heterogenous-VISA, Infect Genet EVOL 21:575–582, 2014.
Rasigade J, Raulin O, Picaud JC, et al: Methicillin-resistant Staphylococcus capitis with reduced vancomycin susceptibility causes late-onset sepsis in intensive care neonates, PLoS One 7:e31548, 2012.

20. In what situations may treatment with vancomycin be considered appropriate?
• Serious infections (e.g., meningitis, endocarditis) attributable to β-lactam–resistant, gram-positive organisms (e.g., coagulase-negative Staphylococcus spp., MRSA, some enterococci spp.)
• Neonates, immune-compromised or ill-appearing children with risk factors for invasive disease, such as the presence of an indwelling central venous device
• Infections attributable to gram-positive microorganisms in patients with serious allergies to
β-lactam antibiotics
• Prophylaxis, as recommended by the American Heart Association, for endocarditis in certain high-risk patients
• Prophylaxis for certain procedures (e.g., implantation of prosthetic materials or devices) at institutions with high rates of MRSA
• Enterally administered vancomycin is indicated for antimicrobial-associated colitis (e.g., Clostridium difficile, especially the NAP-1 strain) that fails to respond to metronidazole or is life threatening

American Academy of Pediatrics: Antimicrobial agents and related therapy. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 805–806.

21. Are fluoroquinolones safe to use in children? Members of the fluoroquinolone class of antibiotics act against bacterial DNA gyrase and topoisomerase II, two enzymes that are required for bacterial DNA replication. No member of the class is approved by the
U.S. Food and Drug Administration (FDA) for routine use in patients <18 years. Part of the basis for
this recommendation is the occurrence of arthropathy in immature beagle dogs treated with ciprofloxacin
or other quinolones. However, there is growing experience with the use of these antibiotics in adolescents and children, primarily those with cystic fibrosis in whom endogenous P. aeruginosa strains may
display high-level resistance to other antibiotic classes (e.g., anti-pseudomonal penicillins, carbapenems,

aminoglycosides). FDA-approved pediatric indications for ciprofloxacin include postexposure treatment for inhalation anthrax and topical therapy for conjunctivitis. The AAP endorses the use of ciprofloxacin as oral therapy for urinary tract infection (UTI) and pyelonephritis caused by P. aeruginosa or other multidrug-resistant gram-negative bacteria in children aged 1 through 17 years. Fluoroquinolones may also be considered when parenteral therapy is not feasible and the infection is caused by multidrug- resistant organisms for which there are no other effective oral agents available, such as UTIs.

Bradley JS, Kauffman RE, Balis DA, et al: Assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin,
Pediatrics 134:e146–e153, 2014.
Bradley JS, Jackson mA: Committee on Infectious Diseases; American Academy of Pediatrics: the use of systemic and topical fluoroquinolones, Pediatrics 128:e1034–e1045, 2011.

22. What are the uses of ribavirin?
Ribavirin is a guanosine analog that inhibits RNA polymerase and subsequently RNA synthesis. It was originally developed in 1972 and was used in the 1980s and 1990s as an inhaled therapy against respiratory syncytial virus (RSV). Both cohort and trial data failed to prove a benefit in mortality or ventilator days in mechanically ventilated infants who had been previously well. However, cohort data have shown that both the inhaled and the IV forms may be of use to prevent lower tract spread of upper tract disease and mortality in allogenic stem cell transplant patients. Most recently, it has shown activity against hepatitis C and is an approved therapy in children in combination
with peginterferon gamma. Ribavirin also has activity against certain viral hemorrhagic fevers and is used to treat Lassa virus infections.

American Academy of Pediatrics: Hepatitis C. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 393.
Moler F, Steinhart CM, Ohmit SE, Stidham GL: Effectiveness of ribavirin in otherwise well infants with respiratory syncytial virus-associated respiratory failure. Pediatric Critical Study Group, J Pediatr 128:422–428, 1996.

23. Why is chicken soup so helpful for upper respiratory infections (URIs)? The benefits of chicken soup have been of lore for hundreds of years, beginning in the twelfth century, when physician and philosopher Maimonides extolled its virtue. The precise mechanisms of its anecdotal therapeutic benefits remain elusive. A 2000 study at the University of Nebraska found that the nonparticulate component of chicken soup in VItro inhibited neutrophil migration in a concentration-dependent manner. A component of chicken soup, the dipeptide carnosine, may offer protection against reactive oxygen radical species-dependent injury. These anti-inflammatory effects may be some of the mechanisms by which chicken soup mitigates the symptoms of URIs. Of course, placebo effects should not be minimized.

Babizhayev MA, Deyev Al, Yegorov YE: Non-hydrolyzed in digestive tract and blood natural L-carnosine peptide (“bioactivated Jewish penicillin”) as a panacea of tomorrow for various flu ailments, J Basic Clin Physiol Pharmacol 24:1–26, 2013.
Rennard BO, Ertl RF, Gossman GL, et al: Chicken soup inhibits neutrophil chemotaxis in vitro, Chest 118:1150–1157, 2000.

24. Is there any physiologic basis to the adage “starve a fever, feed a cold”? Some studies indicate that anorexia increases the number of type 2 T helper (Th2) cells, which are key in fighting bacterial infections. This would serve as a potentially useful behavioral adaptation, particularly in preantibiotic times. Eating, on the other hand, promotes type 1 T helper (Th1) cells by gastrointestinal (GI) stimulation of vagal and neurohormonal factors. The Th1 cells are essential components of the antiviral immune reaction, which might include rhinoviruses and others involved in the common cold.

Bazar KA, Yun AJ, Lee PY: “Starve a fever and feed a cold”: feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance, Med Hypotheses 64:1080–1084, 2005.

CLINICAL ISSUES
25. Name the three stages of pertussis infection (whooping cough)
1. Catarrhal (may last 1 to 2 weeks): This stage is characterized by low-grade fever, URI symptoms, mild cough, and apnea in infants.

2. Paroxysmal (may last 1 to 6 weeks): Symptoms include severe cough occurring in paroxysms and onset of inspiratory “whoop.”
3. Convalescent (may last 2 to 3 weeks): Resolution of symptoms occurs; however, coughing fits may persist. Because of the protracted nature of the disease, it is called the “hundred day cough”
in China.
26. What is the most common cause of death in children with whooping cough? Almost one quarter of infants and children will contract pneumonia, and approximately 2% will die from whooping cough. Ninety percent of deaths are attributable to pneumonia, which most often develops as a secondary bacterial infection. These cases can be easily missed during the paroxysmal phase, when respiratory symptoms are so prominent and usually attributed solely to pertussis.
A new spiking fever should prompt a careful search for an evolving pneumonia.
27. Is antibiotic therapy of value in pertussis infection?
If used during the first 14 days of illness or before the paroxysmal stage, macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin can decrease the severity of symptoms during the paroxysmal stage and help prevent transmission of the illness. If the diagnosis is established later in the course, these antibiotics should still be administered to eliminate the nasopharyngeal carriage of Bordetella pertussis and limit the spread of disease. Evidence suggests that treatment with macrolides is effective for eradicating carriage and preventing transmission.
28. What are ways on physical exam to help distinguish swelling as a result of mumps from swelling caused by lymphadenitis?
• Hatchcock sign: Upward pressure applied to the angle of the mandible produces tenderness with mumps; this maneuver produces no tenderness with adenitis.
• Have the patient sip on lemon juice or suck a lemon wedge. Stimulation of salivation will cause pain in mumps with enlargement of the parotid gland, but no change is noted in patients with adenitis.
• As swelling progresses, the angle of the jaw is obscured. In mumps, when the patient is viewed from behind, the ear lobe is commonly lifted upward and outward.
• With enlargement of the parotid gland, the parotid gland remains in its anatomic relationship with the long axis of the ear, but lymphoid enlargement typically is posterior (Fig. 10-2).

Parotid gland
Ear-gland axis
Sternocleidomastoid muscle
Figure 10-2. A parotid gland infected with mumps (right) is compared with a normal gland (left) in this schematic drawing. An imaginary line bisecting the long axis of the ear divides the parotid gland into 2 equal parts. In mumps, these anatomic relationships are not altered, but in lymphadenitis, an enlarged cervical lymph node is usually posterior to the imaginary line. (From Kleigman RM, Stanton BF, Schor NF, et al: Nelson Textbook of Pediatrics, ed 19. Philadelphia, 2011, ELSEVIER Saunders, p 1079.)

29. What is the empiric treatment of a skin and soft tissue infection (SSTI) in the setting of the increasing prevalence of CA-MRSA?
As with any SSTI, the principle of incision and drainage (I & D) of localized collections should prevail. In pediatric patients, data suggest that skin abscesses in the immunocompetent host will be adequately

treated with I & D alone, without adjuvant antibiotic therapy. Whenever possible, specimens should be obtained for culture and susceptibility testing. For children with minor skin infections (such as impetigo), mupirocin 2% topical ointment can be used. Some authorities have suggested a change in empiric antibiotic therapy to include MRSA coverage is warranted when the patient-specific population prevalence of CA-MRSA infection exceeds 10% to 15%. However, in some communities, there is increasing resistance of both MRSA and methicillin-sensitive S. aureus (MSSA) to clindamycin and emerging resistance to trimethoprim-sulfamethoxazole. In hospitalized children with SSTI, empiric vancomycin is recommended. In patients who are clinically stable and do not have bacteremia and/or additional intravascular focus, empiric or step-down therapy with clindamycin may be started.

Singer AJ, Talan DA: Management of skin abscesses in the era of methicillin-resistant Staphylococcus aureus, N Engl J Med 370:1139–1047, 2014.
Liu C, Bayer A, Cosgrove SE, et al: Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary, Clin Infect Dis 52:285–292, 2011.

30. What are the distinguishing features of staphylococcal scalded skin syndrome, staphylococcal toxic shock syndrome, and streptococcal toxic shock syndrome? See Table 10-1.

Table 10-1 Distinguishing Features of Staphylococcal Scalded Skin Syndrome, Staphylococcal Toxic Shock Syndrome, and Streptococcal Toxic Shock Syndrome
GROUP A
STAPHYLOCOCCAL STAPHYLOCOCCAL STREPTOCOCCAL
CLINICAL SCALDED SKIN TOXIC SHOCK TOXIC SHOCK-LIKE
FEATURES SYNDROME SYNDROME SYNDROME
Organism Staphylococcus aureus Staphylococcus aureus Group A streptococci
Usually phage group 11, type 71 Usually phage group 1, type 29 Usually type 1, 3, or 18
Exotoxin A production
Site of
infection Usually focal Mucous membranes Blood, abscess, pneumonia, empyema, cellulitis, necrotizing fasciitis
Mucocutaneous border: nose, mouth, diaper area Infected wound or furuncle
Sometimes inapparent Sometimes inapparent Sometimes inapparent
Skin rash Tender erythroderma: face, neck, generalized Tender erythroderma: trunk, hands, feet Erythroderma: trunk, extremities
Bullae, no petechiae Edema of hands, feet
Desquamation Early, first 1-2 days, generalized, feet Late, 7-10 days, mostly hands and feet Late, 7-10 days, mostly hands
Hyperemia of oral and vaginal mucosa Hyperemia of oral and vaginal mucosa
Mucous
membranes Normal Hypertrophy of tongue papillae Hypertrophy of tongue papillae
Continued on following page

Table 10-1 Distinguishing Features of Staphylococcal Scalded Skin Syndrome, Staphylococcal Toxic Shock Syndrome, and Streptococcal Toxic Shock Syndrome (Continued )
GROUP A
STAPHYLOCOCCAL STAPHYLOCOCCAL STREPTOCOCCAL
CLINICAL SCALDED SKIN TOXIC SHOCK TOXIC SHOCK-LIKE
FEATURES SYNDROME SYNDROME SYNDROME
Conjunctivae Normal Markedly injected Injected
Course Insidious, 4-7 days Fulminant, shock with secondary multiorgan failure, 10% mortality Fulminant, shock with early primary multiorgan failure, 30-50% mortality
Benign, <1% mortality
Adapted from Bass JW: Treatment of skin and skin structure infections, Pediatr Infect Dis J 11:152–155, 1992.

31. Can antiviral medications be used to prevent or treat oral herpes simplex virus (HSV) infections? In immunocompetent hosts, oral acyclovir or valacyclovir offers significant therapeutic benefit in primary HSV gingivostomatitis but has limited efficacy for the treatment of recurrent herpes labialis. Valacyclovir is the prodrug of acyclovir, meaning it is converted to acyclovir after absorption. Valacyclovir achieves higher plasma levels of acyclovir than oral preparations of acyclovir and is dosed less frequently, making it the agent of choice. Topical antivirals have not shown consistent benefit in either of these settings. Prophylaxis with valacyclovir can reduce the number of recurrences in adults (especially pregnant women) with herpes labialis, but it has not been well studied in children.
32. What is the proper medical term for oral thrush?
Acute pseudomembranous candidiasis is the proper medical term for oral thrush—quite a mouthful.
Although thrush is sometimes confused with residual formula in the mouth in infants, formula is more easily removed with a tongue blade. When thrush is scraped, small bleeding points often occur on the underlying mucosa.
33. What is the most common specific etiology diagnosed in patients with systemic febrile illness after international travel? Malaria, both in children and adults is the most common etiology. Next in frequency are dengue fever, typhoid fever, rickettsioses, and leptospirosis. Leishmaniasis should also be considered in travelers from endemic areas. Malaria, caused by the protozoan parasite of the genus Plasmodium, should be considered in the differential diagnosis in anyone with fever who has travelled to an endemic area in the previous year. More than half of the world’spopulation lives in areas where malaria is endemic. Although there are more than 100 Plasmodium species, human infection is caused primarily by five: P. falciparum, P. ViVax, P. oVale,
P. malariae, and P. knowlesi. P. falciparum is responsible for the majority of malarial deaths globally.

Wilson ME, Weld LH, Boggild A, et al: Fever in returned travellers: results from the GeoSentinel surveillance network, Clin Infect Dis 44:1560–1568, 2007.
Freedman DO, Weld LH, Kozarsky PE, et al: Spectrum of disease and relation to place of exposure among ill returned travellers, N Engl J Med 354:119–130, 2006.

34. What is the classic triad of malaria?
Spiking fevers, anemia, and splenomegaly. Malaria is caused by species of Plasmodium (transmitted by the Anopheles mosquito), which infect red blood cells (RBCs); certain species (particularly P. VIVAX and P. OVALE) can have a dormant liver stage. The classic malarial fever involves a periodicity (typically 48 to 72 hours) associated with the rupture of RBCs. Chills, headache, abdominal pain, and myalgias are also common symptoms.

Cavagnaro CS, Brady K, Siegel C: Fever after international travel, Clin Pediatr Emerg Med 9:250–257, 2008.

35. How is malaria diagnosed?
Thick and thin blood smears. Thick smears are made by applying the blood film twice to a slide (and incorporating more RBCs). Giemsa stain is applied to both with an attempt to identify parasites in the cells. The thick smear is better for determining the presence of parasites, and the thin smear is better for species identification from the presence of specific cytologic characteristics (Fig. 10-3). A determination of parasite density (arough gauge to severity of infection) can be made. Therapy depends on the species identified. If smears are negative and clinical suspicion remains strong, repeat smears should be obtained sequentially over a 3-day period; effort should be made to collect specimens when the patient is febrile, and parasitemia is heaviest.

Figure 10-3. Plasmodium malariae, peripheral blood smear. The smear shows a red cell containing a P. malariae ring form trophozoite with one chromatin dot. The cytoplasm ring is thicker than that of P. falciparum, which also typically has two chromatin dots. (From Morgan EA: Malaria. In Aster JC, POZDNYAKOVA O, Kutok JL: Hematopathology: A Volume in the High Yield Pathology Series, VOL 33. Philadelphia, ELSEVIER, 2013, p 43.)

36. Which illness is associated with the term “breakbone fever”?
Dengue fever. The term refers to the classic presentation of fever, severe headache, retro-orbital pain, fatigue, and severe myalgias or arthralgias. Most cases are less severe. The illness is caused by an arbovirus, transmitted by mosquitoes, that is endemic in tropical areas worldwide, including the Caribbean and Central and South America. Leukopenia, thrombocytopenia, and mild elevations of hepatic transaminases are common. Children, more commonly than adults, may develop dengue hemorrhagic FEVER, which encompasses fever, epistaxis, mucosal bleeding, and platelet counts lower than 100,000/μL. This may progress to dengue shock syndrome with significant mortality.
37. What causes leptospirosis?
Spirochetes of the genus Leptospira cause leptospirosis. These are typically acquired from animal contact, or water or soil contaminated by the urine of dogs, rats, or livestock in the course of recreation or work. Acquisition of illness is more common after heavy rainfall or flooding. The incubation period can be up to 1 month. In 90% of cases, the disease is self-limited.
38. What are the phases of leptospirosis?
• Septicemic phase: Initially, there are nonspecific symptoms of fever, chills, headache, and a transient rash. Conjunctivitis without purulent discharge occurs in about one-third of cases. Eighty percent of cases feature severe myalgias of the calves and lumbar area. Symptoms may last up to 1 week and improve for 1 to 4 days, when the second phase occurs.
• Immune-mediated: Fever returns, accompanied by potentially more severe findings, including aseptic meningitis and Weil syndrome (jaundice, nonoliguric renal failure, hemorrhage due to thrombocytopenia). Severe pulmonary hemorrhages with hemoptysis may develop. The protean manifestations are due to the pathophysiology as a generalized vasculitis.

American Academy of Pediatrics: Leptospirosis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 469–471.

39. Which organisms are particularly dangerous to clinical microbiology laboratory workers? The laboratory should be alerted when highly transmissible bacterial agents are suspected in specimens that have been submitted for culture. These bacteria include Francisella tularensis (the causative agent of tularemia), Bacillus anthracis (anthrax), and Coxiella burnetii (Q fever). In addition, the laboratory should process fungal cultures that contain molds and dimorphic fungi (e.g., Histoplasma, Blastomyces) in a biosafety cabinet to prevent exposure to spores.

CONGENITAL INFECTIONS
40. Which congenital infections cause cerebral calcifications?
Cerebral calcifications are most frequently observed in congenital Toxoplasma and cytomegalovirus (CMV) infections. They are seen occasionally in patients with congenital HSV infection and rarely in patients with congenital rubella infection or congenital varicella. The calcifications seen in CMV infections are typically found in the periventricular region (Fig. 10-4) because CMV has a predilection for the germinal matrix, as opposed to the calcifications of Toxoplasma, which are more generally seen in the brain parenchyma.

Figure 10-4. CT scan of infant with congenital CMV infection with periventricular calcification, hydrocephalus, and cerebral atrophy. (From Shakoor A, Sy A, Acharya N: Ocular manifestations of intrauterine infections. In Pediatric Ophthalmology and Strabismus, ed 4. Philadelphia, ELSEVIER, 2013, p 81.)

41. What are the late sequelae of congenital infections?
The late sequelae of chronic intrauterine infections are relatively common and may occur in
infants who are asymptomatic at birth. Most sequelae present symptoms later in childhood rather than infancy.
• CMV: Hearing loss, minimal to severe brain dysfunction; motor, learning, language, and behavioral disorders. Longitudinal data from the National Health and Nutrition Examination Surveys (NHANES) have also implicated CMV as a risk factor for cardiovascular disease.
• Rubella: Hearing loss, minimal to severe brain dysfunction (motor, learning, language, and behavioral disorders), autism, juvenile diabetes, thyroid dysfunction, precocious puberty, progressive degenerative brain disorder
• Toxoplasmosis: Chorioretinitis, hydrocephalus, minimal to severe brain dysfunction, hearing loss
• Neonatal herpes: Recurrent eye and skin infection, minimal to severe brain dysfunction
• Hepatitis B VIRUS: Chronic subclinical hepatitis, rarely fulminant hepatitis

Maldonado A, Nizet V, Klein J, et al: Current concepts of infections of the fetus and newborn infant. In Remington J, Klein J, Wilson C, Baker C, editors: Infectious Diseases of the Fetus and Newborn Infant, ed 7. Philadelphia, 2011, Elsevier Saunders, pp 2–23.
Plotkin SA, Alpert G: A practical guide to the diagnosis of congenital infections in the newborn infant, Pediatr Clin North Am 33:465–479, 1986.

42. What is the most common congenital infection? Congenital CMV infection is the most common; in some large screening studies, it occurs in up to 1.3% of newborns. However, the majority (80% to 90%) of infected neonates are asymptomatic at birth or in early infancy.
43. How common is hearing loss from congenital CMV?
It’s estimated that one third to two-thirds of children with symptomatic congenital CMV infection and 7% to 15% of asymptomatic newborns with CMV will develop hearing loss at a median age of 3½ years. There is debate regarding possible universal screening for newborn CMV infection, especially if the initiation of antiviral therapy could prevent or limit hearing loss. Postnatal exposure to CMV is not associated with hearing loss.

Johnson J, Anderson B: Screening, prevention, and treatment of congenital cytomegalovirus, Obstet Gynecol Clin North Am 41:593–599, 2014.
Misono S, Sie KCY, Weiss NS, et al: Congenital cytomegalovirus infection in pediatric hearing loss, Arch Otolaryngol Head Neck Surg 137:47–53, 2011.

44. How is CMV transmitted from mother to infant? CMV can be transmitted by the transplacental route and through contact with cervical secretions or breast milk. On occasion, transmission may occur by contact with saliva or urine.
45. How should congenital CMV be treated?
The goals of treatment for congenital CMV have historically been to prevent the late sequelae of the disease, primarily sensory-neural hearing loss. However, the optimal treatment strategy (including choice of medication and duration of therapy) and which infants to treat are questions currently under investigation. Treatment is recommended for infants with life-threatening or vision-threatening disease, such as severe retinitis, interstitial pneumonitis, and active central nervous system infection. Whether treatment is indicated for isolated thrombocytopenia, mild hepatitis, viruria, or viremia without other symptoms is unclear. Treatments currently being studied include 6 weeks of IV ganciclovir and oral valganciclovir for 6 months or longer.
46. What is the risk to the fetus if the mother is infected with parvovirus B19 during pregnancy?
Approximately 30% to 50% of pregnant women are susceptible to parvovirus infection. The risk of fetal loss after seroconversion is 5% to 10% and is greatest when maternal infection occurs during the first half of pregnancy. Fetal loss occurs as a consequence of hydrops, which develops as a result of parvovirus-induced anemia. The signs of parvovirus infection in adults are not very distinctive but may include fever; a maculopapular or lacelike rash, especially in a stocking-glove pattern; and joint pain. There are case reports of aplastic anemia persisting for weeks in surviving neonates.
47. What are the consequences of primary varicella infection during the first trimester?
The congenital varicella syndrome consists of a constellation of features:
• Limb atrophy, usually associated with a cicatricial (scarring) lesion
• Neurologic and sensory defects
• Eye abnormalities (chorioretinitis, cataracts, microphthalmia, Horner syndrome)
• Cortical atrophy and mental retardation This syndrome usually follows maternal infection during the first trimester, although it may be seen
after infection up to 20 weeks into gestation.
48. What are the indications for postexposure prophylaxis for varicella in the newborn?
Prophylaxis should be given as soon as possible to a newborn whose mother develops varicella from 5 days before to 2 days after delivery. During this period of high risk, the fetus is exposed to high circulating titers of the virus without the benefit of maternal antibody synthesis. Currently, Varizig is the purified human immune globulin preparation licensed and available for use in the United States. It is most ideally given within 96 hours (4 days) for greatest effectiveness, but can be given up to 10 days after exposure. Other indications for use in the newborn include the following:
• Premature infants 28 weeks of gestation who are exposed in the neonatal period and the mother has no history of chickenpox or positive varicella serology

• Premature infants 28 weeks of gestation or whose weight is 1000 g or less and who are exposed in the neonatal period regardless of maternal history, because little maternal antibody crosses the placenta before the third trimester of pregnancy

Centers for Disease Control and Prevention: Updated recommendations for use of VariZIG—United States, 2013, Morb Mortal Wkly Rep 62:574–576, 2013.

49. Do urogenital mycoplasmas have a role in neonatal disease?
Ureaplasma urealyticum has been associated with low birth weight and bronchopulmonary dysplasia. This organism has been recovered from neonates with respiratory distress, pneumonia, and meningitis, but a causative role in these diseases has not been proven. Several reports of apparent Mycoplasma hominis meningitis and eye infection have been published.
Vertical transmission occurs in up to 60% of newborns whose mothers have positive cultures for these organisms. Risk for transmission is higher in preterm and low-birth-weight infants and correlates with the prolonged rupture of membranes and maternal fever. Infants delivered by cesarean section over intact membranes have a very low rate of colonization compared with infants delivered vaginally.
50. What are the features of congenital rubella syndrome (CRS)?
The most characteristic features of CRS are congenital heart disease, cataracts, microphthalmia, corneal opacities, glaucoma, and radiolucent bone lesions. The features of CRS can be divided into three broad categories:
• Transient: Low birth weight, hepatosplenomegaly, thrombocytopenia, hepatitis, pneumonitis, and radiolucent bone lesions
• Permanent: Deafness, cataracts, and congenital heart lesions (patent ductus arteriosus> pulmonary artery stenosis> aortic stenosis> ventricular septal defects)
• Developmental: Psychomotor delay, behavioral disorders, and endocrine dysfunction
Indigenous rubella transmission and CRS were declared eliminated in the United States in 2004 as a result of universal screening and vaccination policies in pregnant women. However, worldwide
CRS remains a major health issue. The World Health Organization has targeted regional elimination of CRS by 2015.
51. Should all pregnant women be screened for HSV infection during pregnancy? Existing data indicate that antepartum cultures of the maternal genital tract fail to predict viral shedding at the time of delivery. Thus, routine antepartum cultures are not currently recommended. However, surveillance data have shown a decline in the overall seroprevalence of HSV in women of childbearing age from 2005 to 2010 compared with 2001 to 2004. About one fifth to one-third of women of childbearing age are seronegative for HSV-1 and HSV-2. This is in part driven by a significant reduction in the seroprevalence of HSV-1 in young people ages 14 to 19. Concern has been raised that this may lead to an increased incidence of primary HSV infection during pregnancy. Recent algorithms have been developed that incorporate maternal serologic status into the diagnosis and treatment strategies of infants born to mothers with active HSV lesions. Consequently, routine serologic screening (HSV-1 and HSV-2, IgG, and IgM) may be incorporated into antepartum screening in the future.

Bradley H, Markowitz LE, Gibson T, McQuillan GM: Seroprevalence of herpes simplex virus types 1 and 2—United States, 1999-2010, J Infect Dis 209:325–333, 2014.
Kimberlin DW: The Scarlet H, J Infect Dis 209:315–317, 2014. Kimberlin D, Baley J; Committee on Infectious Diseases; Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions, Pediatrics 131:e635–e646, 2013.

52. What are risk factors for the development of neonatal HSV disease? HSV infection of the neonate infant may be acquired before delivery (in utero), during delivery (intrapartum or perinatal), and after delivery (postpartum or postnatal). The majority of illness, approximately 85%, is acquired during the intrapartum period. Classic risk factors for intrapartum or perinatal transmission include:
• Primary, rather than recurrent, maternal infection, especially if acquisition is in the third trimester. (Women with primary genital HSV infections who are shedding HSV at delivery are 10 to 30 times more likely to transmit the virus than women with a recurrent infection.)
• Negative maternal HSV IgG antibody status

• Prolonged rupture of membranes
• Violation of mucocutaneous barriers (e.g., use of fetal scalp electrodes)
• Vaginal rather than cesarean delivery

Stephenson-Famy A, Gardella C: Herpes simplex virus infection during pregnancy, Obstet Gynecol Clin North Am 41:601– 614, 2014.
Kimberlin D, Baley J; Committee on Infectious Diseases; Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions, Pediatrics 131:e635–e646, 2013.
Corey L, Wald A: Maternal and neonatal herpes simplex virus infections, N Engl J Med 361:1376–1385, 2009.

53. What are the three forms of neonatal HSV disease?
• Mucocutaneous disease (localized to the skin, eye, or mouth [SEM])
• Central nervous system (CNS) disease
• Disseminated disease; multiple organ systems are involved and the clinical syndrome resembles bacterial sepsis Up to 50% of infants will have CNS complications, from either primary CNS disease or disseminated
disease with CNS involvement. It is important to note that infants with CNS or disseminated disease may not have visible skin lesions.
54. When should HSV disease be suspected in newborn or infants?
Current recommendations distinguish neonatal HSV infection, which is the asymptomatic period when viral replication is occurring, from HSV disease, when clinical signs and symptoms of HSV
are present. In full-term infants <4 weeks and premature infants (<32 weeks of gestation) <8 weeks, HSV disease should be considered in the following cases:
• Skin lesions suspicious for HSV on the infant (may be single or grouped vesicles, pustules, bullae, or denuded skin)
• Ill-appearing infant with findings of poor feeding, irritability, lethargy, vomiting, and hypothermia or hyperthermia
• Seizures or encephalopathy associated with the current illness
• Abnormal liver function tests (elevated alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST])
• Sterile CSF pleocytosis In general, infants with SEM and disseminated disease present with clinical symptoms 10 to 14 days
after infection and those with CNS disease 17 to 19 days after infection.

Kimberlin D, Baley J; Committee on Infectious Diseases; Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics,131:e635–e646, 2013.

55. How should the neonate with suspected HSV disease be treated?
Progression from infection to disease is considered inevitable. One of the goals of therapy is to accurately identify infants with infection and intervene to prevent progression to disease. Intravenous acyclovir is the preferred drug and is administered pending definitive diagnosis. For confirmed mucocutaneous disease, treatment is continued for 14 days. For encephalitis and disseminated disease, treatment is continued for 21 days. For infants who have been recognized as having a high risk of progression to disease (e.g., infants born to mothers with primary HSV), 10 days of therapy with intravenous (IV) acyclovir is recommended even if cultures or polymerase chain reaction (PCR) testing of the infant is negative for HSV.

Kimberlin D, Baley J; Committee on Infectious Diseases; Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions, Pediatrics,131:e635 to e646, 2013.

56. In which groups of women is prenatal hepatitis B surface antigen (HBsAg) screening recommended?
In the past, women were screened for HBsAg if they fell into a high-risk group based on ethnic origin, immunization status, or history of exposure to blood products, IV drugs, or a high-risk partner. However, historic information revealed that at most 60% of HBsAg carriers were captured using these screening criteria. Thus, it is recommended that all pregnant women be screened for HBsAg.

57. What is the risk to the fetus if the mother is infected with hepatitis B virus?
Very significant. Ten percent to 20% of women who are HBsAg positive and 90% of women who are both HBsAg positive and seropositive for hepatitis B e antigen (HBeAg) will transmit the virus to their infants in the absence of hepatitis B vaccine at birth. Of women who are acutely infected during pregnancy, the risk of neonatal infection is greatest when maternal infection occurs during the third trimester; up to 90% of these neonates will be seropositive
for HBsAg. Chronic hepatitis B virus infection with persistence of HBsAg occurs in 85% to 95% of infants who are infected by perinatal transmission, with a 25% to 30% lifetime prevalence of severe liver disease or liver cancer.
58. How should infants born to mothers with hepatitis B infection be managed? For infants born to women who are HBsAg positive, hepatitis B immunoglobulin (0.5 mL intramuscularly) and the first dose of hepatitis B vaccine should be administered within 12 hours of delivery to
reduce the risk for infection. Although breast milk is theoretically capable of transmitting the hepatitis B virus, the risk for transmission in HBsAg-positive mothers whose infants have received timely hepatitis B immunoglobulin and hepatitis B vaccine is not increased by breastfeeding.

American Academy of Pediatrics: Hepatitis B. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 384.

59. How should infants born to mothers with hepatitis A infection be managed? Neonates born to mothers with active hepatitis A infection are unlikely to contract the virus, and efficacy of postnatal prophylaxis with hepatitis A immunoglobulin has not been proven. Some experts recommend immunoglobulin if the mother’s symptoms begin within 2 weeks before or 1 week after delivery, but this is controversial.

American Academy of Pediatrics: Hepatitis A. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 368.

60. How should infants born to mothers with hepatitis C infection be managed?
The risk for vertical transmission of hepatitis C virus (HCV) is about 6% in mothers who demonstrate the presence of HCV RNA in the blood. This risk is increased in mothers who are coinfected
with HIV. No preventive therapy exists. Nucleic amplification testing can be done at 1 to 2 months of age, if desired, to assess for neonatal infection. Antibody testing cannot be done until after
18 months because that is the expected duration of the passively acquired maternal antibody in infants. Mothers with hepatitis C infection should be advised that transmission of hepatitis C by breastfeeding has not been documented. Accordingly, maternal hepatitis C infection is not a contraindication to breastfeeding, although mothers with cracked or bleeding nipples should consider abstaining.

Wen JW, Haber BA: Maternal-fetal transmission of hepatitis C infection: what is so special about babies? J Pediatr Gastroenterol Nutr 58:378–382, 2014.
American Academy of Pediatrics: Hepatitis C. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 395.

61. How do the clinical features of early and late congenital syphilis differ?
The manifestations of congenital syphilis are variable and may be divided into early and late findings. Early manifestations occur during the first 2 years of life, (e.g., “snuffles); late manifestations, such as peg-shaped or notched central incisors, so-called “Hutchinson teeth” occur after 2 years of age (Fig. 10-5 and Table 10-2).
62. How is the diagnosis of congenital syphilis made?
• All pregnant women and infants should be screened for possible infection with a nontreponemal test for Treponema pallidum. Such tests include the rapid plasma reagin card test (RPR) and the Venereal Disease Research Laboratory (VDRL) slide test.
• If blood from the mother or infant yields a positive nontreponemal serologic test, a specific treponemal test should be performed on the infant’s blood. Examples include the fluorescent treponemal antibody (FTA) absorption test and the microhemagglutination test for T. pallidum.

Figure 10-5. Hutchinson teeth. Note the notched, peg-shaped incisors with enamel defects and incipient caries. (From Rodriguez- Cerdeira C, Silami-Lopes VC: Congenital syphilis in the 21st century, Actas Dermo-Sifiliográficas (English Edition) 103:687, 2011.)

Table 10-2 Early and Late Manifestations of Congenital Syphilis
EARLY CONGENITAL SYPHILIS (310 PATIENTS) LATE CONGENITAL SYPHILIS (271 PATIENTS)
Hepatomegaly 32% Pseudoparalysis of Parrot 87%
Skeletal abnormalities 29% Short maxilla 84%
Splenomegaly 18% High palatal arch 76%
Birth weight <2500 g 16% Hutchinson triad 75%
Pneumonia 16% Saddle nose 73%
Severe anemia, hydrops, edema 16% Mulberry molars 65%
Skin lesions 15% Hutchinson teeth 63%
Hyperbilirubinemia 13% Higoumenakis sign 39%
Snuffles, nasal discharge 9% Relative protuberance of mandible 26%
Painful limbs 7% Interstitial keratitis 9%
Cerebrospinal fluid abnormalities 7% Rhagades 7%
Pancreatitis 5% Saber shin 4%
Nephritis 4% Eighth nerve deafness 3%
Failure to thrive 3% Scaphoid scapulae 0.70%
Testicular mass 0.30% Clutton joint 0.30%
Chorioretinitis 0.30%
Hypoglobulinemia 0.30%
Adapted from Sanchez PJ, Gutman LT: Syphilis. In Feigin RD, Cherry JE, Demmler GJ, Kaplan SL (eds): Pediatric Infectious Diseases, 5th ed. Philadelphia, W.B. Saunders, 2004, pp 1730–1732.

• Evaluation of infants with suspected congenital syphilis should also include a complete blood count, analysis of the CSF (including a CSF VDRL), and long-bone radiographs (unless the diagnosis has otherwise been established) to look for characteristic findings (Fig. 10-6).
63. What are the pitfalls of RPR and VDRL testing?
• Nontreponemal tests detect antibodies to cardiolipin and may yield false-positive results in a variety of maternal conditions, such as systemic lupus.

Figure 10-6. Radiograph of an infant with congenital syphilis shows periosteal reaction along the shaft of the left tibia (arrowheads) and a characteristic lucency of the medial proximal tibial metaphysis (arrow) called the Wimberger sign, which represents localized bony destruction. (From Donnelly LF: Pediatric Imaging: The Fundamentals. Philadelphia, 2009, Saunders, p 171.)

• False-negative tests may occur because of high titers of antibodies; this is termed the “prozone effect.” It is recommended that the sample be diluted before testing to avoid this.
• A reactive serologic titer may persist after the initial decline (usually 4-fold) in response to treatment. This low level titer is usually <1:8 and may persist for life; this so-called “serofast” state can make interpretation of nontreponemal tests difficult.
• A mother who has been treated adequately for syphilis during pregnancy can still passively transfer antibodies to the neonate, which results in a positive titer in the infant in the absence of infection. In this circumstance, the infant’s titer isusually less than the mother’s and reverts tonegative over several months.
64. If a pregnant woman is found to have Chlamydia trachomatis in her birth canal, what is the most appropriate course of action? The U.S. Preventative Task Force recommends that all pregnant women <25 years of age or those with high risk behavior patterns be screened for C. trachomatis. Pregnant women with a known chlamydial infection should be treated with oral azithromycin to reduce the risk for neonatal chlamydial pneumonia and conjunctivitis
because untreated mothers may transmit Chlamydia to babies born vaginally about 50% of the time. Simultaneous treatment of the male partners with doxycycline or azithromycin should also be undertaken.

U.S. Preventative Task Force: USPSTF Recommendations for STI Screening. www.uspreventiveservicetaskforce.org. Accessed on Mar. 20, 2015.

65. Should newborns of mothers with untreated chlamydial infection receive prophylactic antibiotic therapy?
Although these infants are at increased risk for infection, the efficacy of prophylactic antibiotics is
not known and treatment is not indicated. Infants should be followed carefully for signs of conjunctivitis or pneumonia and treated if they are symptomatic.

American Academy of Pediatrics: Chlamydia trachomatis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 276–277.

66. What is the risk to a fetus after primary maternal Toxoplasma infection?
The risk depends on the time during pregnancy that the mother becomes infected. Assuming that
the mother is untreated, first-trimester infection is associated with a fetal infection rate of about 25%,

second-trimester infection with a rate of more than 50%, and third-trimester infection with a rate of roughly 70%. The severity of clinical disease in congenitally infected infants is inversely related to gestational age at the time of primary maternal infection.
67. What is the typical presentation of congenital toxoplasmosis?
At birth, 70% to 90% are asymptomatic. As with other congenital infections, the symptomatic neonatal presentations are varied, ranging from severe disease with hepatosplenomegaly, chorioretinitis, and/or neurologic features (e.g., seizures, hydrocephalus, microcephaly) in about 10% of infected infants to an asymptomatic infection. Among clinically asymptomatic infants, findings such as intracranial calcifications or retinal cysts may be present, and long-term risks include impaired vision, learning disabilities, mental retardation, and seizures.
68. How can a woman minimize the chance of acquiring a Toxoplasma infection during pregnancy?
Measures relate to personal hygiene, food preparation, and exposure to cats.
• Avoid raw meat. Using a food thermometer for confirmation, cook whole cuts of meat (excluding poultry) to at least 145 °F (63 °C), cook ground meat to at least 160 °F (71 °C) and cook all poultry to at least 165 °F (74 °C).
• Wash fruits and vegetables before consumption.
• Wash hands and kitchen surfaces thoroughly after contact with raw meat and unwashed fruits or vegetables, and wash thoroughly after gardening.
• Avoid changing cat litter boxes, or wear gloves while changing the litter and wash hands thoroughly afterwards. Changing the litter every 1 to 2 days will also reduce risk.
• Avoid untreated water in high-risk areas, such as developing countries.

EMERGING INFECTIOUS DISEASES
69. Which mycobacterium may infect someone who has a home aquarium? Mycobacterium marinum. This atypical mycobacterial infection typically begins with clusters of superficial nodules or papules, which can become fluctuant. The condition can be misdiagnosed as a cellulitis. A detailed history can help establish the diagnosis.
70. What are possible sources for an anthrax infection in a 17-year-old who lives on a cattle farm, makes and plays drums as a hobby, and works in a microbiology lab after school?
• Cutaneous anthrax is the most common form of anthrax. It occurs when spores invade a violation in local skin integrity. Infection usually develops from 1 to 7 days after exposure. Without treatment, cutaneous anthrax is fatal 20% of the time, but it is curable with therapy. Cutaneous anthrax has been called “wool sorters disease,” because the spores are found in animal hides (as well as other raw animal products), such as those used in wool processing or in making traditional hide drums. It can be contracted through improper handling of laboratory specimens. It was used as an agent of bioterror in the United States in 2001.
• Inhalation anthrax occurs when the spores are inhaled. Dissemination then occurs through lymphatic spread. Infection usually develops 7 to 14 days after exposure but may occur up to 60 days after exposure. Survival with treatment is 55%.
• Gastrointestinal anthrax occurs when spores are ingested, typically through raw or undercooked meat. Infection usually develops from 1 to 7 days after exposure. Survival with treatment is 60%.
Our patient could have contracted any form of the disease from a variety of his exposures. As with many infectious diseases, a careful history will often reveal the source of the infection.
71. What are the novel coronaviruses?
CORONAVIRUSEs are named for the crownlike spikes on their surface; they typically cause respiratory disease on the spectrum of the common cold. Two novel coronaviruses have been implicated in severe and sometimes fatal respiratory disease:
• Severe acute respiratory syndrome (SARS), termed SARS-CoV, was first recognized in China in 2002. It spread to multiple countries and caused several hundred deaths from 2002 to 2003. Since 2004, there have not been any known cases of SARS-CoV infection reported anywhere in the world. The virus is felt to have originated in wild animals (civit cats and bats have been implicated) with transmission to humans who contacted them in markets in urban areas.

• Middle East respiratory syndrome (MERS), termed MERS-CoV, was first recognized in Saudi Arabia in 2012. It has also spread to several countries. All cases to date have been linked to countries in and near the Arabian Peninsula. The true incidence of the disease is not known because there may be reporting bias of milder cases. The disease is thought to have a natural reservoir in camels.
72. What viral etiology should be considered in a patient with acute, unexplained respiratory illness who is not febrile?
Enterovirus D68 (EV-D68). This is a non-polio enterovirus first described in California in 1968. Symptoms range from mild respiratory illness with rhinorrhea, sneezing, cough and myalgia to severe symptoms such as wheezing, hypoxia and acute respiratory distress syndrome. However, even patients with serious illness due to EV-D68 may not have fever. Additionally, EV-D68 has been associated (although not causally substantiated) in a cluster of cases in 2014 of acute limb weakness. Most patients were found to have a distinctive pattern of abnormalities of the grey matter of the spinal cord on MRI.

Foster CB, Friedman N, et al: Enterovirus D68: a clinically important respiratory enterovirus. CLEVE Clin J Med 82:26–31, 2015.

73. What two diseases in particular should be in the differential diagnosis for a traveler returning from the Caribbean with a fever and rash? Dengue fever and Chikungunya virus infection. Dengue and Chikungunya viruses are both transmitted by the Aedes aegypti and Aedes albopictus mosquitoes and have overlapping clinical features and similar endemicity. Dengue has three clinical syndromes:
• Undifferentiated fever presents as a general febrile illness with fever, malaise, and other mild symptoms that overlap with a number of other viral syndromes. This is a typical presentation in children with their first infection.
• Dengue fever with or without hemorrhage presents with 2 to 7 days of high fever and 2 other symptoms such as severe headache, retro-orbital eye pain, myalgias, arthralgias, maculopapular rash, or petechial rash.
• Dengue hemorrhagic fever or Dengue shock syndrome presents initially as Dengue fever, but progresses to plasma leak and disseminated intravascular coagulation.
• Dengue fever or hemorrhagic fever usually occurs in older children or adolescents who have had previous infection.
Chikungunya infection is characterized by acute onset of fever >39 °C (>102 °F) and joint pain that is usually severe, bilateral, and symmetric, as well as headache, myalgia, arthritis, nausea/vomiting, and a maculopapular rash, similar to dengue fever.
Real-time PCR diagnosis is available for both Dengue and Chikungunya through the CDC and may be performed within 5 days of onset of symptoms. After that time frame, IgG and IgM serologic testing should be performed.
74. What is the most common viral intestinal infection you can get from eating at a salad bar? Noroviruses are estimated to be responsible for up to 50% of foodborne outbreaks of viral gastroenteritis. Additionally, the majority (>90%) of diarrheal disease outbreaks on cruise ships are caused by noroviruses. The source of these outbreaks often stems from unsafe food handling practices from
infected food service workers. Foods such as raw fruits and leafy green vegetables are often involved. Nausea, vomiting, and watery diarrhea with abdominal cramping have an acute onset 12 to 48 hours after exposure and resolve without treatment 24 to 72 hours later.
75. When was the Ebola virus first discovered? 1976. There were two simultaneous outbreaks, one in Sudan and one in the Republic of Congo. The name derives for a village in the Congo near the Ebola River where the outbreak occurred.
76. What are the clinical features of an Ebola infection? Following an incubation period of 2 to 21 days, clinical disease begins with nonspecific signs and symptoms including fever, headache, myalgia, abdominal pain, and malaise, which overlap with many other viral and parasitic diseases in endemic regions. This is then followed several days later by vomiting and diarrhea.
Conjunctival injection or subconjunctival hemorrhage, hepatic dysfunction (AST> ALT), and metabolic derangements also are common at this stage. In the most severe cases, microvascular instability and

subsequent hemorrhage, most commonly from the GI tract will occur. CNS manifestations can occur but are less common in children than in adults. Accompanying respiratory symptoms are more common in children.
Mortality is high ( 50% to 70%), but this is likely confounded by low resource setting, age, baseline health, and comorbid conditions.
77. What is the natural reservoir host of the Ebola virus? Although the reservoir remains unknown, many researchers believe the virus is animal-borne initially and fruit bats are the most likely natural reservoir. Primates (apes and monkeys) are also possibilities.
Humans may contract the disease from exposure to infected bat excreta or saliva or by exposure to blood and bodily fluids from other infected sources, such as nonhuman primates that are
consumed as food. Once the first human becomes infected through contact with an infected animal, person-to-person transmission (as well as spillover from continued contact with an animal reservoir or surface and material contaminated with infected fluids) allows an epidemic to promulgate.

THE FEBRILE CHILD
“.. .since the advent of modern clinical thermometry by Wunderlich in 1871, the ritual of temperature taking has been surpassed only by Alexander Graham Bell’s invention in 1874 as the major curse of pediatrics”

DS Smith: Fever and the pediatrician, J Pediatr 77:935, 1970.

78. At what temperature does a child have fever? This is a simple question without a simple answer. Because body temperatures vary among individuals and age groups and vary over the course of the day in a given individual (lowest around 4:00 to 5:00 AM and highest in late afternoon and early evening), a precise cutoff point is difficult to determine.
In children between the ages of 2 and 6 years, diurnal variation can range up to 0.9 °C (1.6 °F). Infants tend to have a higher baseline temperature pattern, with 50% having daily rectal temperatures higher than 37.8 °C (100.0 °F); after the age of 2 years, this elevated baseline falls. In addition, activity and exercise (within 30 minutes), feeding or meals (within 1 hour), and hot foods (within 1 hour) can cause body temperature elevations. Most authorities agree that, for a child <3 months, a rectal
temperature higher than 38 °C (100.4 °F) constitutes fever. In infants between the ages of 3 and
24 months (who tend to have a higher baseline), a temperature of 38.3 °C (101 °F) or higher likely constitutes fever. In those >2 years, as the baseline falls, fever more commonly is defined as a rectal temperature higher than 38 °C (100.4 ° F).

79. Where did the popular notion that a normal temperature is 98.6 °F originate?
The temperature 98.6 °F was established as the mean healthy temperature in 1868 after >1 million temperatures from 25,000 patients were analyzed. Ironically, these were axillary temperatures, and the waters of what constitutes normal have been muddied since.

Mackowiak PA, Wasserman SS, Levine MM: A critical appraisal of 98.6 °F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich, JAMA 268:1578–1580, 1992.

80. How does temperature vary among different body sites?
There can be significant variability in the relationship between different sites, and conversions should be done with caution. As a general guideline:
• Rectal: Standard
• Oral: 0.5° to 0.6 °C (1 °F) lower
• Axillary: 0.8° to 1.0 °C (1.5° to 2.0 °F) lower
• Tympanic: 0.5° to 0.6 °C (1 °F) lower
There also is a great deal of variability in cutaneous (such as forehead or temporal artery) infrared thermometry, depending on a variety of conditions, including age.

81. How accurate is parental palpation for fever in infants?
It is common for parents to report a subjective fever by palpation without measuring a temperature by thermometry. Palpation by parents has a sensitivity and specificity of about 80% in children >3 months. In infants <3 months, the positive-predictive value of a parent reporting a palpable

fever is about 60%, with a negative-predictive value of 90%. For these younger infants, for whom identification of fever carries potentially greater clinical repercussions, parents seem to overestimate the presence of a fever, but they are more accurate determining when a child is afebrile.

Katz-Sidlow RJ, Rowberry JP, Ho M: Fever determination in young infants: prevalence and accuracy of parental palpation,
Pediatr Emerg Care 25:12–14, 2009.

82. How should the temperature of young infants be taken?
In infants who are <3 months (when fever can be more significant clinically), a rectal temperature is the preferred method. Tympanic recordings are much less sensitive in this age group because the narrow, tortuous external canal can collapse, thereby resulting in readings obtained from the cooler
canal rather than the warmer tympanic membrane. Cutaneous infrared temporal artery thermometry may have reduced diagnostic accuracy in this age group. Axillary temperatures often underestimate fever. The oral route is typically not used until a child is 5 to 6 years of age.
83. How do environmental factors affect an infant’s temperature? Studies in neonates and infants have found mixed results. One study of newborns in a warm environment of 80 °F (26 °C) found that rectal temperatures in bundled infants could be elevated to more than 38 °C, which is the “febrile range,” although newborn infants may have a physiologically lower body temperature. Another study of infants 3-months-old and younger found that in room temperatures of 22.2° to 23.8 °C (72° to 75 °F), the bundling of infants for up to 65 minutes did not produce any rectal temperatures higher than 38 °C. Infants are also prone to hypothermia, especially in the hours following birth. Direct skin-to-skin contact in newborn infants has been shown to raise and sustain newborn temperatures. Smaller or preterm infants may be most susceptible to environmental factors such as cooler ambient temperatures.

Nimbalkar SM, Patel VK, Patel DV, et al: Effect of early skin-to-skin contact following normal delivery on incidence of hypothermia in neonates more than 1800 g: randomized control trial, J Perinatol 34:364–368, 2014.
Grover C, Berkowitz CD, Lewis RJ, et al: The effects of bundling on infant temperature, Pediatrics 94:669–673, 1994.

84. What is occult bacteremia? Occult bacteremia refers to the finding of bacteria in the blood of patients, usually between the ages of 3 and 36 months, who are febrile without a clinically apparent focus of infection.
85. How has the pneumococcal vaccine (PCV) affected the incidence of occult bacteremia?
In trials done after the introduction of the Haemophilus influenzae type B (Hib) vaccine (1990) but before the introduction of the pneumococcal conjugate vaccine (2000), bacteremia rates for pneumococcus ranged from 1.6% to 3.1% in febrile ( 39.0 °C), non–toxic-appearing children from ages 2 to 36 months. Since the introduction of the pneumococcal conjugate vaccine against 7 serotypes and 2 cross-reactive serotypes (PCV-7) of S. pneumoniae, bacteremia rates for S. pneumoniae have fallen to <1%. This benefit was sustained after the introduction in 2010 of the 13-valent PCV, which added
coverage against 6 other serotypes. Other benefits, such as reduction in all types of invasive
pneumococcal disease (e.g., community-acquired pneumonia) have also been noted, especially in children <2 years of age. Children who are incompletely immunized are at higher risk compared with those fully immunized, but this effect is mitigated somewhat by herd immunity in countries and communities with high vaccination rates.

Joffe MD, Alpern ER: Occult pneumococcal bacteremia: a review, Pediatr Emerg Care 26:448–454, 2010.
Wilkinson M, Bulloch B, Smith M: Prevalence of occult bacteremia in children ages 3 to 36 months presenting to the emergency department in the postpneumococcal conjugate vaccine era, Acad Emerg Med 16:220–225, 2009.

86. What is meant by “serotype replacement”? This is an increase in infections caused by serotypes not included in a vaccine. In the case of the initial conjugate pneumococcal vaccine in 2000, 7 vaccine serotypes and 2 cross-reactive serotypes were included in the vaccine and accounted for about 80% of invasive pneumococcal disease. Pneumococci have
>90 serotypes, and after the introduction of that vaccine, there was a rise of infections caused

by nonvaccine serotypes, particularly 19A. The 13-valent conjugate vaccine (which added serotype 19A among others) was licensed in 2010 and early reports do indicate new serotype replacement patterns.

Angoulvant F, Levy C, Grimprel E, et al: Early impact of 13-valent pneumococcal conjugate vaccine on community-acquired pneumonia in children, Clin Infect Dis 58:918–924 2014.
Muñoz-Almagro C, Jordan I, Gene A, et al: Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of the 7-valent conjugate vaccine, Clin Infect Dis 46:183–185, 2008.

87. What is the proper way to evaluate and manage febrile illness in neonates 28 days?
In general, patients <1 month with fever ( 38.0 °C) warrant urgent evaluation (including blood, urine, and CSF cultures) because of higher rates of bacteremia (including pathogens from the neonatal period such as group B streptococci) and greater difficulty in global assessment of wellness.

Jain S, Cheng J, Alpern ER, et al: Management of febrile neonates in US pediatric emergency departments, Pediatrics
133:187–195, 2014.

88. What is the evaluation and management of febrile illness in infants >28 days to 90 days?
This remains controversial as the Hib and pneumococcal conjugate vaccines have altered the landscape of invasive bacterial disease. On average, up to 7% of febrile infants who are
<3 months have serious bacterial infections (SBI), which can include bacteremia, meningitis, osteomyelitis, septic arthritis, UTI, or pneumonia. Of these, UTIs comprise the greatest percentage
of bacterial infections. The incidence of bacterial meningitis and SBI due to S. pneumoniae has fallen; this is likely due in part to herd immunity secondary to vaccination of older infants.
Consequently, in a well-appearing febrile infant, a previous emphasis on a comprehensive evaluation (i.e., urine, serum and CSF testing) has declined significantly. A 2014 study of 37 U.S. pediatric emergency departments (EDs) found that comprehensive evaluations were done in febrile infants (29 to 56 days) only 49% of the time and in older infants (57 to 89 days) only 13% of the time without a change in outcome compared with those without comprehensive evaluations. Thus, local institutional guidelines based on regional epidemiology, institutional experience, provider experience, and cohort data have become the norm in the absence of national guidelines. A urinalysis and
urine culture are now the most important laboratory studies given the higher likelihoods of UTIs compared with other occult bacterial processes. Many centers also obtain a complete blood count and blood culture in this age group. Lumbar punctures (LPs) are commonly deferred in a smiling, well-appearing, febrile infant.

Aronson PL, Thurm C, Alpern ER, et al: Variation in care of the febrile young infant <90 days in US pediatric emergency departments, Pediatrics 134:667–677, 2014.
Hernandez DA, Nguyen V: Fever in infants <3 months old: what is the current standard? Pediatr Emerg Med Rep
16:1–15, 2011.

89. How should older infants and toddlers (3 to 36 months old) with fever and no apparent source be managed? Previously, much of the evaluation that centered on febrile children in this age group dealt with identifying possible occult bacteremia with the intent of using empiric antibiotic treatment to lessen the chance of dissemination to focal complications (particularly meningitis). However, rates of bacteremia and meningitis have fallen dramatically, particularly with the introduction of the conjugate pneumococcal vaccine. The most common cause of SBI in children with fever without a source in this age range is an occult UTI. Most pediatric infectious disease experts no longer recommend a complete blood
count and/or blood culture or any laboratory tests (other than urinalysis and urine culture in certain settings) in the evaluation of a well-appearing febrile infant >90 days who has received Hib and pneumococcal vaccines because of the low risk for bacteremia and meningitis.

Hamilton JL, John SP: Evaluation of fever in infants and young children, Am Fam Physician 87:254–260, 2013. Arora R, Mahajan P: Evaluation of child with fever without source: a review of literature and update, Pediatr Clin North Am 60:1049–1062, 2013.

90. When is a chest radiograph indicated for a febrile young infant?
Although some clinicians believe that chest radiographs should be performed for all febrile infants who are <2 to 3 months, in general it is appropriate to perform this study for neurologically normal infants who have respiratory symptoms or signs, including cough, tachypnea, irregular breathing, retractions, rales, wheezing, or decreased breath sounds. In a study done in the pre-PCV era of infants <8 weeks who were admitted with fever, 31% of patients with respiratory manifestations
had an abnormal chest radiograph, compared with only 1% of asymptomatic infants. Leukocytosis (>20,000/mL) in febrile (>39 °C) patients <5 years increases the likelihood of an “occult pneumonia.” In most cases, it is not possible to differentiate viral from bacterial pneumonias radiologically.

Hernandez DA, Nguyen V: Fever in infants <3 months old: what is the current standard? Pediatr Emerg Med Rep
16:1–15, 2011.
Murphy CG, van de Pol AC, Harper MB, et al: Clinical predictors of occult pneumonia in the febrile child, Acad Emerg Med 14:243–249, 2007.
Crain EF, Bulas D, Bijur PE, Goldman HS: Is a chest radiograph necessary in the evaluation of every febrile infant less than 8 weeks of age? Pediatrics 88:821–824, 1991.

91. What is the approach for a 2-week-old, otherwise healthy, afebrile, full-term female who presents to the ED with mastitis?
As the overall incidence of community-acquired S. aureus, including MRSA isolates, increases, this subject is controversial. Case series have shown that the majority of these lesions from which organisms are recovered are “community strains” of S. aureus. Included in the differential diagnosis is group
B streptococcal (GBS) cellulitis-adenitis syndrome caused by serotype III. SSTIs are included in many algorithms as high risk for SBIs, but many of these infants are afebrile and without signs of disseminated infection, making their management unclear. Many providers will proceed with a full sepsis evaluation, including LP because of the age of the infant. As with the febrile infant, there is a diversity of practices both within and among institutions based on local epidemiology, provider experience, and patient demographics. Therapy should include coverage for S. aureus, including MRSA. One large case series found that a number of infants with localized S. aureus SSTIs who had an LP done had a sterile CSF pleocytosis, hypothesized to be an inflammatory reaction to
bacterial toxins, further confounding treatment and diagnosis. GBS cellulitis-adenitis is a manifestation of late-onset GBS disease, and should be aggressively evaluated and treated if there is suspicion for this condition.

Nguyen R, Bhat R, Teshome G: Question 2: Is a lumbar puncture necessary in an afebrile newborn infant with localised skin and soft tissue infection? Arch Dis Child 99:695–698, 2014.
Fortunov RM, Hulten KG, Hammerman WA, et al: Evaluation and treatment of community-acquired Staphylococcus aureus infections in term and late-preterm previously healthy neonates, Pediatrics. 120:937–945, 2007.

92. What is a CLABSI?
A central line–associated blood stream infection (CLABSI) is defined as a BSI in a symptomatic patient with a central venous catheter that terminates at or close to the heart and who has had a hospital stay of at least 3 days. The line must be in place for >2 calendar days, and the BSI must occur while the line is in place or within 1 day of removal. There are multiple initiatives put forth by the National Healthcare Safety Network to reduce rates of CLABSIs because it is estimated that
most of these infections may be preventable.

Hazamy P, Haley VB, Tserenpuntsag B, et al: Effect of 2013 National Healthcare Safety Network definition changes on central line bloodstream infection rates: Audit results from the New York State Department of Health, Am J Infect Control S0196-6553:1332–1337, 2014.
Beekmann SE, Diekema DJ, Huskins WC, et al: Diagnosing and reporting of central line–associated bloodstream infections,
Infect Control Hosp Epidemiol 33:875–888, 2012.

93. How long should one wait before a blood culture is designated negative? Bacterial growth is evident in most cultures of infected blood within 48 hours or earlier. With the use of continuous monitoring techniques, a study at Children’s Hospital of Philadelphia of 200 cultures from central venous catheters found that the median time for a positive blood culture was
14 hours. In addition, 99.2% of cultures with gram-negative bacteria were positive by 36 hours, and 97%

of cultures with gram-positive bacteria were positive by 36 hours. A study from Australia of neonatal blood cultures found that the median time for positivity for group B Streptococcus was 9 hours, that for E. coli was 11 hours, and that for coagulase-negative staphylococci was 29 hours. Although 36 to 48 hours is generally sufficient time to isolate common bacteria present in the bloodstream, fastidious organisms may take longer to grow. Therefore, when one suspects anaerobes, fungi, or other organisms with special growth requirements, a longer time should be allowed before concluding that a culture is negative.

Shah SS, Downes KJ, et al: How long does it take to “rule out” bacteremia in children with central venous catheters?
Pediatrics 121:135–141, 2008. Jardine L, Davies MW, Faoagali J: Incubation time required for neonatal blood cultures to become positive, J Paediatr Child Health 42:797–802, 2006.

94. What is the utility of so-called “rapid” pathogen testing?
Testing of antigens for influenza A and B and RSV was developed several years ago to provide rapid diagnosis of respiratory viruses known to cause severe disease in certain populations and for which some therapy exists. These generally had good specificity but lower sensitivity. More recently, PCR-based testing has a very high sensitivity and specificity for many common viruses and bacteria. These have been combined into panels of common respiratory viruses, pertussis, and bacteria causing atypical pneumonia, as well as a panel of common GI viruses, protozoa, and enteropathic bacteria. On one hand, some believe that the use of these tests may reduce antibiotic use in respiratory viral illnesses; others worry that the diagnosis of a common respiratory virus in a febrile young child may be falsely reassuring. Recommendations developed during the H1N1 influenza epidemic in 2009 discouraged outpatient and ED providers from testing patients for influenza who did not meet guidelines for antiviral therapy, but did recommend testing for patients ill enough to be hospitalized, for those
with risk factors for severe disease, or patients with a suspected nosocomial illness. Initiation of antiviral therapy should not be delayed pending results of any viral testing in a child in whom treatment is indicated.
95. When is a fever considered a fever of unknown origin (FUO)?
FUO is defined as the presence of daily (or nearly daily) fever (temperature of >38.3 °C [101 °F]) for at least 8 days in a single illness in a patient for whom a careful history, thorough physical examination, and preliminary laboratory data fail to reveal the probable cause.
96. What is the eventual etiology of fever in children with FUO?
The differential diagnosis is extremely broad. The three major categories are infectious, inflammatory (e.g., vasculitis, rheumatoid arthritis), and neoplastic. Approximately half of cases have no identifiable cause, and the fever resolves without explanation. The largest category is infectious. As a general rule, in children <6 years, the most common causes involve respiratory or genitourinary tract infections; localized infections (e.g., abscess, osteomyelitis); juvenile rheumatoid arthritis; and, infrequently,
leukemia. Adolescents, on the other hand, are more likely to have tuberculosis; inflammatory bowel disease; another autoimmune process; or, infrequently, lymphoma.

Marshall GS: Prolonged and recurrent fevers in children, J Infect 68:S83–S93, 2014. Edwards KM, Halasa NB: Fever of unknown origin (FUO) and recurrent fever. In Bergelson JM, Shah SS, Zaoutis TE, editors: Pediatric Infectious Diseases: The Requisites in Pediatrics. Philadelphia, 2008, Mosby Elsevier, pp 266–273.

97. How should a child with FUO be evaluated?
FUO is more likely to be an unusual presentation of a common disorder than a common presentation of a rare disorder. The diagnostic approach includes a meticulous fever diary with vigilance for the appearance of new signs and symptoms. A complete and detailed history is key, with particular attention to possible exposures, including animals, unpasteurized milk (Yersinia or Campylobacter), uncooked poultry, ticks, pica, or dirt ingestion (possible Toxocara or Toxoplasma), rabbits (Tularemia), mosquitoes, stagnant water, and reptiles (Salmonella). Travel history is also important. After performing a thorough physical examination, one should avoid indiscriminately ordering a large battery of tests.
Initial tests may include a complete blood count, screen for inflammation (C-reactive protein or erythrocyte sedimentation rate), tests of renal function, liver enzymes, uric acid, LDH, urinalysis, urine and blood cultures, tuberculin skin test, and chest radiograph. Laboratory studies should subsequently be

targeted as much as possible toward the most likely diagnostic possibilities. The pace of the workup is determined by the severity of the illness.

Marshall GS: Prolonged and recurrent fevers in children, J Infect 68:S83–S93, 2014.
Tolan RW Jr: Fever of unknown origin: a diagnostic approach to this vexing problem, Clin Pediatr 49:207–213, 2010.

98. What is PFAPA?
PFAPA is the acronym for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis, a clinical syndrome of unclear etiology that is responsive to very short courses of corticosteroids for individual episodes and is perhaps the most common cause of regular, recurrent fevers in children. Despite the fear it instills in many parents, it is a benign, self-limited condition that resolves without therapy, and typically remits as children grow older. Tonsillectomy may provide benefit in protracted cases.

Feder HM, Salazar JC: A clinical review of 105 patients with PFAPA (a periodic fever syndrome), Acta Paediatr
99:178–184, 2010.

99. In addition to PFAPA, which syndromes are associated with periodic fevers? Predictable periodic fever is a cardinal feature of a small number of autoinflammatory disorders, which are thought to be due to primary dysregulation of the innate immune system and may involve mutated proteins. Many are hereditary and have ethnic predilections. Periodic fever is uncommon in infectious diseases and malignancies. The most common periodic fever syndromes are summarized in Table 10-3.

Table 10-3 Characteristics of PFAPA Versus Other Selected Fever Syndromes
TNF-RECEPTOR-
ASSOCIATED
FAMILIAL HYPER-IGD PERIODIC
MEDITERRANEAN SYNDROME SYNDROME
PFAPA FEVER (HIDS) (TRAPS)
Age at onset Childhood <10 yr (80%) Childhood Variable
Length of fever episode 4 days 2 days 4-6 days 1-3 wk
Interval 2-8 wk Irregular Irregular Irregular
between
fever
episodes
Associated symptoms and signs Aphthous stomatitis, pharyngitis, adenitis Painful pleuritis, peritonitis, oligoarthritis, foot and ankle rash Abdominal pain, cervical adenopathy, splenomegaly Abdominal pain, pleuritis, rash, myalgias, orbital edema
Inheritance Random Autosomal recessive Autosomal recessive Autosomal dominant
IgD Immunoglobulin D; PFAPA syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis; TNF tumor necrosis factor.
Data from Goldsmith DP: Periodic FEVER syndromes, Pediatr Rev 30:e34–e41, 2009.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION
100. How common is the maternal-to-infant transmission of HIV?
Virtually all infants born to mothers who are human immunodeficiency virus (HIV)-1 seropositive will acquire antibody to the virus transplacentally. Without any treatment, about 25% (range, 13% to 39%) of these infants will ultimately develop an active HIV infection. In nonbreastfeeding populations,

about 30% of maternal-to-infant HIV transmission occurs in utero, and the remainder occurs intrapartum. Vertical transmission of HIV-2 is less common, occurring in 0% to 4% of cases.

DeCock KM, Fowler MG, Mercier E, et al: Mother-to-child transmission of HIV-1: timing and implications for prevention,
Lancet Infect Dis 11:726–732, 2006.
Abrams EJ, Weedon J, Bertolli J, et al: New York City Pediatric Surveillance of Disease Consortium, Centers for Disease Control and Prevention: Aging cohort of perinatally human immunodeficiency virus-infected children in New York City. New York City Pediatric Surveillance of Disease Consortium, Pediatr Infect Dis J 20:511–517, 2001.

101. What drugs are recommended for reducing the maternal-to-infant transmission of HIV?
Currently, interventions to prevent transmission target the late intrauterine and intrapartum periods when the highest likelihood of transmission occurs. HIV-infected pregnant women in the United States are treated with combination antiretroviral therapy the same as nonpregnant adults. All
HIV-exposed newborn infants should receive zidovudine (AZT) at a dose of 4 mg/kg orally every 12 hours for the first 6 weeks of life. Among infants born to mothers with high viral loads or those in whom antepartum and/or intrapartum prophylaxis was incomplete or not received, treatment with nevirapine is recommended (first dose at birth to 48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose). Nevirapine should be started as soon as possible after birth. Elective cesarean delivery is also recommended for women with high HIV loads.

AIDS Info: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov. Accessed on Mar. 23, 2015.
Committee on Pediatric AIDS: HIV testing and prophylaxis to prevent mother-to-child transmission in the United States, Pediatrics 122:1127–1134, 2008.

102. What are the risk factors for perinatal transmission of HIV?
• AZT monotherapy during pregnancy (compared with combination antiretroviral therapy)
• High maternal viral load at or near delivery
• Rupture of membranes >4 hours before delivery
• Fetal instrumentation with scalp electrodes and forceps
• Vaginal delivery (especially with high maternal viral loads)
• Episiotomies and vaginal tears
• Prematurity and low birth weight (possible impaired fetal or placental membranes)
• Concurrent maternal HSV-2 infection (increased shedding of HIV in genital secretions)
• Breastfeeding
• Incidence of HIV during pregnancy and postpartum

Landesman SH, Kalish LA, Burns DN, et al: Obstetrical factors and the transmission of HIV, Curr HIV Res 11:10, 2013. Paintsil E, Andiman WA: Update on successes and challenges regarding mother-to-child transmission of HIV, Curr Opin Pediatr 21:95, 2009.

103. Should HIV-infected women breast-feed?
No. HIV has been shown to be present in breast milk and also to be transmissible by breastfeeding. Worldwide, up to one-third to one-half of maternal-to-child transmission of HIV may occur through breastfeeding. This risk is increased when the infection is acquired after birth. Thus, in developed countries where alternative means of nutrition (i.e., formula) are readily available, breastfeeding is not recommended. In developing countries where breastfeeding may be protective against other causes of significant morbidity and mortality (e.g., diarrheal and respiratory illnesses) and alternative means of nutrition are less reliably available, recommendations remain controversial. The World Health Organization (WHO) recommends exclusive breastfeeding when replacement feeding is not acceptable, feasible, affordable, or safe. Exclusive breastfeeding appears to have lower rates of transmission than mixed (e.g., formula and solid foods) breastfeeding. It remains unclear what is the optimal duration of breastfeeding to balance its protective effect with the risk of HIV transmission. It is also unclear

whether maternal antiretroviral treatment during lactation will reduce the risk for HIV-1 transmission during breastfeeding, and what the actual risk of an undetectable maternal viral load is to the breastfeeding infant.

AIDS Info: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ perinatalgl.pdf. Accessed on Jan. 14, 2015.
Kuhn L, Reitz C, Abrams EJ: Breastfeeding and AIDS in the developing world, Curr Opin Pediatr 21:83–93, 2009. Coovadia HM, Rollins NC, Bland RM, et al: Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study, Lancet 369:1107–1116, 2007.

104. How is an infection with HIV confirmed in the newborn infant?
Because maternal antibody may persist in the infant well into the second year of life, enzyme-linked immunosorbent assay (ELISA) testing and Western blot testing are unreliable until about 18 months of age. Therefore, the diagnosis of HIV infection in the newborn usually relies on the direct detection of the virus or viral components in the infant’s blood or body fluids by nucleic acid amplification testing (NAAT). The gold standard for diagnostic testing of infants and children <18 months is
HIV-1 NAAT, which can directly detect HIV-1 deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).
Infants born to HIV-infected women who have not taken antiretroviral therapy should be tested by HIV-1 NAAT during the first 48 hours of life to determine whether in utero acquisition has occurred. If a mother has been taking antiretroviral therapy since the second trimester and has an
undetectable viral load the week before delivery, the risk for in utero transmission is low. An HIV-1 NAAT should be done within the first 14 to 21 days of life and at age 1 to 2 months and again at age
4 to 6 months. HIV can be presumptIVELY excluded with 2 or more negative tests: one at age 14 days or older and the other at age 1 month or older. HIV is considered DEFINITIVELY excluded
(in nonbreast-fed infants) on the basis of two negative virologic tests, with one test performed at age 1 month or older and the other test at age 4 months or older. A negative HIV-1 NAAT at
8 weeks also PRESUMPTIVEly indicates disease exclusion. Any time a positive result is obtained, testing should be repeated on a second blood sample as soon as possible. The diagnosis of HIV infection is established if two separate samples are found to be positive by PCR testing. For children with negative testing, many experts recommend HIV-1 antibody assay testing at 12 to 18 months to confirm the absence of HIV infection.

AIDS Info: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/contentfiles/ lvguidelines/perinatalgl.pdf. Accessed on Jan. 14, 2015.
Havens PL, Mofenson LM: Evaluation and management of the infant exposed to HIV-1 in the United States, Pediatrics
123:175–187, 2009.
Schutzbank WS, Steele RW: Management of the child born to an HIV-positive mother, Clin Pediatr 48:467–471, 2009.

105. What are the earliest and most common manifestations of congenital HIV infection?
• Most infants with congenital HIV infection are asymptomatic at birth, although occasional patients have diffuse lymphadenopathy and hepatosplenomegaly.
• Older infants with HIV infection commonly present symptoms of failure to thrive, loss of or failure to obtain normal developmental milestones, mucocutaneous candidiasis (especially after 1 year), hepatosplenomegaly, interstitial pneumonitis, or a combination of these features.
• Toddlers and older children with HIV infection may have generalized lymphadenopathy, recurrent bacterial infections, recurrent or chronic parotitis, or progressive encephalopathy and loss of developmental milestones.

Simpkins EP, Siberry GK, Hutton N: Thinking about HIV infection, Pediatr REV 30:337–348, 2009.

106. When should Pneumocystis prophylaxis begin and end for an HIV-exposed infant? Historically, the peak incidence of Pneumocystis pneumonia in HIV-infected infants occurred at the age of 3 months (range, 4 weeks to 6 months). Pneumocystis prophylaxis should be initiated at the age of 4 to 6 weeks and continued until the infant is at least 4 months old unless the infant meets criteria for being DEFINITIVELY or presumptIVELY HIV-uninfected. If the HIV status of the child is indeterminate

or confirmed positive, Pneumocystis JIROVECI pneumonia prophylaxis should be continued until the child is 12 months old, at which time reassessment is done (based on CD4 T-lymphocyte counts).

AIDS Info: Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and
HIV-Infected Children. http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf. Accessed on Jan. 14, 2015.

107. Among patients <13 years of age with HIV infection, how is the severity of HIV illness classified?
According to the 1994 revised Pediatric HIV Classification System, for children 12 months of age and younger, three categories are used, which include CD4 count, percentage of total lymphocytes, and clinical staging (Table 10-4).

Terms, definitions and calculations used in CDC HIV surveillance publications: www.cdc.gov/hiv/statistics/ recommendations/terms.html. Accessed on Mar. 23, 2015.

108. What is the significance of the “viral load”?
Viral load refers to a quantification of HIV viral RNA as measured by various assays. It is a measure of the degree of infection; the lower limit of detection on ultrasensitive assays is 20 copies/mL,
with an upper range of 20 to 50 million copies/mL. Higher levels are associated with increased likelihoods of rapid disease progression and poorer long-term prognosis. Viral loads are used as an ongoing measure of efficacy of treatment with the goal to achieve an undetectable level for as long as possible.

109. What are the classes of antiretroviral agents (ARTs) used to treat HIV?
• Nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs) competitively inhibit the HIV reverse transcriptase (which converts HIV RNA into DNA) and terminate the elongation of viral DNA. They require intracellular phosphorylation for activation. NRTIs have little or no effect on chronically infected cells because their site of action is before the incorporation of viral DNA into host DNA. This class of drugs includes zidovudine, lamivudine, stavudine, zalcitabine, didanosine (ddI), tenofovir, emtricitabine, and abacavir.
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs) also inhibit the HIV reverse transcriptase, although they do so at a different site than do the NRTIs. They bind directly to the active site of HIV reverse transcriptase and do not require activation. This class of drugs includes efavirenz, nevirapine, etravirine, and rilpivirine.
• Protease inhibitors (PIs) inhibit the HIV protease, which cuts HIV polyprotein precursors before viral budding. This class of drugs includes atazanavir, darunavir, fosamprenavir, nelfinavir, ritonavir, indinavir, saquinavir, tipranavir, and lopinavir/ritonavir (Kaletra).
• Integrase inhibitors block the action of a viral enzyme that inserts the viral genome into the DNA of host cells. This class of drugs includes raltegravir, dolutegravir, and elvitegravir.
• Entry and fusion inhibitors include enfuvirtide and maraviroc.

Guidelines for treatment of HIV-infected children and adolescents are regularly updated and available at http://www. aidsinfo.nih.gov/Guidelines. Accessed on Jan. 27, 2015. 5 Generally, triple-drug therapy (so-called potent combination antiretroviral therapy [c ART]) is recommended.
Patel K, Hernán MA, Williams PL, et al: Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study, Clin Infect Dis 46:507–515, 2008.

110. What are the common toxicities associated with antiretroviral therapy?
• Anemia occurs in up to 9% of children receiving AZT (compared with 4% to 5% of those on other regimens), and may be exacerbated in newborns because of the coincident physiologic nadir. Neutropenia occurs in 6% to 27% of children receiving antiretroviral therapy, particularly those taking AZT and ddI.
• Thrombocytopenia occurs in 30% of untreated children with HIV infection and is more commonly an initial presentation of HIV infection than a complication of antiretroviral therapy. In initial trials, severe thrombocytopenia was seen in 2% of children receiving either ddI and AZT or lamivudine and AZT.

Table 10-4 Pediatric Human Immunodeficiency Virus (HIV) Classification for Children Younger Than 13 Years of Age

IMMUNOLOGIC DEFINITIONS Immunologic Categories
AGE-SPECIFIC CD4+ T-LYMPHOCYTE COUNT AND PERCENTAGE OF TOTAL LYMPHOCYTES
Younger
Than 12 mo 1 Through 5 y 6 Through 12 y Clinical Classificationsa
N: No A: Mild B: Moderate Signs or Signs and Signs and
μL % μL % μL % Symptoms Symptomsb Symptoms

C: Severe Signs and Symptoms
1: No evidence of suppression ≤1500 ≤25 ≤1000 ≤25 ≤500 ≤25 N1 A1 B1 C1
2: Evidence of moderate suppression 750–1499 15–24 500–999 15–24 200–499 15–24 N2 A2 B2 C2
3: Severe suppression <750 <15 <500 <15 <200 <15 N3 A3 B3 C3
aChildren whose HIV infection status is not confirmed are classified by using this grid with a letter E (for perinatally exposed) placed before the appropriate classification code (eg, EN2).
bLymphoid interstitial pneumonitis in category B or any condition in category C is reportable to state and local health departments as acquired immunodeficiency syndrome (AIDS-defining conditions).
AAP Committee on Infectious Diseases, Larry K. Pickering, Carol J. Baker, DAVID W. Kimberlin. Red Book, 29th Edition (2012). American Academy of Pediatrics.

• Lipodystrophy can occur in children treated with NRTI, protease inhibitors (PIs), and efavirenz.
• GI side effects: Many children experience GI adverse effects such as nausea, vomiting, diarrhea, and abdominal pain, especially when AZT and PIs are initiated.
• CNS effects are encountered when initiating therapy with efavirenz. Commons symptoms include dizziness, drowsiness, vivid dreams, or insomnia. Rarely, seizures have been reported in children.
• Hepatitis can occur with almost all ARTs, but is seen less commonly in children than adults. Atazanavir and indinavir commonly cause indirect hyperbilirubinemia and for this reason are generally not used in neonates.
• Metabolic abnormalities such as dyslipidemia and insulin resistance can occur with most ART regimens.

http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/31/adverse-effects-of-arv. Accessed on Mar. 20, 2015.

111. How should nonadherence to HIV medication be addressed?
Noncompliance with highly active antiretroviral therapy (HAART) regimens has been estimated as
>50%, with the number being much higher for high-risk groups such as newly diagnosed teenagers and adolescents who acquired HIV perinatally. Close follow-up and simplification of medical therapy, when possible, are key. Recognizing and treating comorbid conditions such as depression and
alcohol and drug abuse are also important. Intense follow-up (e.g., weekly) for some high-risk patients is recommended. Youth-friendly technology-based support interventions, such as cell phone and text message follow-up, are showing some promise in improving adherence.

Belzer ME, Naar-King S, Olson J, et al: The use of cell phone support for non-adherent HIV-infected youth and young adults: an initial randomized and controlled intervention trial, AIDS BEHAV 18:686–696, 2014.

112. Should a classroom teacher be told that a child is HIV positive? There is no absolute requirement to inform a classroom teacher, a school principal, or childcare provider about a child’s HIV status. It is not necessary for anyone except the child’s physician to be aware
of the diagnosis. In certain circumstances such as children with conditions that may lead to blood exposure, such as severe excoriated eczema or bleeding diathesis, it is advisable for a family to discuss this with the child’s physician before starting any out-of-home program.

American Academy of Pediatrics: School health. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 147.

113. What are the risk factors for HIV transmission after a needlestick injury?
In a case-controlled study that involved 33 health-care workers and 665 controls, the following risk factors were identified:
• High viral inoculum (patient with advanced disease)
• Large volume of blood (from a large-bore hollow needle)
• Deep puncture wound
Overall, the risk for transmission from needles contaminated with the blood of an HIV-infected patient is roughly 0.3%. Risk from a puncture wound in a random community setting is thought to be lower. There are no known transmissions from accidental nonoccupational (community) needlesticks.

American Academy of Pediatrics: Human immunodeficiency virus infection. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 438–439.
Cardo DM, Culver DH, Ciesielski CA, et al: A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group, N Engl J Med 337:1485–1490, 1997.

KEY POINTS: HUMAN IMMUNODEFICIENCY VIRUS INFECTION
1. Interventions to prevent maternal HIV transmission target the late intrauterine and intrapartum periods when the highest likelihood of transmission occurs.
2. Most infants with congenital HIV infection are asymptomatic at birth.
3. The gold standard for diagnostic testing of infants and children <18 months is HIV-1 nucleic acid amplification testing (NAAT), which can directly detect HIV-1 DNA or RNA.
4. Viral loads are used as an ongoing measure of treatment efficacy.
5. Triple-therapy (so-called potent combination antiretroviral therapy [cART]) is recommended for HIV-infected children.
6. Risk factors for increased HIV transmission after a needlestick injury include a high viral inoculum, large volume of blood, and deep puncture wound.

IMMUNIZATIONS
114. What is the derivation of the word “vaccination”?
Edward Jenner, an eighteenth century British physician, had observed that dairymaids were protected naturally from smallpox, the infectious scourge of the world at that time, after they had developed cowpox, a milder blistering disease. In 1796, he inoculated a young boy with material from fresh cowpox lesions that had been taken from a dairymaid. Two months later, he again inoculated the boy, but with matter from a fresh smallpox lesion. No disease developed and the science of immunization was born. Because the Latin word for cow was VACCA and for cowpox was VACCINIA, Jenner called his new procedure VACCINATION.

Riedel S: Edward Jenner and the history of smallpox and vaccination, Proc (Bayl UNIV Med Cent) 18:21–25, 2005.

115. Why are the buttocks a poor location for intramuscular (IM) injections in infants?
The gluteus maximus is not a good choice for injections because of the following:
• The gluteal muscles are incompletely developed in some infants.
• There is a potential for injury to the sciatic nerve or the superior gluteal artery if the injection is misdirected.
• Some vaccinations may be less effective if they are injected into fat (e.g., vaccines for rabies, influenza, and hepatitis B).
If injections into the buttocks are given to older children, the proper site is the gluteus medius in the upper outer quadrant rather than the gluteus maximus, which is more medial.

Zuckerman JN: The importance of injecting vaccines into muscle, BMJ 321:1237–1238, 2000.

116. When administering an IM vaccination, is aspiration necessary before injection?
Traditionally, the plunger has been withdrawn to verify that the needle tip is not in a vein. However, when vaccinations are given as recommended in the anterior lateral thigh in an infant or in the deltoid in toddlers >18 months, aspiration before injection is not required because no large blood vessels are located at those preferred sites. Additionally, the process of aspiration before injection is more painful and it takes longer to administer the vaccine.

Ipp M: Vaccine-related pain: randomized controlled trial of two injection techniques, Arch Dis Child 92:1105, 2007. American Academy of Pediatrics: Acute immunization. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 24.

117. Is there any risk associated with administering multiple vaccines simultaneously? Most vaccines can be administered simultaneously at separate sites without concern about effectiveness because the immune response to one vaccine generally does not interfere with immune responses to others. The immune system is capable of recognizing hundreds of thousands of antigens. However, some exceptions exist. For example, the simultaneous administration of cholera vaccine and yellow fever vaccine is associated with interference.

118. Should premature babies receive immunization on the basis of postconception age or chronologic age?
In most cases, premature babies should be immunized in accordance with postnatal chronologic age.
If a premature infant is still in the hospital at 2 months of age, the vaccines routinely scheduled for that age should be administered with the exception of the rotavirus vaccine, which should be deferred until the infant leaves the hospital because spread of this virus in patient units has been reported. Among premature infants who weigh <2 kg at birth, seroconversion rates to hepatitis B vaccine (HBV) are relatively low when immunization is initiated shortly after birth. Accordingly, in
these infants, if the mother is HBsAg negative, immunization should be delayed until just before hospital discharge or until 30 days of age. If HBV is given at birth in infants< 2 kg, this should not be counted toward the primary series.

American Academy of Pediatrics: Immunization in special clinical circumstances and hepatitis B. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 69–71 and 384–384.
Saari TN, American Academy of Pediatrics Committee on Infectious Diseases: Immunization of preterm and low birth weight infants. American Academy of Pediatrics Committee on Infectious Diseases, Pediatrics 112:193–198, 2003.

119. Which vaccines are egg-embryo–based vaccines? Of the immunizations that are commonly administered to children, the measles-mumps-rubella (MMR) vaccine and certain rabies vaccine preparations are grown in chick embryo fibroblast culture. However, they do not contain significant amounts of egg protein. Children with egg allergy are at low risk for anaphylaxis to MMR and do not require skin testing or special precautions before or during the administration of this vaccine.
120. What is the difference between whole-cell and acellular pertussis vaccines? Whole-cell pertussis vaccines consist of whole bacteria that have been inactivated and are nonviable. These vaccines contain lipooligosaccharide and other cell wall components that result in a high incidence of adverse effects. This vaccine is no longer given in the United States.
Acellular pertussis vaccines contain one or more B. pertussis proteins that serve as immunogens.
All acellular pertussis vaccines contain at least detoxified pertussis toxin, and most contain other antigens as well, including filamentous hemagglutinin, fimbrial proteins, and pertactin. The acellular vaccines are associated with a much lower incidence of side effects and thus are given for all doses in the United States. Children <7 years of age who have received the whole-cell vaccine abroad should have the series continued with the acellular vaccine formulations.

American Academy of Pediatrics: Pertussis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, p 560.

121. What are the absolute contraindications to pertussis immunization?
The adverse events after pertussis immunization that represent absolute contraindications to further administration of pertussis vaccine include the following:
• Immediate anaphylactic reaction
• Encephalopathy within 7 days of vaccination
• Unstable or evolving neurologic conditions in children <1 year of age warrant postponement of the vaccine.
The adverse events that represent precautions for further administration of pertussis vaccine include the following:
• Moderate or severe acute illness with or without fever
• Guillain-Barré syndrome within 6 weeks after a previous dose of tetanus toxoid-containing vaccine
• History of arthus-type hypersensitivity reactions (local vasculitis associated with deposition of immune complexes and activation of complement) after a previous dose of tetanus or diphtheria toxoid–containing vaccine

Centers for Disease Control and Prevention: Vaccines and Immunizations. http://www.cdc.gov/vaccines/recs/vac-admin/ contraindications-vacc.htm. Accessed on Jan. 14, 2015.
American Academy of Pediatrics: Pertussis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 562–566.

122. How long does protection against pertussis last after immunization?
Vaccine-induced immunity to pertussis is relatively short-lived. On the basis of studies of patients who have been immunized with a whole-cell pertussis vaccine and exposed to a sibling with pertussis, protection against infection isabout 80% duringthe first 3 years after immunization, dropping to 50% at 4 to 7 years and to near 0% at 11 years. Teenagers and adults thus become susceptible to pertussis and serve as vectors for infants, for whom morbidity and mortality are much higher. Because of the slow, steady resurgence of pertussis in the past two decades and the availability of an acellular pertussis vaccine combined with diphtheria and tetanus toxoid (Tdap), the Advisory Committee on Immunization Practices of the CDC has
recommended that all adolescents >11years of age should receive a booster dose. Anyone 19 years of age and olderwho hasnotreceived a dose of Tdapshouldalsobe vaccinated. This Tdap boosterdose can replace
1 of the 10-year Td booster doses and is especially important for health-care workers. Additionally, all pregnant women should receive a Tdap booster during each pregnancy at 27 to 36 weeks.

Centers for Disease Control and Prevention: Pertussis: Summary of Vaccine Recommendations. http://www.cdc.gov/ vaccines/vpd-vac/pertussis/recs-summary.htm. Accessed on Jan 14, 2015.
Halperin SA: The control of pertussis—2007 and beyond, N Engl J Med 356:110–113, 2007.

123. What is cocooning?
Pertussis vaccination in the United States has reduced annual pertussis-attributable morbidity and mortality by >90%. Despite this, the annual incidence of pertussis continues to rise. Some of the increase may be attributed to outbreaks in unvaccinated pockets of the country. Infants <6 months of age, who are too young to have completed the primary vaccination series, have up to a 20-fold higher incidence of
pertussis than does the general population. Two-thirds of pertussis-infected infants in this age group require hospitalization, and pertussis-related deaths occur almost exclusively in young infants, the risk being inversely proportional to age and number of infant DTaP vaccine doses received. It is estimated that 75% of infants are infected by a household contact or caregiver. The Advisory Committee on Immunization Practices recommended Tdap vaccination of all adults, who come in close contact with children <1 year of
age, especially health-care workers to help prevent pertussis-related complications and deaths. This circle
of providing protected and protective caregivers is termed cocooning.
It is also recommended that all pregnant women should receive Tdap during each pregnancy at 27 to 36 weeks to facilitate transfer of passively acquired maternal IgG against pertussis to the infant and to ensure immunity.

American Academy of Pediatrics: Pertussis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 562–566.
Grizas AP, Camenga D, Vázquez M: Cocooning: a concept to protect young children from infectious diseases, Curr Opin Pediatr 24:92–97, 2012.
Healy CM, Rench MA, Baker CJ: Implementation of cocooning against pertussis in a high-risk population, Clin Infect Dis
52:157–162, 2011.

124. Which vaccines offer protection against cervical cancer? Vaccination for human papillomavirus (HPV). The first vaccine against HPV (Gardasil) was approved in 2006. It is a quadrivalent vaccine (HPV4) that prevents disease caused by HPV types 6, 11, 16, and 18. A bivalent vaccine (HPV2, Cervarix) was approved in 2009. HPV types 16 and 18 have been causally linked with cervical, vulvar, and vaginal cancers, as well as penile, anal, and oropharyngeal cancers. In December 2014, a new 9-valent HPV preparation (Gardasil 9) was approved by the FDA. The latest recommendations are that all boys and girls aged 11 or 12 years should get vaccinated. Catch-up vaccines are recommended for males through age 21 and for females through age 26, men having sex with men (MSM), and immunocompromised people through age 26 (including those with HIV and AIDS).

Human Papilloma Virus (HPV): http://www.cdc.gov/std/hpv/stdfact-hpv.htm#a4. Accessed on Jan. 14, 2015.
Jenson HB: Human papillomavirus vaccine: a paradigm shift for pediatricians, Curr Opin Pediatr 21:112–121, 2009.

125. How effective is the pneumococcal conjugate vaccine? The pneumococcal conjugate vaccine is highly effective against invasive pneumococcal disease, reducing rates by up to 98% for vaccine-associated serotypes in children fully vaccinated during the first 2 years of

life. The greatest decline in invasive disease has been in the number of children experiencing bacteremia without a focus. This vaccine has a modest effect on pneumococcal otitis media, preventing about 35% of culture-confirmed cases in young children. Both of these effects were noted after the original heptavalent vaccine (PCV-7) was introduced in 2000. This reduction has continued at a more modest rate following the introduction of a 13-valent (PCV-13) vaccine, which includes serotype 19a, a serotype that has been noted to cause invasive disease but was not included in the PCV-7.

Angoulvant F, Levy C, Grimprel E, et al: Early impact of 13-valent pneumococcal conjugate vaccine on community-acquired pneumonia in children, Clin Infect Dis 58:918–924, 2014.

126. What is the “grandparent effect” of vaccination?
The rate of invasive pneumococcal disease has declined in people >65 years since the introduction of the conjugate pneumococcal vaccine in 2000. Meningitis rates have declined by 54%. Decreased nasopharyngeal carriage among vaccinated infants has likely reduced transmission to older individuals
caring for them. This type of “herd effect” in elderly people is referred to as the grandparent effect.

Hsu HE, Shutt KA, Moore MR, et al: Effect of pneumococcal conjugate vaccine on pneumococcal meningitis, N Engl J Med 360:244–256, 2009.
Millar EV, Watt JP, Bronsdon MA, et al: Indirect effect of 7-valent pneumococcal conjugate vaccine on pneumococcal colonization among unvaccinated household members, Clin Infect Dis 47:989–996, 2008.

127. What serogroup capable of causing meningococcal infections is lacking in licensed polyvalent vaccines in the United States?
Serogroup B isolates account for about one-third of cases of meningococcal disease, but serogroup B polysaccharide is absent from these vaccines. Two quadrivalent meningococcal vaccines containing capsular polysaccharide from serogroups A, C, Y, and W135 are widely available in the United States, including a plain polysaccharide vaccine that is approved for use in children at least 2 years old and a polysaccharide diphtheria toxoid conjugate vaccine that is licensed for use in individuals 11 to 55 years old. A study in infants with the new tetravalent vaccine using a nontoxic mutant of diphtheria toxoid as the carrier protein has demonstrated good immunogenicity and may become part of the vaccination schedule for infants in the future.
All 11- to 12-year-olds should be routinely vaccinated with the conjugate vaccine. In addition, unvaccinated college freshmen living in dormitories should be offered either the plain polysaccharide vaccine or the conjugate vaccine. Vaccination is considered advisable for children at least 2 years old who are in high-risk groups, including those with functional or anatomic asplenia or complement deficiency. A meningococcal vaccine is given to all military recruits in the United States and should be considered for individuals traveling to areas of epidemic or hyperendemic disease. In addition, the current vaccines may be useful as an adjunct to chemoprophylaxis for the control of outbreaks caused by a vaccine serogroup.
Until recently, no vaccine was available in the United States with coverage of serogroup B.
In October 2014, in response to recent outbreaks of serogroup B meningococcal disease on college campuses (with attributable fatalities), the first serogroup B meningococcal vaccine (Trumenba®) was approved for use in individuals 10 to 25 years of age as a 3-dose series. This vaccine does not provide coverage for serogroups A, C, Y, and W135.

Centers for Disease Control and Prevention: Meningococcal Disease. http://www.cdc.gov/meningococcal/outbreaks/ vaccine-serogroupB.html. Accessed on Jan. 14, 2015.
Snape MD, Perrett KP, Ford KJ, et al: Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial, JAMA 299:173–184, 2008.
Bilukha OO, Rosentein N: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, MMWR 54:1–21, 2005.

128. How effective is the varicella vaccine if given after exposure to the illness? The varicella vaccine is highly effective (95% for the prevention of any disease, 100% for the prevention of moderate to severe disease) when used within 36 hours of exposure in an environment involving close contact. Ideally, it is given as soon as possible after the exposure but is recommended up to 5 days after exposure. The reason for the high efficacy is that naturally acquired varicella-zoster virus

usually takes 5 to 7 days to propagate in the respiratory tract before primary viremia and dissemination occur, whereas vaccine virus may elicit humoral and cellular immunity in significantly less time.

Watson B, Seward J, Yang A, et al: Postexposure effectiveness of varicella vaccine, Pediatrics 105:84–88, 2000.

129. Is the MMR vaccine effective in preventing measles if given after exposure to the illness?
The measles vaccine, if given within 72 hours of measles exposure, will provide protection in some cases. In the case of a known measles exposure, such as during an outbreak, vaccination within 72 hours is recommended for all unvaccinated contacts, including children as young as 6 months. In children <1 year, this vaccine should not count as part of the primary series, which should continue as usual (with a minimum of 28 days separating vaccines).
130. Of the vaccines included in the routine schedule, which ones contain live viruses? MMR, varicella, rotavirus, and influenza. Oral polio vaccine is a live attenuated virus vaccine, but it is no longer recommended for routine use. Other live virus vaccines include yellow fever virus vaccines.

KEY POINTS: IMMUNIZATIONS
1. Premature babies should be immunized in accordance with postnatal chronologic age.
2. Without a booster after age 5 years, protection against pertussis infection is about 80% during the first 3 years after immunization, dropping to 50% at 4 to 7 years and to near zero at 11 years.
3. Live vaccines include measles-mumps-rubella, varicella, cold-adapted, live-attenuated influenza, rotavirus, and yellow fever virus.
4. Vaccination of both boys and girls for human papillomavirus offers protection against cervical and other forms of cancer.
5. When administering an intramuscular vaccination, aspiration is not necessary before injection.

131. What are the indications for palivizumab? PALIVIZUMAB is a humanized mouse monoclonal antibody that is directed against a RSV protein and that is approved for the prevention of RSV disease in selected children. It is typically administered intramuscularly for five doses, starting in November (or earlier if RSV infections are detected in the community). According to the AAP, updated recommendations for the consideration of palivizumab administration include the following:
• Infants born before 29 weeks in the first year of life
• Infants born before 32 weeks with chronic lung disease, defined as requirement for >21% oxygen for at least 28 days, also in the first year of life.
• Infants and children <2 years with chronic lung disease who are requiring ongoing medical therapy such as supplemental oxygen, chronic corticosteroid, or diuretic therapy
• Infants <12 months with hemodynamically significant congenital heart disease (i.e., not small ventricular septal defects [VSDs], atrial septal defects [ASDs], or infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure)
• Certain infants with neuromuscular disease or congenital abnormalities of the airways that compromise handling of respiratory secretions in the first year of life
• Infants and children <2 years who will be profoundly immunocompromised during the RSV season
Committee on Infectious Diseases and Bronchiolitis Guidelines Committee: Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection, Pediatrics 134:415–420, 2014.

132. What are the recommendations regarding the administration of live-virus vaccines to patients receiving corticosteroid therapy? Children receiving corticosteroid treatment can become immunosuppressed. Although some uncertainty exists, there is adequate experience to make recommendations about the administration of live-virus vaccines to previously healthy children receiving steroid treatment. In general, live-virus vaccines
should not be administered to children who have received prednisone or its equivalent in a dose of 2 mg/kg/day or greater (or 20 mg per day for individuals whose weight is >10 kg) for more than 14 days. Treatment for shorter periods, with lower doses, or with topical preparations, local injections, or

inhaled corticosteroids should not contraindicate the use of these vaccines. However, immune suppression is possible with these medications and that should be taken into account at the time of vaccination.

American Academy of Pediatrics: Immunization in special clinical circumstances. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 81–82.

133. What is thimerosal?
Thimerosal is a mercury-containing preservative that has been used as an additive to vaccines for decades because of its effectiveness for preventing contamination, especially in open, multidose containers. In an effort to reduce exposure to mercury, vaccine manufacturers, the FDA, the AAP, and other groups have worked to remove thimerosal from vaccines that contain this compound. By the end of 2001, all vaccines in the routine schedule for children and adolescents were free or virtually free of thimerosal, with the exception of some inactivated influenza vaccines.
134. Does thimerosal or any vaccine or vaccine combination cause autism?
No. In the totality of studies to date, there is no compelling evidence that thimerosal or any vaccine combination causes autism, attention-deficit/hyperactivity disorder, or other neurodevelopmental disorders.

Taylor LE, Swerdfeger AL, Eslick GD: Vaccines are not associated with autism: an evidence-based meta-analysis of case- control and cohort studies, Vaccine 32:3623–3629, 2014.

135. How should parents who refuse vaccinations be handled?
Many parents are aware about alleged controversial issues concerning routine childhood vaccines. A dialogue about specific parental concerns and beliefs should be undertaken calmly and without judgment because an ongoing discussion may be the most important step to eventual vaccine
acceptance. The AAP recommends that generally, physicians should continue to care for children whose families reject immunization. However, if a physician truly believes that they cannot ethically provide care for a family, the professional relationship may be terminated after transfer of care to another physician has been ensured, and the parents have been given notice that the physician intends to terminate care. Parents who reject immunization should be advised of local laws restricting entry into school or childcare for unvaccinated or undervaccinated children. Documentation of such discussions in the medical record are advised, and sample “Refusal to Vaccinate” forms can be found on the AAP website; many states also have their form for providers generally available on individual state health department websites.

American Academy of Pediatrics: Immunization. http://www2.aap.org/immunization/pediatricians/refusaltovaccinate. html. Accessed on Jan. 14, 2015.
American Academy of Pediatrics: Active Immunization. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 10–11.
Gilmour J, Harrison C, Asadi L, et al: Childhood immunization: when physicians and parents disagree, Pediatrics
128:S167 –S174, 2011.

INFECTIONS WITH RASH
136. What is the traditional numbering of the “original” six exanthemas of childhood, and when were they first described?
• First disease: Measles (rubeola), 1627
• Second disease: Scarlet fever, 1627
• Third disease: Rubella, 1881
• Fourth disease: Filatov-Dukes disease (described in 1900 and though to be a distinct scarlatiniform type of rubella, attributed more recently to exotoxin-producing S. aureus; term is no longer used)
• Fifth disease: Erythema infectiosum, 1905
• Sixth disease: Roseola infantum (exanthema subitum), 1910

Weisse ME: The fourth disease: 1900–2000, Lancet 357:299–301, 2001.

137. What conditions are associated with fever and petechiae? The list is extensive because many viral and bacterial pathogens may cause a petechial rash as part of the syndrome or from associated thrombocytopenia or disseminated intravascular coagulopathy. Obviously, not all of these will be high on the differential diagnosis, but should be taken into account when evaluating the child returning from abroad.
• Human monocytic ehrlichiosis
• Drug hypersensitivity
• Meningococcemia
• Rocky mountain spotted fever
• Immune thrombocytopenic purpura
• Enteroviral infection
• Henoch-Sch€onlein purpura
• Staphylococcal sepsis
• Streptococcal infection
• Toxic shock syndrome
• “Infectious mononucleosis”
• Cytomegalovirus
• Epstein-Barr virus
• Toxoplasmosis
• Kawasaki disease
• Adenovirus infection
• Dengue fever
• Typhus
• Arenavirus (e.g., Lassa)
• Arboviruses (e.g., yellow fever, Chikungunya)

Razzaq S, Schutze GE: Rocky mountain spotted fever, Pediatr REV 26:125–129, 2005.

138. What are the three Cs of measles? Cough, coryza, and conjunctivitis. After an incubation period of 4 to 12 days, these symptoms develop and are followed by a characteristic erythematous and maculopapular rash (typically on day 14 after exposure), which spreads from head to feet. The rash is described as morbilliform because it has both macular and papular features (Fig. 10-7).

Figure 10-7. Morbilliform rash of measles. (From Hobson RP: Infectious disease. In Walker BR, Colledge NR, Ralston SH, Penman ID: Davidson’s Principles and Practice of Medicine, ed 22. Philadelphia, ELSEVIER, 2014.)

139. What do Koplik spots look like?
Koplik spots are thought to be pathognomonic for measles. They are punctate white-gray papules that occur on a red background, initially opposite the lower molars, but they may spread to involve other parts of the mucosa (Fig. 10-8). However, they may be present for a day or less, are often difficult to appreciate, and should not be relied on to rule in or out the diagnosis.

Figure 10-8. Koplik spots (arrows). (From Hobson RP: Infectious disease. In Walker BR, Colledge
NR, Ralston SH, Penman ID: Davidson’s Principles and Practice of Medicine, ed 22. Philadelphia, ELSEVIER, 2014.)

140. What is “atypical” about atypical measles?
• Koplik spots are rarely present.
• Conjunctivitis and coryza are not part of the prodrome.
• Rash begins on the distal extremities and spreads toward the head (opposite what is seen in typical measles) or has a nondescript distribution and appearance.
• Respiratory distress with clinical and radiographic signs of pneumonia and pleural effusions are increased in frequency.
Atypical measles occurs primarily in patients who have received inactivated measles vaccine, which was used in the United States from 1963 to 1968 and is therefore more commonly seen in adults.
141. How is measles diagnosed?
Measles IgM antibody requires only a single serum specimen and is diagnostic if positive. A capture IgM test is performed by the CDC. This test should be used to confirm every case of measles that is reported to have some other type of laboratory confirmation. It is important to note that in the first 72 hours after measles rash onset, up to 20% of tests for IgM may be negative. Tests that
are negative in the first 72 hours after rash onset should be repeated. PCR-based testing is also available through the CDC. A high index of suspicion is warranted in identifying measles, whether typical or atypical because many providers, especially those in training, are not likely to have seen cases during their career. This may change as outbreaks in the United States and Canada are becoming more common in the era of vaccine refusal.

CDC: Vaccines and Immunizations. http://www.cdc.gov/vaccines/pubs/pinkbook/meas.html#diagnosis. Accessed on Jan. 14, 2015.

142. Why is postmeasles blindness so common in underdeveloped countries?
Up to 1% of patients with measles in underdeveloped regions experience the progression of measles keratitis to blindness. By contrast, measles keratitis in developed countries is usually self-limited and benign. There are two principal reasons for the progression to blindness among patients with measles in underdeveloped countries:
• Vitamin A deficiency: Vitamin A is needed for corneal stromal repair, and a deficiency allows epithelial damage to persist or worsen. Many malnourished children have accompanying vitamin A deficiency, and vitamin A supplements are of benefit during active illness.
• Malnutrition: Malnutrition may predispose a patient to corneal superinfection with HSV.
143. How is measles treated?
No antiviral therapy exists for measles. Measles immune globulin has been shown to attenuate the disease if given within 6 days of exposure. It is recommended presently for infants <1 year of age (all infants <6 months or infants <1 year who have missed the window for vaccination), pregnant women without documentation of vaccination or immunity, and certain immunocompromised children.
Although the incidence of postmeasles blindness is minimal in the United States, the WHO does

recommend that vitamin A be given to all children with acute measles, regardless of their country of residence. Vitamin A is administered once daily for 2 days:
• 200,000 IU for children 12 months of age or older
• 100,000 IU for infants 6 through 11 months of age; and
• 50,000 IU for infants <6 months of age
An additional age-specific dose should be given 2 through 4 weeks later to children with
suspicion of vitamin A deficiency.
144. What are the most feared neurologic complications of measles?
• Acute encephalitis: Occurring in about 1 in every 1000 cases with permanent sequelae in a significant number of cases
• Subacute sclerosing panencephalitis: A rare progressive neurodegenerative CNS disease with seizures and intellectual deterioration that occurs on a delayed basis (average time of 11 years) following measles in unvaccinated children

Perry RT, Halsey NA: The clinical significance of measles: a review, J Infect Dis 189:S4–S16, 2004.

145. Which viruses comprise the human herpesviruses (HHV)?
HHV 1 & 2: herpes simplex virus (HSV-1 and HSV-2)
HHV 3: varicella-zoster virus (VZV) HHV 4: Epstein-Barr virus (EBV) HHV 5: cytomegalovirus (CMV) HHV 6: human herpesvirus-6
HHV 7: human herpesvirus-7
HHV 8: Kaposi sarcoma herpesvirus

All human herpesviruses share characteristics of virion morphology, basic mode of replication, and capacity for latent and recurrent infections. HSV-1, HSV-2, and VZV are alpha-herpesviruses with short reproductive cycles that establish latent infections, primarily in sensory ganglia. CMV, HHV-6, and HHV-7 are β-herpesviruses with longer reproductive cycles with latency in white blood cells (WBCs) and other tissues. EBV and HHV-8 are gamma-herpesviruses with specificity for either
T or B lymphocytes and latency in lymphoid tissue.

Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL: Herpesvirus infections of the nervous system, Nat Clin Pract Neurol
3:82–94, 2006.

146. What is the derivation of the word herpes?
Herpes comes from the Greek “herpein,” which means “to creep.” This describes the tendency of this group of infections both to have spreading cutaneous lesions and to have chronic, latent, or recurrent manifestations.

Beswick TSL: The origin and the use of the word herpes, Med Hist 6:214–232, 1962.

147. What are the typical features of roseola (exanthema subitum)?
Roseola occurs most commonly between ages 6 and 24 months. Most children have an abrupt onset of high fever (>39 °C) with no prodrome. Fever usually lasts 3 to 4 days but can range from 1 to 8 days. Within 24 hours of defervescence, a discrete erythematous macular or maculopapular rash appears on the face, neck, and/or trunk. Erythematous papules (Nakayama spots) may be noted on the soft
palate and the uvula in two-thirds of patients. Other common findings on examination include mild cervical lymph node enlargement and edematous eyelids. A variety of symptoms can accompany the fever, including diarrhea, cough, coryza, and headache.
148. What causes roseola? Multiple agents are implicated in the syndrome. Human herpesvirus 6 (HHV-6) was discovered in 1986, and in 1988, Japanese investigators isolated HHV-6 from four children with exanthema subitum.
In 1994, HHV-7 was also isolated from children with the clinical features of roseola. Roseola-like

illnesses are also noted with various echoviruses (including coxsackieviruses A and B), parainfluenza virus, and adenoviruses.

Caserta MT, Hall CB, Schnabel K, et al: Primary human herpesvirus 7 infection: a comparison of human herpesvirus 7 and human herpesvirus 6 infections in children, J Pediatr 133:386–389, 1998.

149. How common is human herpesvirus type-6 (HHV-6) infection in children? Infection with HHV-6 is ubiquitous and occurs with high frequency in infants, 65% of whom have serologic evidence of primary infection by their first birthday. Nearly all children are seropositive by
age 4 years. HHV-6 infection results in typical cases of roseola and is also associated with a number of other common pediatric problems, including “fever without localizing findings,” nonspecific rash, and EBV-negative mononucleosis. In a study by Hall and colleagues, up to one-third of all febrile seizures in children <2 years were the result of HHV-6 infections. On rare occasions, the virus has been associated with fulminant hepatitis, encephalitis, and a syndrome of massive lymphadenopathy
called Rosai-Dorfman disease. These manifestations are more common in immune-suppressed children, such as those who have received a bone marrow transplant. Reactivation is common and can also lead to graft-versus-host disease in this population.

Fule Robles JD, Cheuk DK, Ha SY, et al: Human herpesvirus types 6 and 7 infection in pediatric hematopoietic stem cell transplant recipients, Ann Transplant 19:269–276, 2014.
Hall CB, Long CE, Schnabel KC, et al: Human herpesvirus-6 infection in children, N Engl J Med 331:432–438, 1994.

150. What is the spectrum of disease caused by parvovirus B19?
• Erythema infectiosum (most common; a childhood exanthem, also called fifth disease or “slapped- cheek disease” because of the classic appearance of the rash)
• Papular-purpuric gloves and socks syndrome (self-limited condition of edematous plaques with petechial purpura over the palms and soles)
• Arthritis and arthralgia (most common in immunocompetent adults)
• Intrauterine infection with hydrops fetalis
• Transient aplastic crisis in patients with underlying hemolytic disease
• Persistent infection with chronic anemia in patients with immunodeficiencies
• No symptoms
151. Describe the characteristic rash of Rocky Mountain spotted fever (RMSF) from
Rickettsia rickettsii.
• Usually seen by day 3 of illness (5 to 11 days after tick bite), but may not appear until day 6
• Begins as blanching red macules and maculopapules, which evolve into petechiae in 1 to 3 days
• Begins on flexor surfaces of wrists and ankles and spreads to extremities, face, and trunk within hours
• As rash progresses, may become pigmented with areas of desquamation
• Involves palms and soles
Ten percent to 20% of patients do not develop a rash. Because of the relatively common lack of classic features and the importance of early treatment, RMSF should be considered in the differential diagnosis of any patient in an endemic area who presents with fever, myalgia, severe headache, nausea, and vomiting without rash. Presumptive empirical therapy can be begun pending diagnostic studies (biopsy or serology). The risk for death increases when therapy is delayed for more than 5 days.

Dantas-Torres F: Rocky Mountain spotted fever, Lancet Infect Dis 7:724–732, 2007.

152. Why is doxycycline recommended for all ages in patients with suspected RMSF? Alternatives for older individuals could include tetracycline or a fluoroquinolone, but doxycycline is advised even in younger patients for the following reasons:
• Tetracycline at the recommended dose is associated with dental staining in children <8 years.
• Doxycycline at the recommended dose is unlikely to cause dental staining in younger children.
• Doxycycline is also effective against ehrlichiosis, which can mimic RMSF.

• Fluoroquinolones may cause cartilage damage in juvenile animal models, and their use is not recommended for children for this indication.
• Chloramphenicol, an alternative that has been used in the past, may have serious adverse effects (e.g., aplastic anemia), no oral preparation is available in the United States, and it may be less effective for RMSF than doxycycline.

American Academy of Pediatrics: Rickettsial diseases. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 620–625.
Lochary ME, Lockhart PB, Willliams WT Jr: Doxycycline and staining of permanent teeth, Pediatr Infect Dis J
17:429–431, 1998.

153. How long after exposure to chickenpox (varicella) do symptoms develop?
Ninety-nine percent of patients develop symptoms between 11 and 20 days after exposure.
154. What is the risk for varicella-associated complications in normal children 1 to 14 years old?
The most common complications of VZV infection include secondary bacterial skin infections (generally due to streptococci or staphylococci), neurologic syndromes (cerebellitis, encephalitis, transverse myelitis, and Guillain-Barré syndrome), and pneumonia. Thrombocytopenia, arthritis, hepatitis, and glomerulonephritis occur less commonly. Myocarditis, pericarditis, pancreatitis, and orchitis are described but are rare.
The frequency of these complications in normal children is not precisely known, but it is estimated to be low on the basis of hospitalization and mortality data. Before the introduction of the varicella vaccine in 1995, about 4 million cases of chickenpox occurred in the United States each year, resulting in roughly 10,000 hospitalizations and 100 deaths. Since the introduction of routine immunization against varicella, rates of infection have decreased by more than 95%.

Watson B: Varicella: a vaccine preventable disease—a review, J Infect 44:220–225, 2002.

155. How common are second episodes of varicella after natural infection? About 1 in 500 cases involve a second episode. These are more likely to occur in children who develop their first episode during infancy or whose first episode is subclinical or very mild.

Gershon A: Second episodes of varicella: degree and duration of immunity, Pediatr Infect Dis J 9:306, 1990.

156. What is herpes zoster?
Reactivated varicella-zoster virus infection (VZV). After the primary infection of chickenpox, the virus establishes a latent infection in the dorsal root ganglion. When reactivation occurs, the virus spreads to the skin through nerves, and a typical vesicular pattern along dermatomal lines occurs (Fig. 10-9). In its primary form, the infection is varicella; in its recurrent form, it is zoster and in common parlance is known as shingles. Varicella is also known as human herpesvirus 3 (HHV-3) and is one of 9 distinct herpes viruses known to cause disease in humans. This has led to the rather confusing name of herpes zoster for the reactivated varicella zoster virus.
157. In children with herpes zoster, what is the distribution of the rash?
Compared with adults, children have relatively more cervical and sacral involvement with resultant extremity and inguinal lesions:
• 50% thoracic
• 20% cervical
• 20% lumbosacral
• 10% cranial nerve If there are lesions on the tip of the nose, herpes zoster keratitis is more likely because of possible
involvement of the nasociliary nerve. When the geniculate ganglion is involved, there is risk for developing the Ramsay Hunt syndrome, which consists of ear pain with auricular and periauricular vesicles and facial nerve palsy.

Feder HM Jr, Hoss DM: Herpes zoster in otherwise healthy children, Pediatr Infect Dis J 23:451–457, 2004.

Figure 10-9. Herpes zoster with distribution along the S1 dermatome. (From Lissauer T, Clayton G: Illustrated Textbook of Pediatrics, ed 2. London, 2001, Mosby, p 193.)

158. Is it possible to get herpes zoster after the varicella vaccine?
Yes. Varicella is a live vaccine, and there was initial concern about how the live, attenuated vaccine strain would act in terms of development of subsequent zoster infection. Zoster is difficult to study because there is a long latent period between acquisition of varicella and development of zoster.
However, cohort studies have shown a decreased risk in children of certain age groups, as well as adults, after childhood immunization with the varicella vaccine versus those infected with the wild-type virus. In adults, the use of a live-attenuated VZV vaccine has been shown to be effective in reducing the incidence and burden of herpes zoster and postherpetic neuralgia.

Adams EN, Parnapy S, Bautista P: Herpes zoster and vaccination: a clinical review, Am J Health Syst Pharm 67:724– 727, 2010.
Civen R, Chaves SS, Jumaan A, et al: The incidence and clinical characteristics of herpes zoster among children and adolescents after implementation of varicella vaccination, Pediatr Infect Dis J 11:954–959, 2009.
Hambleton S, Steinberg SP, Larussa PS, et al: Risk of herpes zoster in adults immunized with varicella vaccine, J Infect Dis 197: S196–S199, 2008.

159. Should chickenpox be treated with an antiviral medication? Neither oral acyclovir nor valacyclovir is recommended for routine use in otherwise healthy children with varicella. Early administration after onset of rash results in only a modest decrease in symptoms as antiviral drugs have a limited window of opportunity for efficacy. In immunocompetent hosts, most virus replication has stopped by 72 hours after onset of rash. By the time the disease is recognized, this window is usually passed. Oral acyclovir or valacyclovir may be considered for people at increased risk of moderate
to severe varicella, such as unvaccinated people >12 years of age; children with severe eczema; children receiving long-term salicylate therapy; and people receiving short, intermittent, or inhaled courses of
corticosteroids. IV acyclovir instead of oral acyclovir or valacyclovir is recommended for immunocompromised patients such as children receiving chemotherapy and patients being treated with chronic corticosteroids. Varicella-zoster immune globulin (or IVIG if this product is not available) can prevent or modify the course of disease if given up to 10 days after exposure and is indicated in certain situations such as
• Immunocompromised children without evidence of immunity
• Pregnant women without evidence of immunity
• Newborn infant whose mother had onset of chickenpox within 5 days before delivery or within 48 hours after delivery
• Hospitalized preterm infant (28 weeks or more of gestation) whose mother lacks evidence of immunity against varicella

• Hospitalized preterm infants (<28 weeks of gestation or birth weight 1000 g or less), regardless of maternal immunity
Treatment with immune globulin is not effective after clinical disease is diagnosed.

Updated Recommendations for Use of VariZIG — United States, 2013: www.cdc.gov/mmwr/preview/mmwrhtml/ mm6228a4.htm. Accessed on January 14, 2015.
American Academy of Pediatrics: Varicella-zoster infections. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 777–782.

160. Should healthy children with zoster be treated with antiviral medications?
Routine antiviral therapy is not indicated. In general, the prognosis for children with herpes zoster is very good with extremely low probabilities of postherpetic neuralgia.

161. Who gets herpes gladiatorum? Herpes gladiatorum is a term used to describe ocular and cutaneous infection with HSV-1, which occurs in wrestlers and rugby players. The infection is transmitted primarily by direct skin-to-skin contact and is endemic among high school and college wrestlers.

162. What is eczema herpeticum?
Eczema herpeticum (Fig. 10-10) is an extensive cutaneous vesicular eruption that arises from primary infection or reactivation of HSV in those with preexisting skin disease, usually atopic dermatitis (AD). HSV type 1 is the most common pathogen. To further confuse the herpes nomenclature, eczema herpeticum is also known as a form of Kaposi varicelliform eruption, which is a unique skin condition that occurs with viral infections such as HSV or coxsackievirus in those with AD or other underlying dermatologic disease. It is often difficult to distinguish from bacterial superinfection, and in fact, may coexist with a superficial S. aureus infection.

Figure 10-10. Eczema herpeticum. Note the monomorphic punched-out ulcers or vesicopustules within eczematous plaques.
(From Wolter S, Price HN: Atopic dermatitis, Pediatr Clin North Am 61:247, 2014.)

163. What is hand-foot-and-mouth disease?
Hand-foot-and-mouth disease is an illness that is caused most commonly by coxsackie A viruses (especially A16) or enterovirus 71. It is associated with a petechial or vesicular exanthem involving the hands, the feet, and the oral mucosa in the posterior pharynx. Despite its name, it can also affect the buttocks in young children.
164. What is the spectrum of disease caused by enterovirus?
Besides the classic hand-foot-and-mouth disease, enterovirus may manifest as:
• Upper respiratory tract disease
• Coryza, herpangina
• Lower respiratory tract illness
• Pneumonia

• Gastrointestinal illness
• Vomiting, diarrhea, and hepatitis
• Rarely pancreatitis, orchitis
• Systemic disease
• Noted especially in neonates, who may present with an overwhelming sepsislike syndrome
• Neurologic disease
• Meningitis, encephalitis, limb paralysis
• Myocarditis
165. Why do real-time PCR positive test results indicate both “rhinovirus/enterovirus”? Rhinovirus and enterovirus produce clinical syndromes that are distinct, although there generally may be some degree of overlap. However, both viruses are picornaviruses and are classified within the same genus. They share an identical genomic organization and have similar functional RNA secondary structures. As of now, commercially available diagnostics such as the RT-PCR are unable to distinguish between the two.

INFLUENZA
166. What is the difference between an epidemic, an outbreak, and a pandemic?
• Epidemic: Incident cases of an illness (or other health-related events, such as drownings) in a community or region, clearly in excess of normal expectancy
• Outbreak: An epidemic limited to a localized increase in the incidence of a disease (e.g., in a town or closed institution), also clearly in excess of normal expectancy
• Pandemic: An epidemic that has spread across a large region (e.g., multiple continents)
167. What are the types of influenza viruses?
• Influenza A infects many species, including humans, pigs, horses, and birds. It is subtyped on the basis of two surface glycoprotein antigens: hemagglutinin (H), of which there are 18 different subtypes, and neuraminidase (N), of which there are 11 different subtypes. The subtypes can be further divided into strains; for example, the H1N1 virus developed into a new strain in 2009, replacing the H1N1 strain that had previously caused disease in humans. This new strain was responsible for the 2009 H1N1 pandemic.
• Influenza B infects only humans. The disease is generally less severe than influenza A. The virus is not subtyped, but is broken down into lineages and strains.
• Influenza C causes very mild disease and has limited public health significance. The influenza vaccine does not protect against influenza C.
168. What are the functions of hemagglutinin and neuraminidase?
Hemagglutinin is a glycoprotein necessary for the initiation of infection because it allows viral binding to sialic acid residues on the respiratory epithelial cells. Progeny virions result after viral replication and bind to the epithelial cells. Neuraminidase cleaves sialic acid residues, which permits release of progeny virions into the respiratory tree.
169. What clinical features typically distinguish an infection with an influenza virus from the common cold?
See Table 10-5.
170. What is the difference between “antigenic shift” and “antigenic drift”?
• Antigenic drift: A subtle change in the hemagglutinin or neuraminidase gene caused by a point mutation or deletion results in a new strain that requires yearly reformulation of the seasonal influenza vaccine.
• Antigenic shift: This occurs much less frequently than antigenic drift (occurring only in influenza A) and involves a profound change in the virus with a new hemagglutinin or neuraminidase type produced, possibly from another species. For example, simultaneous infection of a host with a human and avian influenza strain can result in genetic reassortment and a novel virus.
171. What made the influenza A H1N1 pandemic strain of 2009 so novel?
The influenza A H1N1 strain caused a worldwide pandemic problem that began in early 2009. This strain was a quadruple reassortment of an influenza A virus involving two swine strains, one

Table 10-5 Influenza Versus Cold Symptoms
SIGNS AND SYMPTOMS INFLUENZA COLD
Onset Sudden Gradual
Fever >38.3 °C (101 °F) lasting >3 days Rare
Cough Can become severe Less common
Headache Prominent Rare
Myalgia Severe Slight
Fatigue Fatigue lasting >1 wk Mild
Extreme exhaustion Early and prominent Rare
Chest discomfort Common Mild
Stuffy nose Sometimes Common
Sneezing Sometimes Common
Sore throat Sometimes Common
From Meissner HC: Reducing the impact of VIRAL respiratory infections in children, Pediatr Clin North Am 52:700, 2005.

human strain, and one avian strain, which likely recombined through pigs as an intermediate mammalian host. Components of the 2009 pandemic virus are thought to have derived from the 1918 influenza pandemic. Transmissibility rates were extremely high.

Zimmer SM, Burke DS: Historical perspective—emergence of influenza A (H1N1) viruses, N Engl J Med
361:279–285, 2009.
Morens DM, Taubenberger JK, Fauci AS: The persistent legacy of the 1918 influenza virus, N Engl J Med
361:225–229, 2009.
Centers for Disease Control and Prevention: H1N1 Flu. www.cdc.gov/h1n1flu/cdcresponse.htm. Accessed on Jan 14, 2015.

172. Which patients should not receive the live-attenuated influenza vaccine?
Contraindications are:
• <2 years or >49 years
• Pregnant women/teens
• Children who have experienced severe allergic reactions to the vaccine or any of its components, or to a previous dose of any influenza vaccine
• Children in close contact with severely immune suppressed persons
• Patients taking salicylates
• Those with a known or suspected immunodeficiency
• Those with a history of egg allergy
• Those who have received a live viral vaccine within past 4 weeks
• Children aged 2 through 4 years who have asthma or who have had a wheezing episode by any history within the past 12 months
Strong precautions to use include the following:
• Children with other conditions considered high risk for severe influenza (chronic pulmonary or cardiac disorders, pregnancy, chronic metabolic disease, renal dysfunction, hemoglobinopathies, or immunosuppressive therapy)
• Children 5 years of age with asthma
• Nasal congestion that could impede vaccine delivery
• A history of Guillain-Barré syndrome
• Moderate to severe febrile illness

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) — United States, 2014–15 Influenza Season:

www.cdc.gov/mmwr/preview/mmwrhtml/mm6332a3.htm#Groups_Recommended_Vaccination_Timing_Vaccination. Accessed on Jan. 14, 2015.
American Academy of Pediatrics: Influenza. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 445–453.

173. What are the main antiviral medications used as treatment for influenza?
• Neuraminidase inhibitors: Oseltamivir (oral) and zanamivir (inhaled) prevent release of virions from the host cell. These agents are used against influenza B and A, including pandemic H1N1.
• Adamantanes (M2 inhibitors): Amantadine and rimantadine target the M2 protein of influenza A, which is involved in ion channels of viral membrane essential for viral replication.

Moscona A: Neuraminidase inhibitors for influenza, N Engl J Med 353:1363, 2005.

174. Does influenza display resistance to antiviral medications?
Yes. The adamantanes are not effective against influenza B viruses because of the difference in ion channel structure. These drugs are also not effective against the H3N2 and the 2009 H1N1 epidemic strain. The majority of these viruses contained a single amino acid substitution in the M2 protein, which conferred adamantane resistance. The H1N1 strain before 2009 (i.e., not the pandemic strain) did have a mutation causing a histidine to tyrosine substitution in neuraminidase, making a proportion of these strains resistant to neuraminidase inhibitors. However, this mutation (as are other resistance mechanisms) is sporadic and rare in the pandemic and other recent seasonal strains.
Fortunately, the majority of influenza A and B isolates remain susceptible to oseltamivir.

Hurt AC: The epidemiology and spread of drug resistant human influenza viruses, Curr Opin Virol 8:22–29, 2014.

175. What are the indications for antiviral medications for influenza in children?
• Any child who is hospitalized or has severe or complicated illness
• Children <2 years of age
• Immunosuppressed children
• Children with conditions considered high risk for severe influenza: asthma, cardiac disorders, chronic metabolic disease, renal dysfunction, hemoglobinopathies
• Children who are taking salicylates
• Pregnant women/teens
• Residents of chronic care facilities
• Children with neurologic or neuromuscular disorders
Ideally, antiviral therapy is initiated with 48 hours of symptom onset, but it may still be of some benefit if given at <5 days. An important point of emphasis is that initiation of therapy should not wait for confirmation of diagnosis, especially in high-risk or ill individuals. First-line therapy is oseltamivir.

Centers for Disease Control and Prevention: Antiviral drugs. www.cdc.gov/flu/professionals/antivirals/index.htm. Accessed on Mar. 24, 2015.

176. What complications can be associated with influenza infections? Death due to exacerbation of an underlying medical condition or invasive coinfection from a secondary bacterial pathogen including bacterial pneumonia from S. aureus, including methicillin-resistant S. aureus (MRSA), S. pneumoniae, or group A streptococci.
Also:
• Otitis media
• Myositis (particularly with influenza B)
• Febrile seizures
• Encephalitis, encephalopathy
• Reye syndrome
• Guillain-Barré syndrome
• Transverse myelitis
• Myocarditis, pericarditis

Mistry RD, Fischer JB, Prasad PA, et al: Severe complications in influenza-like illnesses, Pediatrics 134:e684–e690, 2014. Wong KK, Jain S, Blanton L, et al: Influenza-associated pediatric deaths in the United States, 2004–2012, Pediatrics 132:796–804, 2013.

177. What bacterial coinfection is most commonly identified in influenza-associated pediatric deaths?
Methicillin-resistant S. aureus (MRSA). In children in the United States, most deaths associated with influenza tend to result either from an exacerbation of an underlying medical condition or invasive coinfection from another pathogen. As the percentage of children colonized with MRSA has increased, this bacterium has assumed a greater role in coinfecting lungs after the influenza virus has damaged the tracheobronchial tree. In a child with a suspected secondary pneumonia during influenza season, coverage for a possible MRSA infection should be considered.

Wong KK, Jain S, Blanton L, et al: Influenza-associated pediatric deaths in the United States, 2004–2012, Pediatrics
132:796–804, 2013.
Finelli L, Fiore A, Dhara R, et al: Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection, Pediatrics 122:805–811, 2008.

LYMPHADENITIS AND LYMPHADENOPATHY
178. What are the most common causes of acute and chronic lymphadenitis in normal, otherwise healthy children?
S. aureus and Streptococcus pyogenes (group A streptococci) account for more than 80% of cases of acute lymphadenitis, while nontuberculous mycobacteria and Bartonella henselae (cat-scratch disease) are the most common causes of chronic lymphadenitis.
179. What infectious etiology should be considered in a toddler with an intensely erythematous but minimally tender submandibular or anterior-superior cervical node?
Nontuberculous mycobacterial infection (NTM) manifests as a group of nodes, which can increase in size, coalesce, and eventually spontaneously rupture to form sinus tracts.
180. How is the diagnosis of NTM disease made?
Definitive diagnosis of NTM infection depends on culture and isolation of the organism from infected tissue. Cultures must be sent specifically for mycobacteria to ensure appropriate processing.
Histopathologic examination of the tissue cannot adequately differentiate NTM infection from tuberculosis. PCR-based technology is being validated for NTM.
181. How is NTM lymphadenitis treated? Most experts recommend excision of the infected lymph node. Clarithromycin, rifampin, and ethambutol are effective against many strains of nontuberculous mycobacteria and are generally used when excision is incomplete because of nearby nervous tissue or vascular structures, when surgery is contraindicated, or for recurrent disease. Medical therapy is often prolonged. Organisms can display and develop resistance patterns thatmaybedifficulttomanage medically. Some experts haveproposed“observation” therapy if this is tolerable to the family and patient because the majority of isolated lesions will regress without treatment.

Zeharia A, et al: Management of nontuberculous mycobacteria-induced cervical lymphadenitis with observation alone,
Pediatr Infect Dis J 27:920–922, 2008.
Haverkamp M, et al: Nontuberculous mycobacterial infection in children: a 2-year prospective surveillance study in the Netherlands, Clin Infect Dis. 39:450–456, 2004.

182. What infectious etiology should be considered in a child with swollen, tender axillary nodes?
Cat-scratch disease. This entity is caused by B. henselae, which is a fastidious, slow-growing, gram- negative bacillus rarely grown in culture. Thus, diagnosis is usually made by serologic or PCR tests. This organism is found in the oral flora of kittens, cats, and occasionally dogs.
183. What is the typical course of the lymphadenitis in cat-scratch disease? An otherwise healthy child or adolescent presents with symptoms of regional lymphadenopathy that begin 1 to several weeks after a scratch (unrecalled by many patients). The lymph nodes are usually

moderately tender and are associated with overlying erythema and fluctuance. About 10% to 30% eventually suppurate. The lymph nodes most commonly involved are axillary and cervical, but epitrochlear, submandibular, inguinal, and preauricular nodes may be enlarged. Enlarged pectoral nodes are highly suggestive of cat-scratch disease. Fever is usually absent or low grade, but temperatures as high as 40°C have been described in 30% to 50% of cases. Infected nodes generally spontaneously resolve without specific therapy. Treatment with 5 days of antibiotics (including azithromycin, ciprofloxacin, trimethoprim-sulfamethoxazole, rifampin, or gentamicin) may speed recovery, and excision of the infected nodes is not recommended. Treatment with antimicrobial therapy is recommended for severely ill or immunocompromised individuals.

Klotz SA, Ianas V, Elliott SP: Cat-scratch disease, Am Fam Physician 83:152–155, 2011. English R: Cat-scratch disease, Pediatr REV 27:123–127, 2006.

184. What are other manifestations of cat-scratch disease in addition to lymphadenopathy?
In 20% to 25% of cases, other manifestations may occur including Parinaud oculoglandular syndrome (conjunctivitis, ipsilateral preauricular lymphadenopathy), prolonged fever of unknown origin, encephalitis, osteolytic bone lesions, neuroretinitis, visceral organ involvement (especially hepatosplenic), and erythema nodosum. This organism has also been associated with bacillary angiomatosis (a vascular proliferative disorder with cutaneous and visceral forms) and peliosis hepatitis (a vascular disorder with cystic blood-filled cavities in the liver parenchyma), both of which occur primarily in adults with HIV infection.
185. What are the presentations of Epstein-Barr virus (EBV) infection?
Young children with EBV infection are frequently asymptomatic. In adolescents and young adults, infection typically results in infectious mononucleosis, which is characterized as follows:
• Clinical: Fever, pharyngitis, lymphadenopathy (75% to 95%), splenomegaly (50%)
• Hematologic: More than 50% mononuclear cells, more than 10% atypical lymphocytes
A wide variety of symptoms (e.g., malaise, headache, anorexia, myalgias, chills, nausea) can occur. Neurologic presentations are rare but can include encephalitis, meningitis, myelitis, Guillain-Barré syndrome, and cranial or peripheral neuropathies.
EBV is also associated with posttransplant lymphoproliferative disorder, Burkitt lymphoma, nasopharyngeal carcinoma, and undifferentiated T- and B-cell lymphomas.
186. How was the monospot test developed?
In 1932, Paul and Bunnell observed that patients with infectious mononucleosis make antibodies that agglutinate sheep RBCs. These antibodies are referred to as heterophil antibodies and serve as the basis for the monospot test, which is a rapid slide agglutination test. Today, horse or beef RBCs are usually used because they are more sensitive to agglutination than are sheep RBCs. Heterophil antibodies can also occur in serum sickness and as a normal variant. If there is clinical confusion, differential absorption can pinpoint the cause. Heterophil antibodies in infectious mononucleosis do not react with guinea pig kidney cells, whereas those of serum sickness do. Normal variant heterophil antibodies do not react with beef RBCs.

Durbin WA, Sullivan JL: Epstein-Barr virus infections, Pediatr REV 15:63–68, 1994.

187. What is the natural course of serologic responses to EBV infection?
Serologic responses to viral components, including viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA), occur in a characteristic time frame (Fig. 10-11) and can assist in distinguishing possible acute from past infections. Acute infection is best characterized by the presence of high titers of VCA IgM or IgG with or without high titers of EA and with no or low titers of EBNA.

188. When are steroids indicated for children with EBV infection?
Among patients with acute EBV infection, steroids should NOT be considered for treatment of uncomplicated mononucleosis. Steroids are indicated for treatment of impending respiratory obstruction as a result of enlarged tonsils, autoimmune hemolytic anemia, aplastic anemia, neurologic disease, and severe life-threatening infection (e.g., liver failure).

Primary infection Convalescent serology

640
320
160
80
40
20

0

VCA-lgM EA

VCA-lgG

EBNA

High

Medium

Low

Weeks Months
Time following onset of illness
Figure 10-11. Idealized time course for antibody responses to various EBV antigens after primary infection with the virus. EA, Early antigen; EBNA, Epstein-Barr nuclear antigen; IgG, immunoglobulin G; IgM, immunoglobulin M; VCA, viral capsid antigen. (From Katz BZ: Epstein-Barr VIRUS (mononucleosis and lymphoproliFERATIVE disorders. In Long SS, editor: Principles and Practice of Pediatric Infectious Disease, ed 4. Philadelphia, 2012, ELSEVIER, p 1062.)

189. What are the clinical presentations of acquired CMV infection?
In normal hosts who develop symptomatic acquired CMV infection, clinical manifestations include fever, malaise, and nonspecific aches and pains. The peripheral blood smear reveals an absolute lymphocytosis and many atypical lymphocytes. In contrast with EBV-infectious mononucleosis, exudative pharyngitis is not prominent. Liver involvement is very common, and liver function tests are usually abnormal. Like EBV disease, CMV mononucleosis can persist for several weeks.

190. What is the most common form of tularemia?
Ulceroglandular. Seventy-five percent of cases of tularemia are ulceroglandular. Three to 5 days (range, 1 to 21 days) after exposure, fever, myalgia, headaches, muscle soreness, and regional lymphadenopathy develop. The original lesion is a papule, which ulcerates. Bacteremia may result in multiorgan involvement.

Eliasson H, Broman T, Forsman M, et al: Tularemia: current epidemiology and disease management, Infect Dis Clin North Am 20:289–311, 2006.

191. What vectors are commonly associated with tularemia?
Francisella tularensis (the causative agent of tularemia) is a zoonotic infection caused by contact with infected animals (rabbits, deer, and muskrats) or invertebrate vectors (ticks). Streptomycin, gentamicin, tetracyclines, chloramphenicol, and fluoroquinolones have been shown to be effective therapy for tularemia.
192. Which other organisms can cause a mononucleosis-like clinical picture? Toxoplasma gondii, HHV-6, adenovirus, acute HIV infection, group A streptococcal infection, hepatitis B, and rubella.

193. Why is it called “mononucleosis”?
This refers to the tendency of certain infections, primarily EBV, to cause the development of morphologically abnormal lymphocytes (which may resemble monocytes), mainly from CD8 + T cells that respond to infection. These atypical cells can account for up to 30% of the WBC count.
Atypical lymphocytes may also be present in a host of illnesses including B. henselae, babesiosis, tuberculosis, lymphoma and leukemia, and pertussis.

MENINGITIS
194. What are the most common signs and symptoms of meningitis in infants
< 2 months?
The findings of meningitis among neonates and young infants are often subtle. Temperature instability
(fever is more common in full-term infants while hypothermia is more common in preterm infants) occurs in about 60% of infected infants. Neurologic symptoms including irritability, poor tone, and lethargy are noted in 60% of infants with meningitis. Seizures may be the presenting symptom in 20% to 50% of cases. Poor feeding or vomiting can occur as well. On physical examination, about 25% of newborns and young infants have a bulging fontanel. Only 13% have nuchal rigidity. Thus, the diagnosis of meningitis cannot be excluded in infants on the basis of the absence of these physical findings.

Pong A, Bradley JS: Bacterial meningitis and the newborn infant, Infect Dis Clin North Am 13:711–733, 1999.

195. What percentage of neonates <30 days of age with bacterial sepsis and positive blood cultures have meningitis?
As many as 20% of such infants will have culture-confirmed meningitis. Conversely, >30% of all infants evaluated for sepsis with negative blood cultures may have meningitis. This is especially notable in low- birth-weight infants.

Garges HP, Moody MA, Cotton CM, et al: Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics 117:1094–1100, 2006.
Stoll BJ, Hansen N, Fanaroff AA, et al: To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants, Pediatrics 113:1181–1186, 2004.

196. What is the most common cause of viral meningitis?
More than 80% of infectious cases are caused by enteroviruses (i.e., coxsackievirus, enterovirus, and echovirus).
197. What is the diagnostic test of choice for enteroviral meningitis?
Enteroviruses can be diagnosed by PCR testing, which is rapid, sensitive, and specific.
198. What are common arthropod-borne viral causes of meningoencephalitis in the United States? Several arboviruses can cause meningoencephalitis including the LaCrosse virus; Powassan virus; West Nile virus; and the St. Louis, Eastern, and Western equine encephalitis viruses; and the Japanese encephalitis virus. Human infections are most common in the summer and fall when mosquito and tick activity are highest. West Nile virus is an increasingly common cause of aseptic meningitis and meningoencephalitis, especially in the late summer and early fall. Mosquitoes are the primary vector, with a variety of birds (e.g., crows, jays, sparrows) known to serve as hosts. Significant avian mortality is often the first sign of significant West Nile virus activity in a locale. Non–vector-borne transmission (e.g., contaminated blood products, organ transplantation) has been described. Many state health departments and commercial laboratories have PCR-based tests to diagnose these infections.

Lanteri MC, Lee TH, Kaidarova Z, et al: West Nile virus nucleic acid persistence in whole blood months after clearance in plasma: implication for transfusion and transplantation safety, Transfusion 54:3232–3241, 2014.
American Academy of Pediatrics: Arboviruses In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Park, IL, 2012, American Academy of Pediatrics, pp 232–235.

199. Should computed tomography (CT) scans be performed before an LP during the evaluation of possible meningitis?
Cranial imaging is not routinely indicated before LP, unless one of the following is present:
• Signs of herniation (rapid alteration of consciousness, abnormalities of pupillary size and reaction, absence of oculocephalic response, fixed oculomotor deviation of eyes)
• Papilledema
• Abnormalities in posture or respiration
• Generalized seizures (especially tonic), which are often associated with impending cerebral herniation

• Overwhelming shock or sepsis, possibly precluding the procedure
• Concern about a condition mimicking bacterial meningitis (e.g., intracranial mass, lead intoxication, tuberculous meningitis)

Tunkle AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis, Clin Infect Dis
39:1267–1284, 2004.
Haslam RH: Role of CT in the early management of bacterial meningitis, J Pediatr 119:157–159, 1991.

200. What is the range of normal parameters for CSF in infants and children who do not have meningitis?
• Term newborn infants: WBC count, 0 to 20/mm3; protein, 30 to 100 mg/dL; glucose, 30 to 120 mg/dL
• Infants and children: WBC count, 0 to 9/mm3; protein, 20 to 40 mg/dL; glucose, 40 to 80 mg/dL

Kestenbaum LA, Ebberson J, Zorc JJ, et al: Defining cerebrospinal fluid white blood cell count reference values in neonates and young children, Pediatrics 125:257–264, 2010.
Mann K, Jackson A: Meningitis, Pediatr REV 29:425, 2008.

201. If bloody CSF is collected during LP, how is CNS hemorrhage distinguished from a traumatic artifact?
Most often, the blood is a result of the traumatic rupture of small venous plexuses that surround the subarachnoid space, but pathologic bloody fluid can be seen in multiple settings (e.g., subarachnoid hemorrhage, herpes simplex encephalitis). Distinguishing features that suggest pathologic bleeding include the following:
• Bleeding that does not lessen during the collection of multiple tubes
• Xanthochromia of the CNS supernatant
• Crenated RBCs noted microscopically
202. How is a traumatic LP interpreted?
A “bloody tap” is a common result of an unsuccessful LP. Numerous formulas have been devised to adjust leukocyte totals in blood-contaminated CSF to determine whether CSF pleocytosis (and thus possible meningitis) is present. However, no formulas in neonates or older children have been useful to guide clinical decisions about bacterial meningitis.

Greenberg RG, Smith PB, Cotten CM, et al: Traumatic lumbar punctures in neonates, Pediatr Infect Dis J 27:1047– 1051, 2008.
Bonsu BK, Harper MB: Corrections for leukocytes and percent of neutrophils do not match observations in blood- contaminated cerebrospinal fluid and have no value over uncorrected cells for diagnosis, Pediatr Infect Dis J 25:8– 11, 2006.

203. What is the best way to position the patient for an LP?
Some studies have shown increase in successful LPs in the sitting position with flexed hips, both in children and neonates, compared with the lateral flexed position (although the latter is more commonly practiced in the United States). Data obtained through measurements using ultrasound have shown that the interspinous space may increase in this position, leading to a higher likelihood of entering the appropriate space. Since the diameter of a 1.5 inch, 22-guage needle is 0.7 mm, even a small difference of 1 to 2 mm in those spaces could contribute to increased success. Data are conflicting whether differences occur in the subarachnoid space between the sitting and lateral flexed positions. Measurement of oxygenation levels via pulse oximetry for preterm infants in the sitting versus lateral knee-flexed positions during a LP have found better oxygenation in the sitting flexed position, which also suggests that this position might be better tolerated and potentially safer for the infant.

Hanson AL, Ros S, Soprano J: Analysis of infant lumbar puncture success rates: sitting flexed versus lateral flexed positions, Pediatr Emerg Care 30:311–314, 2014.
Oulego-Erroz I, Mora-Matilla M, Alonso-Quintela P, et al: Ultrasound evaluation of lumbar spine anatomy in newborn infants: implications for optimal performance of lumbar puncture, J Pediatr 165:862–865, 2014.
Gleason CA, Martin RJ, Anderson JV, et al: Optimal position for a spinal tap in preterm infants, Pediatrics 71:31–35, 1983.

204. How do the CSF findings vary in bacterial, viral, fungal, and tuberculous meningitis in children beyond the neonatal period?
A large overlap in parameters for meningitis caused by different pathogens is possible. For example, bacterial meningitis can be associated with a low WBC count early in the illness, or viral meningitis can be associated with a persistent dominance of neutrophils. The usual findings are summarized in Table 10-6.

Table 10-6 Typical Findings in Bacterial, Viral, Fungal, and Tuberculous Meningitis
CEREBROSPINAL FLUID FINDINGS
BACTERIAL
VIRAL FUNGAL, TUBERCULOUS
White blood cells per mm3 >500 <500 <500
Polymorphonuclear neutrophils >80% <50% <50%
Glucose (mg/dL) <40 >40 <40
Cerebrospinal fluid–to-blood ratio <30% >50% <30%
Protein (mg/dL) >100 <100 >100

205. What CSF indices help in the diagnosis of bacterial versus viral meningitis?
In the absence of culture data, there is no way one can differentiate bacterial from viral meningitis with certainty. In a study that derived prediction rules for children to determine which group of patients with CSF pleocytosis was most likely to have bacterial rather than viral meningitis, 5 high-risk criteria were defined. If all were absent, 100% of children did not have bacterial meningitis
(100% negative-predictive value).
• CSF Gram stain positive
• CSF absolute neutrophil count (ANC) >1000 cells/μL
• CSF protein >80 mg/dL
• Peripheral blood ANC >10,000 cells/μL
• Seizure at or before presentation

Nigrovic LE, Malley R, Kuppermann N: Cerebrospinal fluid pleocytosis in children in the era of bacterial conjugate vaccines,
Pediatr Emerg Care 25:112–120, 2009.

206. When is the best time to obtain a serum glucose level in an infant with suspected meningitis?
Because the stress of an LP can elevate serum glucose, the serum sample is ideally obtained just before the LP. When the blood glucose level is elevated acutely, it can take at least 30 minutes before the blood glucose equilibrates with that of the CSF.
207. Does antibiotic therapy before LP affect CSF indices?
Many children with presumptive meningitis are begun on antibiotic therapy before an LP often because a delay in performing the LP is anticipated. Prior administration of antibiotics does increase the likelihood of falsely negative CSF cultures in patients with bacterial meningitis. Similarly, the CSF Gram stain will still demonstrate bacteria with typical staining properties. Prior antibiotic use decreases the CSF protein concentration and increases the CSF glucose concentration. However,
it does not substantially affect the CSF WBC or CSF ANC counts.

Nigrovic LE, Malley R, Macias CG, et al: Effect of antibiotic pretreatment on cerebrospinal fluid profiles in children with bacterial meningitis, Pediatrics 122:726–730, 2008.
Nigrovic LE, Kuppermann N, McAdam AJ, Malley R: Cerebrospinal latex agglutination fails to contribute to the microbiologic diagnosis of pretreated children with meningitis, Pediatr Infect Dis J 23:786–788, 2004.

208. How quickly is the CSF sterilized in children with meningitis? Data are limited, and trial data are obviously not tenable. In successful therapy, the CSF is usually sterile within 36 to 48 hours of the initiation of antibiotics. In patients with meningococcal meningitis, CSF is typically completely sterile within 2 hours after starting treatment. With other organisms such as

pneumococcus, the time until sterilization is generally at least 4 hours. In neonates the CSF may sterilize more slowly. Furthermore, absence of a positive culture in CSF obtained from the lumbar subarachnoid space does not exclude a positive culture from ventricles.

Kanegaye JT, Soliemanzadeh P, Bradley JS: Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment, Pediatrics 108:1169–1174, 2001.

209. What are the most common organisms responsible for bacterial meningitis in the United States?
0 to <1 month old:
• GBS (Streptococcus agalactiae)
• E. coli (if presents after first week of life, galactosemia should be excluded)
• Miscellaneous Enterobacteriaceae
• Listeria monocytogenes (rare)
• Streptococcus pneumoniae (rare)
• S. aureus (in hospitalized preterm infants)
• Coagulase-negative staphylococci (in hospitalized preterm infants)
1 to <3 months old
• GBS
• Gram-negative bacilli
• S. pneumoniae
• Neisseria meningitidis
3 months to <3 years
• S. pneumoniae
• N. meningitidis
• GBS
• Gram-negative bacilli (including E. coli and H. influenzae)
3 to 10 years old
• S. pneumoniae
• N. meningitidis
10 to 18 years old
• N. meningitidis
Before the development of conjugate vaccines for important bacterial pathogens, childhood bacterial meningitis was mostly due to N. meningitidis, S. pneumoniae and H. influenzae type b (Hib) in infants and children, and GBS and E. coli in neonates. Although the epidemiology of meningitis in young infants and neonates has remained fairly unchanged, the rate of meningitis due to S. pneumoniae has decreased following the introduction of the PCV-7 and PCV-13.

Angoulvant F, Levy C, Grimprel E, et al: Early impact of 13-valent pneumococcal conjugate vaccine on community- acquired pneumonia in children, Clin Infect Dis 58:918–924, 2014.
Nigrovic LE, Kuppermann N, Malley R, Bacterial Meningitis Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics: Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era, Acad Emerg Med 15:522–528, 2008.

210. What are the drugs of choice for the empiric treatment of bacterial meningitis in children >1 month?
Empiric therapy for suspected bacterial meningitis should include both vancomycin and a third-
generation cephalosporin agent (e.g., cefotaxime, ceftriaxone) because of increasing resistance to penicillin and cephalosporins among some S. pneumoniae isolates. These agents also provide excellent coverage against N. meningitidis and H. influenzae. Treatment failures have been reported when the dosage of vancomycin is <60 mg/kg per day. Vancomycin should not be used alone to treat S. pneumoniae meningitis because data from animal models indicate that
bactericidal levels may be difficult to maintain in the CSF. The combination of vancomycin plus cefotaxime or ceftriaxone has been shown to produce a synergistic effect in VITRo, in animal models, and in the CSF of children with meningitis. Empiric therapy may be expanded for children

with suspected bacterial meningitis who have immune deficiency, recent neurosurgery, penetrating head trauma, and anatomic defects.

Richard GC, Lepe M: Meningitis in children: diagnosis and treatment for the emergency clinician, Clin Pediatr Emerg Med
14:146–156, 2013.
Tunkle AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis, Clin Infect Dis
39:1267–1284, 2004.
Alter SJ: Pneumococcal infections, Pediatr REV 30:155–164, 2009.

211. What is the role of corticosteroids in the treatment of bacterial meningitis? The inflammatory response plays a critical role in producing the CNS pathology and resultant sequelae of bacterial meningitis. Several studies have demonstrated that treatment with dexamethasone reduces the incidence of hearing loss and other neurologic sequelae in infants and children with meningitis caused by H. influenzae type b when given before or at the same time as the first dose of antimicrobial therapy. However, a 2013 Cochrane review found no reduction in hearing loss in children with the use of steroids in meningitis due to non-Haemophilus species. For cases of meningitis caused by other pathogens, such as N. meningitides or S. pneumoniae, the current AAP recommendations are to “consider” the use of dexamethasone with or shortly before the first dose of antimicrobial therapy after considering the potential risks and benefits. The role of steroids in meningitis caused by other bacterial pathogens remains controversial. In adults, adjuvant corticosteroids decrease mortality in patients with pneumococcal meningitis, but this does not appear to be the case in children. Dexamethasone is not indicated for infants with early-onset sepsis/meningitis.

Brouwer MC, McIntyre P, Prasad K, van de Beek D: Corticosteroids for acute bacterial meningitis, Cochrane Database Syst REV 6:CD004405, 2013.
American Academy of Pediatrics: Pneumococcal infections. In Pickering LK, editor: 2012 Red Book, Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, p 576. Mongelluzzo J, Mohamad Z, Ten Have TR, Shah S: Corticosteroids and mortality in children with bacterial meningitis, JAMA 299:2048–2055, 2008.

212. How long after treatment has been initiated must individuals with meningitis remain on droplet precautions? Droplet precautions, which mandate a single, closed room and that surgical masks be worn by the staff, are recommended for patients with suspected H. influenzae type b or meningococcal meningitis, but it can be discontinued after 24 hours of effective antimicrobial therapy.

213. Should children receiving therapy for bacterial meningitis undergo repeat LP? Repeat LPs are not recommended for uncomplicated courses of meningitis. However, a repeat LP should be strongly considered for the following patients:
• Those with no clinical or poor clinical response to appropriate therapy within 24 to 36 hours
• Those with meningitis caused by penicillin-nonsusceptible or cephalosporin-resistant S. pneumoniae
• Those with S. pneumoniae who received dexamethasone because this agent might interfere with the ability to interpret clinical changes (e.g., fever)
• Those with prolonged or recurrent fever
• Those with recurrent meningitis
• Immunocompromised hosts
• Neonates with Streptococcus agalactiae and gram-negative meningitis should have a repeat LP after 2 to 3 days of treatment to determine appropriate duration of therapy.

Tunkle AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis, Clin Infect Dis
39:1267–1284, 2004.

214. What is the accepted duration of treatment for bacterial meningitis? The duration of antibiotic treatment is based on the causative agent and clinical course. In general for uncomplicated clinical courses, a minimum of 7 days of therapy is required for meningococcal meningitis, 7 to 10 days for H. influenzae meningitis, and 10 days for pneumococcal meningitis. Meningitis caused by GBS or L. monocytogenes should be treated for 14 to 21 days, and meningitis caused by gram-negative

enteric bacilli should be treated for a minimum of 21 days or 21 days after the CSF is sterilized. Among patients with complications such as brain abscess, subdural empyema, delayed CSF sterilization, persistence of meningeal signs, or prolonged fever, the duration of therapy may need to be extended and should be individualized.
Repeat CSF cultures should be sterile. The duration of therapy should be extended if organisms are seen on Gram stain or isolated from CSF cultures from the repeat CSF examination. The duration of therapy should be extended if CSF examination at the conclusion of the standard duration of treatment shows >30% neutrophils, CSF glucose of <20 mg/dL, or CSF-to-blood
glucose ratio of <20 percent, respectively.
Tunkle AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis, Clin Infect Dis
39:1267–1284, 2004.

215. In a patient with meningitis, what are the findings that suggest intracranial complications and provide indications for CT or magnetic resonance imaging (MRI)?
• Prolonged obtundation
• Prolonged irritability
• Seizures developing after day 3 of therapy
• Focal seizures
• Focal neurologic deficits
• Increasing head circumference
• Persistent elevation of CSF protein or neutrophil count
• Recurrence of disease

Oliveira CR, Morriss MC, Mistrot JG, et al: Brain magnetic resonance imaging of infants with bacterial meningitis, J Pediatr 165:134–139, 2014.
Wubbel L, McCracken GH: Management of bacterial meningitis, Pediatr REV 19:78–84, 1998.

216. What are the most common causes of prolonged fever in patients with meningitis?
• Inadequate treatment
• Suppurative disease at other foci (e.g., pericarditis, arthritis, subdural empyema)
• Healthcare-acquired infection (e.g., central line-associated bloodstream infection)
• Thrombophlebitis (related to IV catheters and infusates)
• Drug fever

217. What should the parents of a child with bacterial meningitis be told about long-term outcomes?
Disease resulting from S. pneumoniae is associated with considerably more morbidity and mortality than is meningitis caused by N. meningitidis or H. influenzae. The mortality ranges from 8% to 15%. A 3-year multicenter surveillance study of invasive pneumococcal infections examined outcomes of meningitis caused by S. pneumoniae in 180 children. Twenty-five percent of children had evidence of neurologic sequelae at the time of hospital discharge, and 32% had unilateral or bilateral deafness. Predictors of mortality included coma on admission, requirement for mechanical ventilation, and shock. Hearing loss occurs in 5% to 10% of patients with meningitis caused by H. influenzae and
N. meningitidis. Survivors of bacterial meningitis in the neonatal period often have much poorer neurodevelopmental outcomes. Survivors should be followed for hearing loss and other sequelae such as gross motor or cognitive impairment.

Oliveira CR, Morriss MC, Mistrot JG, et al: Brain magnetic resonance imaging of infants with bacterial meningitis, J Pediatr 165:134–139, 2014.
Koomen I, Grobbee DE, Roord JJ, et al: Hearing loss at school age in survivors of bacterial meningitis: assessment, incidence, and prediction, Pediatrics 112:1049–1053, 2003.
Arditi M, Mason EO Jr, Bradley JS, et al: Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics and outcome related to penicillin susceptibility and dexamethasone use, Pediatrics 102:1087–1097, 1998.

218. How should contacts of children with N. meningitidis disease be managed? The attack rate of secondary cases among household contacts of an index patient with invasive disease caused by N. meningitidis is 500 to 800 times that of the general population. Antibiotic prophylaxis is indicated for the following exposed individuals:
• Household members, roommates, intimate contacts, contacts at childcare center, young adults exposed in dormitories, and military recruits exposed in training centers within the 7 days before the onset of the index patient’s symptoms
• Airplane travelers seated next to an index patient on a flight lasting more than 8 hours or who were exposed to the index patient’s respiratory secretions within the 7 days before the onset of the index patient’s symptoms
• Medical personnel who were exposed to the index patient’s respiratory secretions through intubation, endotracheal tube management, or mouth-to-mouth resuscitation
Options for prophylaxis include:
• Rifampin given twice daily for 2 days
• IM ceftriaxone (1 dose)
• Oral ciprofloxacin (for those 18 years of age)
Prophylaxis is not recommended for casual contacts at school, work, or hospital setting without direct exposure to the index patient’s respiratory secretions.

American Academy of Pediatrics: Meningococcal infections. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, pp 503–505.

219. What is the most common parasitic infection of the CNS?
Neurocysticercosis. This is a tapeworm disease that is most commonly initiated by the ingestion of undercooked pork containing Taenia solium larvae. After these larvae mature, eggs from adult tapeworms are then acquired by fecal-oral transmission among humans or by
autoinoculation. If hematogenous spread of these eggs to the brain occurs, two types of complications can occur.
• Parenchymal cystic lesions can form a calcified granuloma that can result in seizures and/or headache.
• Extraparenchymal cysticerci can become trapped within the ventricles, foramina, or aqueduct and cause obstructive hydrocephalus manifesting as headache, nausea, vomiting, or change in mental status.

Garcia HH, Nash TE, Del Brutto OH: Clinical symptoms, diagnosis, and treatment of neurocysticercosis, Lancet Neuro
13:1202–1215, 2014.

OCULAR INFECTIONS
220. Among neonates with conjunctivitis, what is the timing for the various etiologies?
• Chemical: Onset in <2 days
• Neisseria gonorrhoeae: Onset in 2 to 7 days
• C. trachomatis: Onset in 5 to 14 days
• HSV: Onset in 10 to 14 days

221. What is the best method of prophylaxis for ophthalmia neonatorum?
Ophthalmia neonatorum is conjunctivitis in the first month of life. Historically, this referred to
N. gonorrhoeae as the causative agent from acquisition at birth. Unrecognized and untreated maternal
N. gonorrhoeae before delivery is now quite rare in the United States. C. trachomatis is now the more predominant etiology of neonatal conjunctivitis in the United States. Other bacterial microbes and HSV can be pathogens. As a consequence, erythromycin 0.5% ophthalmic ointment is now used routinely in nurseries in the United States to prevent conjunctivitis, although the efficacy for preventing chlamydial disease (primarily pneumonia) remains unclear. Worldwide, other methods are used, including gentamicin ointment, 2.5% povidone-iodine ophthalmic solution, and silver nitrate drops.
222. Can newborns with chlamydial conjunctivitis be treated with topical therapy alone? No. Newborns diagnosed with chlamydial conjunctivitis should receive systemic therapy withoral erythromycin for 14 days. One study has suggested that oral azithromycin, 20 mg/kg/day for 3 days, is also effective. Topical

therapy willnot eradicate the organism fromtheupper respiratory tract, and itfails to prevent the development of chlamydial pneumonia. Close follow-up evaluation is indicated to ensure the absence of relapse.

Hammerschlag M, Gelling M, Roblin PM, et al: Treatment of neonatal chlamydial conjunctivitis with azithromycin, Pediatr Infect Dis J 17:1049–1050, 1998.

223. In children with conjunctivitis and otitis media, what are the most likely etiologic agents?
• Bacterial: Nontypeable H. influenzae is the most common cause of the so-called conjunctivitis- otitis syndrome, which is characterized by concurrent conjunctivitis and otitis media.
• Viral: Adenovirus may also cause a conjunctivitis-otitis syndrome.
224. Can bacterial conjunctivitis be distinguished from viral conjunctivitis on clinical grounds alone? No. Classically, bacterial conjunctivitis is more common in infants and young children with the discharge being purulent or mucopurulent. A history of sticky eyelids with eyelash closure on awakening is predictive of a bacterial etiology. The most commonly implicated organism is nontypeable H. influenzae. Viral conjunctivitis is accompanied by a serous exudate in children of all ages, classically from adenovirus infections. Bacterial infections are commonly associated with otitis media, and otoscopy should be performed on all patients. However, clinical findings can overlap. Both bacteria and viruses can cause unilateral or bilateral symptoms.

Azari AA, Barney NP: Conjunctivitis: a systematic review of diagnosis and treatment, JAMA 310:1721–1729, 2013. Richards A, Guzman-Cottrill JA: Conjunctivitis, Pediatr REV 31:196–208, 2010.
Patel PB, Diaz MC, Bennett JE, et al: Clinical features of bacterial conjunctivitis in children, Acad Emerg Med 14:1–5, 2007.

225. What is keratoconjunctivitis?
KERATOCONJUNCTIVitis is an inflammatory process that involves both the conjunctiva and the cornea. Superficial inflammation of the cornea (keratitis) occurs commonly in association with viral and bacterial conjunctivitis, particularly in adults. Hence, many cases of conjunctivitis are more correctly called keratoconjunctIVITIS. Epidemic keratoconjunCTIVITIS is caused by adenovirus serotypes 8, 19, and 37. Some organisms, including measles virus, P. aeruginosa, N. gonorrhoeae, and HSV have a propensity to cause more severe infection of the cornea. Infection as a result of these pathogens must be recognized early to prevent corneal scarring with subsequent vision loss.
226. What are the most common causative organisms of acute bacterial conjunctivitis?
• Neonate: S. aureus, H. influenzae, C. trachomatis
• Child: S. aureus, S. pneumoniae, H. influenzae, M. catarrhalis
• Adolescent/adult: S. aureus, S. pneumoniae, Streptococcus spp., H. influenzae, M. catarrhalis, Acinetobacter spp.
227. How does the treatment vary by age for suspected acute bacterial conjunctivitis? Topical therapy for neonatal chlamydial conjunctivitis should never be used as sole therapy because of the high likelihood of concomitant respiratory tract colonization (which can eventually progress to pneumonia). Infections resulting from N. gonorrhoeae, P. aeruginosa, H. influenzae type b, and N. meningitidis require systemic therapy to prevent the serious complications seen with these organisms. Ophthalmic ointments are usually preferred for infants and young children because they can be instilled more reliably and remain in the eye for a longer time. In older children, ophthalmic solutions may be preferred to prevent the blurring of vision that occurs with ointments. In general, the efficacy of ophthalmic ointments is presumed to be superior to that of solutions. However, several antibiotics are available in high-concentration solutions. These “fortified” formulations have not been compared prospectively
with other preparations, but they are widely used because of their presumed enhanced efficacy.
228. What should be the specific treatment for a 5-year-old diagnosed with infectious conjunctivitis in an outpatient setting?
This is controversial because viral and bacterial causes (and even allergic conjunctivitis) have clinical overlap, and cultures are not usually obtained on the initial evaluation to obtain a precise diagnosis. Two questions are paramount:

1. Should empiric antibiotic therapy be started? Topical antibiotics have been shown to decrease the duration of bacterial conjunctivitis, which does allow an earlier return to school and to work for parents. Treatment can thus reduce the socioeconomic costs of conjunctivitis and help prevent the spread of infection. However, the majority of cases of bacterial conjunctivitis are self- limiting and resolve without treatment. If the cause is indeed viral, antibiotic therapy is unnecessary and may contribute to resistance and unwarranted side effects. Given these options of treatment versus “watchful waiting,” physician style and parental preferences hold large sway. Antibiotic treatment should be considered for purulent conjunctivitis, for those with significant discomfort, for contact lens wearers, for immunocompromised patients, and for
any cases suspicious for either chlamydial or gonococcal conjunctivitis.
2. If therapy is begun, which topical antibiotic is preferable? Options are considerable, including newer (and expensive) therapies (e.g., fluoroquinolones) designed to counteract the growing resistance patterns of typical pathogens, such as S. pneumoniae, H. influenzae, and Moraxella spp. Once again, physician style, compliance considerations, and prescription coverage play a large role in choice of antibiotic therapy because clear-cut evidence-based guidelines are lacking.

Azari AA, Barney NP: Conjunctivitis: a systematic review of diagnosis and treatment, JAMA 310:1721–1729, 2013. Williams L, Malhotra Y, Murante B, et al: A single-blinded randomized clinical trial comparing polymyxin B-trimethoprim and moxifloxacin for treatment of acute conjunctivitis in children, J Pediatr 162:857–861, 2013.

229. What is Parinaud oculoglandular syndrome?
Parinaud syndrome is characterized by granulomatous or ulcerating conjunctivitis and prominent preauricular or submandibular adenopathy. The most common cause is cat-scratch disease, but other causes include tularemia, sporotrichosis, tuberculosis, syphilis, and infectious mononucleosis. An important condition in the differential diagnosis to exclude is Kawasaki disease.
230. How is orbital cellulitis distinguished from periorbital (or preseptal) cellulitis? Periorbital cellulitis involves the tissues anterior to the eyelid septum (Fig. 10-12), whereas orbital cellulitis involves the orbit and is sometimes associated with abscess formation and cavernous sinus thrombosis. Distinction between these processes requires assessment of ocular mobility, pupillary reflex, VISUAL acuity, and globe position (e.g., proptosis), which are normal in periorbital cellulitis but may be abnormal in orbital cellulitis. An abnormality in any of these four areas mandates radiologic evaluation (usually CT scan of the orbit) and possible surgical drainage.

Figure 10-12. Periorbital cellulitis. (From Zitelli BJ, DAVIS HW: Atlas of Pediatric Physical Diagnosis, ed 4. St. Louis, 2002, Mosby, p 848.)

231. What is the pathogenesis of periorbital and orbital cellulitis?
• Periorbital: This cellulitis may result from direct inoculation in and around the eyelid, trauma (blunt or penetrating), and spread of microorganisms from the sinuses or nasopharynx into the preseptal space

• Orbital: Most cases originate in nearby paranasal sinuses (especially ethmoid) as a complication of sinusitis. The walls (lamina papyracea) of the ethmoid and sphenoid sinuses are paper thin with natural bony dehiscencesthat allow spread of infection. In addition, orbital and sinus veins anastomose and are valveless, which allows communicating blood flow and easier spread of infection.
• Complications of orbital cellulitis include subperiosteal orbital abscess, vision loss (from optic neuritis due to surrounding inflammation or thrombophlebitis in adjacent vessels), cavernous sinus thrombophlebitis, and brain abscess.

Sethuraman U, Kamat D: The red eye: evaluation and management, Clin Pediatr 48:588–600, 2009.

232. What are the most common organisms causing orbital cellulitis?
• Staphylococci are the most common organisms causing orbital cellulitis. They are implicated in both orbital and periorbital cellulitis because it is a colonizing organism of both the upper respiratory tract and the skin.
• Streptococci:
• Group A Streptococcus
• S. pneumoniae and other alpha hemolytic strep such as S. anginosus
Anaerobic organisms and fungi, such as Mucor species and Aspergillus, should be considered in immunocompromised hosts.
233. What are treatment options for orbital cellulitis?
Treatment should be guided by the likely epidemiology of the disease. In this era of increasing MRSA colonization in the general population, empiric therapy often is comprised of coverage for MRSA, such as vancomycin combined with a third-generation cephalosporin, such as ceftriaxone. This choice also has the advantage of good CSF penetration, while an evaluation is being done for intracranial complications. Other choices include vancomycin and ampicillin/sulbactam or piperacillin/ tazobactam, with the caveat that these latter agents do not have complete CNS penetration.
234. What is the difference between a hordeolum, a stye, and a chalazion?
• A hordeolum is a purulent infection of any one of the sebaceous or apocrine sweat glands of the eyelid, including the glands of Moll and Zeis, which drain near the eyelash follicle, and the meibomian glands, which drain nearer the conjunctiva. Clinically, a hordeolum is recognized as a red, tender swelling. It is usually caused by S. aureus.
• A stye is an external hordeolum, on the skin side of the eyelid.
• A chalazion is an internal hordeolum, on the conjunctival side of the eyelid.
In all cases, these lesions are treated with warm compresses and topical antibiotic drops or ointment (although their value is debatable) and usually resolve within 7 days. Intralesional triamcinolone injection can be beneficial for a chalazion. A chalazion is more likely to become chronic and require surgical excision.
235. Why is the “ciliary flush” particularly worrisome when evaluating a patient with a pink or red eye? Ciliary flush refers to circumcorneal hyperemia in which conjunctival redness is concentrated in the area adjacent to the cornea (limbus). This can be a sign of significant ocular pathology (e.g., keratitis, anterior uveitis, acute angle-closure glaucoma) and requires hastened referral to an ophthalmologist.
236. What organism should not be overlooked when treating ocular infections following penetrating trauma?
Bacillus cereus. This organism is a gram-positive, spore-forming rod, which is ubiquitous in soil. The spores can be very heat resistant. It may be a cause of severe ocular infection following penetrating trauma with contaminated foreign bodies, such as glass, metal, or sticks. Similar to its related bacillus of anthrax fame (B. anthracis), B. cereus is generally sensitive to and treated with ciprofloxacin.

OTITIS MEDIA
237. Is ear pulling a reliable sign of infection?
No. In the absence of other signs or symptoms (e.g., fever, URI symptoms), ear pulling alone is a very poor indicator of acute otitis media (AOM).

Baker RB: Is ear pulling associated with ear infection? Pediatrics 90:1006–1007, 1992.

238. What are the landmarks of the tympanic membrane?
See Fig. 10-13.

Figure 10-13. Right tympanic membrane. (From Bluestone CD, Klein JO: Otitis Media in Infants and Children. Philadelphia, 1988, WB Saunders, p 76.)

239. What are the most reliable ways, on physical examination, to accurately diagnosis AOM?
Good visualization of the tympanic membrane (TM) and the use of a pneumatic otoscope are key.
• Visualization of position: Bulging of the TM implies fluid under pressure, whereas retraction is more commonly seen with effusion rather than suppuration.
• Color and translucence: Normal TM color is pearly gray and translucent; cloudiness implies suppuration; distinct redness (especially if unilateral) can indicate infection, but can be seen in other settings, particularly with high fever. Marked redness without TM bulging is unusual in AOM.
• Mobility: Impaired mobility of the TM to positive pressure by pneumatic otoscopy implies a fluid- filled space.

Shaikh N, Hoberman A, Kaleida PH, et al: Otoscopic signs of otitis media, Pediatr Infect Dis J 10:822–826, 2011. Rothman R, Owens T, Simel DL: Does this child have acute otitis media? JAMA 290:1633–1640, 2003.

240. What are the most common viral and bacterial agents that cause AOM? Tympanocentesis is now rarely done except under the auspices of tympanostomy tube placement, but historically it has yielded bacteria and/or viruses in up to 96% of patients with AOM (66% bacteria and viruses together, 27% bacteria alone, and 4% virus alone).
The most common organisms that are recovered from patients with AOM (either from the nasopharynx or middle ear) are S. pneumoniae, nontypeable H. influenzae, and M. catarrhalis. The microbiology of AOM changed with the introduction of the initial 7-valent pneumococcal conjugate vaccine (PCV-7) with a shift towards increasing prevalence of H. influenzae, and serotypes of
S. pneumonia that display antibiotic resistance or are not covered by PCV-7. The effect of PCV-13 on the microbiology of AOM remains under study.

Lieberthal A, Carroll AE, Chonmaitree T, et al: The diagnosis and management of acute otitis media, Pediatrics 131; e964–e999, 2013.
Ruohola A, et al: Microbiology of acute otitis media in children with tympanostomy tubes: prevalences of bacteria and viruses, Clin Infect Dis.43:1417–1422, 2006.

241. What is the “watchful waiting” approach for otitis media?
This is the observational option (“watchful waiting”) for patients >2 years for whom the diagnosis of otitis media is certain, but the illness is not severe. Anticipating a high percentage of spontaneous improvement, clinicians defer antibiotic therapy. If the patient does not improve with observation for
48 to 72 hours, antibiotics are initiated. The intent is to reduce potentially unnecessary antibiotics. When using this option, reliable follow-up must be ensured.
242. Should all children with AOM be treated with antibiotics? Observation as initial management for AOM in properly selected children does not increase the risk for serious complications, provided that follow-up is ensured and a rescue antibiotic is given for persistent or worsening symptoms. AAP guidelines published in 2013 endorse the following practices:
• Antibiotic therapy should be prescribed for AOM (bilateral or unilateral) in children 6 months and older with severe signs or symptoms
• Severe AOM is defined as moderate or severe otalgia or otalgia for at least 48 hours or temperature 39 °C (102.2 °F) or higher
• Children 6 months to 23 months of age without severe signs or symptoms:
• Antibiotic therapy should be prescribed for bilateral AOM in young children.
• For nonsevere unilateral AOM in young children: it is reasonable to offer observation with close follow-up based on joint decision-making with caregivers, provided that follow-up can be ensured and there is a mechanism to begin antibiotic therapy if the child worsens or fails to improve within 48 to 72 hours of onset of symptoms.
• In children >23 months of age with AOM (unilateral or bilateral) without severe signs or symptoms, it is reasonable to offer observation with close follow-up.

Lieberthal A, Carroll AE, Chonmaitree T, et al: The diagnosis and management of acute otitis media, Pediatrics 131; e964–e999, 2013.
Spiro DM, Tay KY, Arnold DH, et al: Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial, JAMA 296:1235, 2006.
Marcy M, Takata G, Chan LS, et al: Management of acute otitis media, EVID Rep Technol Assess (Summ) 15:1–4, 2000.

243. What is the recommended therapy for children for whom treatment for AOM is indicated?
High-dose (80 to 90 mg/kg/day) amoxicillin is recommended for children who have not taken amoxicillin in the previous 30 days and who do not have concurrent conjunctivitis (indicating
H. influenza infection and the need for a β-lactamase inhibitor).

Lieberthal A, Carroll AE, Chonmaitree T, et al: The diagnosis and management of acute otitis media, Pediatrics 131; e964–e999, 2013.

244. After an acute episode of otitis media (OM), how long does the middle ear effusion persist? About 70% of patients will continue to have an effusion at 2 weeks, 40% at 1 month, 20% at 2 months, and 5% to 10% at 3 months.

Teele DW, Klein JO, Rosner BA: Epidemiology of otitis media in children, Ann Otol Rhinol Laryngol Suppl 89:5, 1980.

245. What are the indications for tympanostomy tubes? Tympanostomy tubes are most commonly inserted for the treatment of otitis media with effusion (OME) or for prophylaxis against recurrent otitis media. The newest AAP recommendations state that tympanostomy tubes may be offered for recurrent AOM (3 episodes in 6 months or 4 episodes in 1 year, with 1 episode in the preceding 6 months). This recommendation is based on limited trial data. For patients with recurrent otitis media, the benefit of tube placement is modest and must be weighed against the risk for complications, which include sclerosis, retraction, atrophy of the eardrum, and complication related to general anesthesia.

Lieberthal A, Carroll AE, Chonmaitree T, et al: The diagnosis and management of acute otitis media, Pediatrics 131; e964–e999, 2013.

Feldman HM, Paradise JL: OME and child development, Contemp Pediatr 26:40–41, 2009.
Paradise JL, Feldman HM, Campbell TF, et al: Tympanostomy tubes and developmental outcomes at 9 to 11 years of age, N Engl J Med 356:248–261, 2007.

246. Should a child with tympanostomy tubes be allowed to swim?
Otolaryngologists differ widely in their guidance to parents about issues of swimming and bathing. Controlled studies have shown that the rate of otorrhea is similar between nonswimmers (15%)
and surface swimmers without earplugs (20%). Neither earplugs nor prophylactic eardrops appear to be necessary for most children who swim at the surface in the ocean or in a pool. If diving or underwater swimming is planned, fitted earplugs are often recommended. Bath water with shampooing can cause inflammatory changes in the middle ear, and thus, earplugs should be used if head dunking is anticipated during bathing. An in VITRO study (using a head model) found water entry greatest with submersion in soapy water and with deeper swimming.

Wilcox LJ, Darrow DH: Should water precautions be recommended for children with tympanostomy tubes? Laryngoscope 124:10–11, 2014.
Hebert RL II, King GE, Bent JP III: Tympanostomy tubes and water exposure: a practical model, Arch Otolaryngol Head Neck Surg 124:1118–1121, 1998.

247. A child with the acute onset of ear pain and double vision likely has what condition?
Gradenigo syndrome is an acquired paralysis of the abducens muscle with pain in the area that is served by the ipsilateral trigeminal nerve. It is caused by inflammation of the sixth cranial nerve in the petrous portion, with involvement of the gasserian ganglion. The inflammation is usually the result of infection from otitis media or mastoiditis. Symptoms may include weakness of lateral gaze on the affected side, double vision, pain, photophobia, tearing, and hyperesthesia.

248. What are differences between acute and chronic mastoiditis?
• Acute mastoiditis: Presents as complication of acute otitis media with retroauricular inflammation (swelling and tenderness) and protrusion of the auricle; patients are younger; most likely causes are S. pneumoniae and S. pyogenes with MRSA increasing as a pathogen.
• Chronic mastoiditis: Typically with more extensive history of otitis media, including tympanostomy tubes; <50% with retroauricular swelling and tenderness; patients are older; most likely cause is
P. aeruginosa with MRSA also increasing as a pathogen.

Lin HW, Shargorodsky J, Gopen Q: Clinical strategies for the management of acute mastoiditis in the pediatric population,
Clin Pediatr 49:110–115, 2010.
Stähelin-Massik J, Podvinec M, Jakscha J, et al: Mastoiditis in children: a prospective, observational study comparing clinical presentation, microbiology, computed tomography, surgical findings and histology, Eur J Pediatr 167:541–548, 2008.

249. What are the potential complications of mastoiditis? Epidural abscess, brain abscess, cervical abscess, sinus vein thrombosis, cervical vein thrombosis, and sensorineural hearing loss are potential complications.
250. What famous playwright died of mastoiditis?
Oscar Wilde died from CNS dissemination of mastoiditis, likely due to S. pneumoniae. This was especially ironic as his estranged father and Irish eye and ear surgeon, Sir William Wilde, introduced the retroauricular incision, which at the time was a novel surgical approach for the treatment of mastoiditis.

Bento RF, Fonseca ACO: A brief history of mastoidectomy, Int Arch Otorhinolaryngol 17:168–178, 2013.

PHARYNGEAL AND LARYNGEAL INFECTIONS
251. Can group A β-hemolytic streptococcal (GAS) pharyngitis reliably be distinguished from viral causes?
Streptococcal pharyngitis is a disease with variable clinical manifestations. Clues that suggest streptococcal disease include the abrupt onset of headache, fever, and sore throat with the

subsequent development of tender cervical lymphadenopathy, tonsillar exudate, and palatal petechiae in the winter or early spring. The presence of concurrent conjunctivitis, rhinitis, cough, or diarrhea suggests a viral process. The physical findings are by no means diagnostic and, when present, are more commonly found in children >3 years. Even the most skilled clinician cannot exceed an accuracy rate of about 75%. A throat culture or a rapid antigen test is essential for confirming
streptococcal infection.

Neu J, Walker WA: Streptococcal pharyngitis, N Engl J Med 364:648–655, 2011.

252. What is the typical rash of scarlet fever? The rash, which is caused by a streptococcal pyrogenic exotoxin, usually begins on the neck, face, and upper trunk and generalizes to the remainder of the body over 1 to 2 days. Palms and soles are usually spared. The rash has a sandpaper-like texture—pinpoint, erythematous, blanchable papules. The erythema (and some petechiae from fragile capillaries) may be prominent in skin folds (Pastia lines). Over 5 to 7 days, the rash fades and later is followed by desquamation, particularly on the hands, feet, axillae, and groin.
253. Why is a throat culture for GAS advised if a rapid antigen detection test is negative? A variety of antigen detection tests are available. They have a high degree of specificity, but a lower sensitivity. Thus, a negative test does not exclude the possibility of GAS and a throat culture is recommended. In adults, however, because of the low incidence of GAS infections and the extremely low risk for acute rheumatic fever, the Infectious Disease Society of America recommends that the diagnosis can be made on the basis of antigen detection testing alone without confirmation of a negative antigen test by a negative throat culture.

Shulman S, Bisno AL, Clegg HW, et al: Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America, Clin Infect Dis 55:e86–e102, 2012.

254. What is the rationale for the treatment of GAS pharyngitis?
• To prevent acute rheumatic fever (Even though there is a low incidence of acute rheumatic fever in the United States, worldwide rheumatic heart disease is the leading cause of cardiovascular death during the first five decades of life.)
• To shorten the course of the illness, including headache, sore throat, and lymph node tenderness
• To reduce the spread of infection
• To prevent suppurative complications
255. What is the recommended treatment for GAS pharyngitis?
Except in a patient with a history of penicillin allergy, the recommended therapy is IM benzathine G or oral penicillin V or amoxicillin for a duration of 10 days. Amoxicillin suspension is often prescribed rather than penicillin suspension because of better taste. First-line therapy for penicillin-allergic patients
is narrow-spectrum cephalosporins (e.g., cephalexin, cefadroxil), clindamycin, or a macrolide (e.g., azithromycin, clarithromycin). Tetracyclines, trimethoprim-sulfamethoxazole, and older fluoroquinolones (e.g., ciprofloxacin) are not recommended.

Shulman S, Bisno AL, Clegg HW, et al: Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America, Clin Infect Dis 55:e86–e102, 2012.

256. Why do some clinicians use treatments other than penicillins for GAS pharyngitis? Although 100% of GAS cases have demonstrated in VITRO susceptibility to penicillins, normal oropharyngeal flora (including S. aureus and M. catarrhalis) may produce β-lactamases that can inactivate penicillin and amoxicillin in the local oral environment. Other factors, including tolerability, cost, and prior responses to treatment, are also involved in the choice of antibiotics.

Brook I, Gober AE: Failure to eradicate streptococci and beta-lactamase producing bacteria, Acta Paediatr
97:193–195, 2008.

257. How does one differentiate a patient with a sore throat who is a streptococcal carrier with an intercurrent viral pharyngitis from one who is having repeated episodes of GAS pharyngitis?
Streptococcal carrier
• Signs and symptoms of viral infection (rhinorrhea, cough, conjunctivitis, diarrhea)
• Little clinical response to antibiotics (sometimes difficult to assess because of the self-resolving nature of viral infections)
• Group A Streptococcus present on cultures between episodes
• No serologic response to infection (i.e., anti-streptolysin O, anti-DNase B)
• Same serotype of group A Streptococcus in sequential cultures
Recurrent group A streptococcal pharyngitis
• Signs and symptoms consistent with group A streptococcal infection
• Marked clinical response to antibiotics
• No group A Streptococcus on cultures between episodes
• Positive serologic response to infection
• Different serotypes of group A Streptococcus on sequential cultures

Hill HR: Group A streptococcal carrier versus acute infection: the continuing dilemma, Clin Infect Dis 50:491–492, 2010. Shaikh N, Leonard E, Martin JM: Prevalence of streptococcal pharyngitis and streptococcal carriage in children: a meta-analysis, Pediatrics 126:e557–e564, 2012.
Gerber MA: Diagnosis and treatment of pharyngitis in children, Pediatr Clin North Am 52:729–747, 2005.

258. When can children treated for positive streptococcal throat cultures return to school or day care? Although clinical improvement often occurs promptly, most patients remain culture positive 14 hours after the initiation of antibiotics. However, by 24 hours, nearly all patients are culture negative. To minimize contagion, children should receive a full 24 hours of antibiotic therapy before returning to school or childcare.

American Academy of Pediatrics: Group A streptococcal infections. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, p 677.
Snellman LW, Stang HJ, Stang JM, et al: Duration of positive throat cultures for group A streptococci after initiation of antibiotic therapy, Pediatrics 91:1166–1170, 1993.

259. How commonly do children <3 years of age develop GAS pharyngitis?
Traditional teaching has been that toddlers rarely develop streptococcal pharyngitis. However, studies
indicate that the incidence of infection and the prevalence of carriage are greater than previously thought. In studies of patients <2 years with fever and clinical pharyngitis, 4% to 6% were positive for GAS; among well children, the carrier rate is about 6%. In young children, GAS infection is more commonly associated with a syndrome of fever, mucopurulent rhinitis, and diffuse adenopathy. The rate of rheumatic fever is exceedingly low in children <3 years.

Shulman S, Bisno AL, Clegg HW, et al: Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America, Clin Infect Dis 55: e86–e102, 2012.
Berkovitch M, Vaida A, Zhovtis D, et al: Group A streptococcal pharyngotonsillitis in children less than 2 years of age—more common than is thought, Clin Pediatr 38:365–366, 1999.
Nussinovitch M, Finkelstein Y, Amir J, Varsano I: Group A beta-hemolytic streptococcal pharyngitis in preschool children aged 3 months to 5 years, Clin Pediatr 38:357–360, 1999.

260. How long after the development of streptococcal pharyngitis can treatment be initiated and still effectively prevent rheumatic fever?
Treatment should be started as soon as possible, but little is lost in waiting for throat culture results to establish the diagnosis. Antibiotic treatment prevents acute rheumatic fever even when therapy is initiated as long as 9 days after the onset of the acute illness.

Catanzaro FJ, Stetson CA, Morris AJ, et al: The role of the streptococcus in the pathogenesis of rheumatic fever, Am J Med 17:749–756, 1954.

KEY POINTS: PHARYNGITIS
1. Clinical pictures of viral and streptococcal pharyngitis have significant clinical overlap.
2. Tetracyclines, trimethoprim-sulfamethoxazole, and older fluoroquinolones (e.g., ciprofloxacin) are not recommended for the treatment of group A β-hemolytic streptococcal pharyngitis.
3. Antibiotic treatment prevents acute rheumatic fever even when therapy is initiated as long as 9 days after the onset of acute illness.
4. Although the incidence of rheumatic fever is low in the United States, worldwide it is the leading cause of cardiovascular death during the first five decades of life.

261. What diagnosis should be suspected in a teenager with pharyngitis followed by multifocal pneumonia and sepsis?
Lemierre syndrome. This is a septic thrombophlebitis of the internal jugular vein that is typically caused by anaerobic organisms, such as the gram-negative rod Fusobacterium necrophorum. The illness begins as a pharyngitis or tonsillitis; once thrombophlebitis develops, it results in seeding of multiple organs with septic emboli. Pneumonia may lead to respiratory failure in untreated cases. Ultrasonography of the jugular vessels and CT scan of the chest are helpful for establishing the diagnosis. Anaerobic organisms may be difficult to capture with traditional cultures.

262. What is the difference between herpangina and Ludwig angina?
• Herpangina is a common viral infection during the summer and fall and is characterized by posterior pharyngeal, buccal, and palatal vesicles and ulcers. Coxsackieviruses A and B and echoviruses are the most common causative agents. In young children, it is often accompanied by a high temperature (39.4° to 40 °C [103° to 104 °F]). Herpangina is distinguished from HSV infections of the mouth, which are more anterior and involve the lips, tongue, and gingiva.
• Ludwig angina is an acute diffuse infection (usually bacterial due to mixed anaerobes) of the submandibular and sublingual spaces with brawny induration of the floor of the mouth and tongue. Airway obstruction can occur. The infections usually follow oral cavity injuries or dental complications (e.g., extractions, impactions).

Lin HW, O’Neill A, Cunningham MJ: Ludwig’s angina in the pediatric population, Clin Pediatr 48:583–587, 2009.

263. What is quinsy?
Quinsy is a peritonsillar abscess. George Washington’s death has traditionally been attributed to quinsy, but historians have debated whether an alternate pathologic explanation—epiglottitis—was more likely.

Morens DM: Death of a president, N Engl J Med 341:1845–1850, 1999.

264. How is a peritonsillar abscess distinguished from peritonsillar cellulitis?
A peritonsillar abscess is diagnosed when a discrete mass is noted, usually in school-age children and adolescents. The bulging abscess causes lateral displacement of the uvula. Trismus, due to spasm of masticator muscles, occurs more commonly in the setting of abscess than does simple cellulitis, which is characterized by signs of diffuse inflammation without a mass. Many patients have a “hot potato” voice, a muffled voice caused by palatal edema and spasm of the internal pterygoid muscle that elevates the palate.

Galioto NJ: Peritonsillar abscess, Am Fam Physician 77:199–209, 2008.

265. What radiographic features suggest the diagnosis of a retropharyngeal abscess?
When a patient’s neck is extended, a measurement of the prevertebral space that exceeds two times the diameter of the C2 vertebra suggests an abscess (Fig. 10-14). Pockets of air in the

Figure 10-14. Thickening of the prevertebral soft tissues (white arrows) in a 3-year-old boy with neck stiffness due to a retropharyngeal abscess. (From Taussig LM, Landau LI, editors:
Pediatric Respiratory Medicine, ed 2. Philadelphia, 2008, Mosby, p 147.)

prevertebral space also suggest abscess. The retropharynx extends to T1 in the superior mediastinum, so empyema or mediastinitis is also possible whenever a retropharyngeal abscess is identified. CT scanning can delineate the extent of these deep neck infections.

266. Which age group is most susceptible to retropharyngeal abscess?
This disease is most common in children between the ages of 1 and 6 years. There are several small lymph nodes in the retropharynx that usually disappear by the age of 4 or 5. These lymph nodes drain the posterior nasal passages and nasopharynx, and they may become involved if those sites are infected.

267. What are the indications for tonsillectomy in children 1 to 18 years old?
• Obstructive sleep apnea syndrome due to adenotonsillar hypertrophy with comorbid conditions such as growth retardation, poor school performance, enuresis, and behavioral problems
• Recurrent throat infection:
• 7 episodes in the past year or
• 5 episodes per year for 2 years or
• 3 episodes per year for 3 years
Each episode of sore throat must be accompanied by one or more of the following: temperature >38.3 °C, cervical adenopathy, tonsillar exudate, or positive test for GAS
Other factors that may be considered in children who do not meet the criteria above that favor
tonsillectomy are:
• Multiple antibiotic allergies/intolerances
• PFAPA (see question #98)
• History of peritonsillar abscess

Baugh RF, Archer SM, Mitchell RM, et al: Clinical practice guideline: tonsillectomy in children, Otolaryngol Head Neck Surg 144:S1–S30, 2011.

268. How should children with epiglottitis be managed?
Acute epiglottitis is a medical emergency and all children should be assumed to have a critical airway (i.e., the potential for imminent occlusion exists). Because of the risk for airway obstruction with agitation of the patient, the patient should be allowed to remain with parents and free from restraint. Examination should be performed as cautiously as possible. Continuous observation regardless of the setting (e.g., radiology suite), avoidance of supine positioning, and arrangements for admission to an intensive care unit are mandatory. Ideally, the epiglottis is visualized directly in an operating room, and the child is intubated immediately afterward.

269. What are the bacterial causes of epiglottitis?
Previously, more than 90% of cases were caused by H. influenzae type b. However, because of the routine use of H. influenzae type b vaccines in infants beginning in 1989 and 1990, the incidence of epiglottitis has decreased dramatically. Pneumococci, staphylococci, and streptococci (group A), and nontypeable H. influenzae now account for a relatively large percentage of cases.
270. How is epiglottitis distinguished clinically from croup?
See Table 10-7.

Table 10-7 Clinical Distinctions Between Croup and Epiglottitis
CROUP EPIGLOTTITIS
Age Younger (6 mo-3 yr) Older (3-7 yr)
Onset of
stridor Gradual (24-72 hr) Rapid (8-12 hr)
Symptoms Prodromal upper respiratory infection
Barking or brassy cough Hoarseness
Slightly sore throat Minimal rhinitis Little coughing Muffled voice Pain in throat
Signs Mild fever High body temperature (>39 °C)
Not toxic Toxic appearance
Variable distress Severe distress; sits upright; may drool
Harsh inspiratory stridor Low-pitched inspiratory stridor
Expiratory sounds uncommon May have a low-pitched expiratory sound
Radiology Subglottic narrowing Edema of epiglottis and aryepiglottic folds (positive thumb sign)

271. What are the criteria for the admission of a child with viral croup?
• Clinical signs of impending respiratory failure:
• Marked retractions, depressed level of consciousness, cyanosis, hypotonicity, and diminished or absent inspiratory breath sounds
• Laboratory signs of impending respiratory failure:
• PCO2 more than 45 mm Hg,
• PaO2 < 70 mm Hg in room air
• Clinical signs of dehydration or inability to tolerate enteral fluids
• Failure of outpatient or emergency room management, such as dexamethasone and inhaled racemic epinephrine after appropriate monitoring interval
• Historic consideration:
• High-risk infant with history of subglottic stenosis or prior intubations

Bjornson CL, Johnson DW: Croup, Lancet 371:329–339, 2008.

272. Are steroids efficacious for the treatment of croup?
The use of corticosteroids (including oral and IM dexamethasone and nebulized budesonide) has been shown to be beneficial in treating croup. In particular, corticosteroid treatment reduces the incidence of intubation and results in more rapid respiratory improvement. In addition, among patients with mild or moderate croup, corticosteroids appear to reduce the use of nebulized racemic epinephrine, the need for return visits, and the need for hospitalization. Optimal doses are not clearly established. Dosing of dexamethasone is often based on the severity of croup ranging from mild croup with oral dosing (0.3 to 0.6 mg/kg up to 10 mg) to severe croup with IV or IM dosing (0.6 mg/kg up to 15 mg).

Russell KF, Liang Y, O’Gorman K, et al: Glucocorticoids for croup, Cochrane Database Syst REV 1:CD001955, 2011. Baumer JH: Glucocorticoid treatment in croup, Arch Dis Child Educ Pract Ed 91:58–60, 2006.

273. If a child has received racemic epinephrine as a treatment for croup, is hospitalization required?
No. In earlier days, children treated with racemic epinephrine were routinely hospitalized to observe for potential “rebound” mucosal edema and airway obstruction, regardless of how they appeared clinically. However, a number of recent studies have shown that children who are free of significant stridor or retractions at rest 2 hours after the administration of racemic epinephrine can be safely discharged, provided that adequate follow-up is ensured. In most of these studies, oral or IM dexamethasone (0.6 mg/kg) was also administered.

Bjornson C, Russell K, Vandermeer B, et al: Nebulized epinephrine for croup in children, Cochrane Database Syst REV 10: CD006619, 2013.
Cherry JD: Croup, N Engl J Med 358:384–391, 2008.
Baumer JH: Glucocorticoid treatment in croup, Arch Dis Child Educ Pract Ed 91:58–60, 2006.

274. Is a cool-mist vaporizer truly of benefit for patients with croup?
Probably not. The usual advice for the home management of croup includes the use of a cool-mist vaporizer. The theory is that the coolness serves as a vasoconstrictor and that the humidified mist serves to thin respiratory secretions. Although this therapy remains time honored, it is largely unproven. The calming effects of being held by a parent during the mist treatment may have greater impact. It certainly can’t hurt.

Cherry JD: Croup, N Engl J Med 358:384–391, 2008. Bjornson CL, Johnson DW: Croup, Lancet 371:329–339, 2008.

275. What are membranous croup and pseudomembranous croup?
Membranous croup is the historical term for diphtheria, and pseudomembranous croup is the historical term for bacterial tracheitis. Bacterial tracheitis is usually caused by S. aureus and may occur after trauma to the neck or trachea or after a viral respiratory tract infection such as croup. The presentation of bacterial tracheitis is similar to that of severe croup or epiglottitis, and consequently a lateral neck radiograph is frequently obtained. In bacterial tracheitis, this study often reveals narrowing of the tracheal lumen as the result of a thick, purulent exudate that can extend into both main stem bronchi.

Woodburn, FC: Is membranous croup diphtheria? Read before the Indiana State Medical Society at Indianapolis, May 17, 1894, JAMA 121:776–778, 1894.

SINUSITIS

KEY POINTS: PNEUMATIZATION OF THE PARANASAL SINUSES
1. Maxillary and ethmoid: Present at birth.
2. Sphenoid: Begins at 2 to 3 years of age, complete by age 6 years.
3. Frontal: Begins at 3 to 7 years of age, complete by age 12 years.
4. Front sinus pneumatization is absent in 1% to 4% of the population.

276. When do the sinuses develop during childhood? The maxillary and ethmoid sinuses are present at birth. Pneumatization of the sphenoid sinuses begins at about 2 to 3 years of age and is usually complete by about age 5. Frontal sinus pneumatization varies considerably, beginning at about 3 to 7 years of age and finishing by age 12 years. Frontal sinus pneumatization is absent in about 1% to 4% of the normal population due to agenesis. About 15% have unilateral frontal sinus hypoplasia.

Adibelli ZH, Songu M, Adibelli H: Paranasal sinus development in children: A magnetic resonance imaging analysis, Am J Rhinol Allergy 25:30–35, 2011.

277. Does a thick, green nasal discharge on day 2 of a respiratory illness indicate a bacterial sinus infection?
No. The character of nasal secretions (e.g., purulent, discolored, tenacious) does not distinguish viral from bacterial. Mucopurulent rhinitis commonly accompanies the common cold. Early treatment (<7 to 10 days) of purulent nasal discharge is a common cause of antibiotic overuse.
278. What is the typical presentation of sinusitis in children? Unlike adults who may present with fever and localized pain, children have persistent nasal symptoms (anterior or posterior discharge, obstruction, or congestion) without improvement for 10 to 14 days or worsening after 5 to 7 days with or without improvement (“second” or “double sickening”) and daytime cough (which may worsen at night). A minority of children may present with a more acute disease accompanied by a temperature of 39 °C or higher and a persistent ( 3 days) purulent nasal discharge. These children generally appear ill. Headache and facial pain are uncommon in younger patients with sinusitis but are seen more commonly in older children and teenagers who have had increased sinus pneumatization.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262 –e280, 2013.
Demuri GP, Wald ER: Acute bacterial sinusitis in children, N Engl J Med 367:1128–1134, 2012.

279. What is the role of sinus imaging in the diagnosis of sinusitis? Both the AAP and Infectious Diseases Society of America (IDSA) guidelines discourage routine imaging to distinguish acute bacterial sinusitis from viral URI. Abnormal radiographs cannot distinguish bacterial or viral etiologies of sinusitis. Plain radiographs may have findings of diffuse opacification, mucosal swelling, and air-fluid levels. CT scans or MRI may also demonstrate abnormalities such as mucosal thickening or air-fluid levels even in children without complaints of upper respiratory symptoms.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262–e280, 2013.
Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults, Clin Infect Dis 54:e72–e112, 2012.

280. What should be suspected in an adolescent male with a very severe frontal headache in the setting of sinusitis? An intracranial complication of sinusitis, such as subdural or epidural empyema, venous thrombosis, brain abscess, or meningitis, should be suspected. For unclear reasons, previously healthy adolescent males with frontal sinusitis are noted to have an increased risk of intracranial complications.
Orbital complications, such as subperiosteal abscess, orbital cellulitis, orbital abscess, and cavernous sinus thrombosis, comprise the other major category of complications of acute sinusitis.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262–e280, 2013.
Rosenfeld EA, Rowley AH: Infectious intracranial complications of sinusitis, other than meningitis, in children: 12 year review, Clin Infect Dis 18:750–754, 1994.

281. When should imaging be considered in cases of sinusitis?
A contrast-enhanced CT scan and/or an MRI with contrast is recommended when there is suspicion of orbital or CNS complications of acute bacterial sinusitis. The evidence for one imaging modality over the other is weak, but in general, CT is more readily available; faster (possibly obviating the need for sedation); will better visualize bony complications of the orbit (which are the most common types of complications); and in most cases, visualizes intracranial pathology. There are case reports of failure of CT to reveal intracranial complications of sinusitis, and so an MRI with contrast may be considered in the case of a negative CT with a high index of suspicion, or specific concern for soft tissue complications.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262–e280, 2013.
Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults, Clin Infect Dis 54:e72–e112, 2012.

282. Which organisms are responsible for acute and chronic sinusitis in the pediatric age group? In acute, uncomplicated sinusitis, the etiologic organisms closely parallel those associated with acute otitis media: S. pneumoniae, H. influenzae, and M. catarrhalis. There is some evidence that in the era of PCV-7 and PCV-13, β-lactamase-producing strains of H. influenzae may supplant S. pneumoniae
as the most common organism. In patients with chronic sinusitis, the most common pathogens remain S. pneumoniae, H. influenzae, and M. catarrhalis, along with S. aureus and anaerobes. Fungal infection with zygomycosis (mucormycosis) is an important concern in immunosuppressed patients.
P. aeruginosa or other colonizing gram-negative organisms must always be considered in patients with cystic fibrosis. S. aureus, both MRSA and MSSA, is emerging as a pathogen in acute and chronic sinusitis, particularly in cases of complicated disease.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262–e280, 2013.
Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults, Clin Infect Dis 54:e72–e112, 2012.

283. What is the management of acute sinusitis?
Antibiotic therapy is designed to target the most common organisms. However, culture data from the postpneumococcal vaccine era are lacking because direct sampling from the sinuses is a procedure not commonly done. Amoxicillin, 45 mg/kg/day, is recommended by the AAP as first-line therapy for children 2 years of age with uncomplicated acute bacterial sinusitis. If there is a suspicion based on
local epidemiology of resistant S. pneumoniae, high-dose (80 to 90 mg/kg/day) amoxicillin may be used. For children <2 years of age, children attending day-care facilities, or patients who have recently been treated with an antibiotic such as amoxicillin, amoxicillin-clavulanate with 80 to 90 mg/kg/day of
the amoxicillin component is recommended. A 10- to 14-day course of therapy is typically advised.

Wald ER, Applegate KE, Bordley C, et al: Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years, Pediatrics 132:e262–e280, 2013.
Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults, Clin Infect Dis 54:e72–e112, 2012.

284. List the predisposing factors for the development of chronic sinusitis
• Allergic rhinitis
• Anatomic abnormalities (e.g., polyps, enlarged adenoids)
• Impairment of mucociliary clearance (e.g., cystic fibrosis, primary ciliary dyskinesia)
• Foreign bodies (e.g., nasogastric tube)
• Abnormalities in immune defense (e.g., IgA deficiency)

TUBERCULOSIS
285. How effective is the Bacillus Calmette-Guerin (BCG) vaccination?
The BCG vaccines are among the most widely used in the world and are also perhaps the most controversial. The difficulties stem from the marked variation in reported efficacy of BCG against M. tuberculosis and Mycobacterium leprae infections. Depending on the population studied, efficacy against leprosy has ranged from 20% to 60% in prospective trials. The efficacy against tuberculosis has ranged from 0% to 80%. The highest protective effect is seen against meningeal and miliary tuberculosis in young children. In areas of high endemicity or in populations where morbidity and mortality is significant, the vaccine is used.
The vaccines were derived from a strain of Mycobacterium BOVIS in 1906 and were subsequently dispersed to several laboratories around the world, where they were propagated under nonstandardized conditions. Hence, the vaccines in use today cannot be considered homogeneous. This may explain the observed variation in efficacy.

286. When are the steps in screening for M. tuberculosis?
1. Assessment of risk: Primary care providers should assess patient risk factors for tuberculosis (TB) at the first visit, every 6 months for the first year of life, and then annually. Risk factors include: children with household contacts with confirmed or suspected TB, children

emigrating from countries with endemic TB or who have traveled to endemic countries and have had significant contact with persons at risk for TB. A validated screening questionnaire is available from the AAP.
2. For those children with a positive risk factor screen, the most common diagnostic test is the standard-strength PPD (Mantoux test); this contains 5 tuberculin units (TU) of purified protein derivative and is injected intradermally.

American Academy of Pediatrics: Tuberculosis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, pp 736–759.

287. How is the Mantoux test interpreted in the context of clinical signs and symptoms and epidemiologic risk factors, such as a known exposure?
Positive tests are defined as follows:
Palpable induration of ≥5 mm
• Children in close contact with confirmed or suspected cases of tuberculosis
• Children with radiographic or clinical evidence of tubercular disease
• Children receiving immunosuppressive therapy
• Children with immunodeficiency disorders, including HIV infection
Palpable induration of ≥10 mm
• Children <4 years
• Children with Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, or malnutrition
• Children born in high-prevalence regions of the world, whose parents were born in such areas, or who have traveled to such areas
• Children frequently exposed to adults who are infected with HIV, homeless, incarcerated, illicit drug users, or migrant farm workers
Palpable induration of ≥15 mm
• Children 4 years or older with no risk factors

American Academy of Pediatrics: Tuberculosis. In Pickering LK, editor: 2012 Red Book Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, 2012, IL, American Academy of Pediatrics, p 737.

288. What are the reasons for a false-negative tuberculin skin test (TST)?
About 10% to 40% of immunologically normal patients with culture-documented disease will have an initial TST that is negative. Reasons include:
• Testing during the incubation period (2 to 10 weeks)
• Young age
• Problems with the administration technique
• Severe systemic TB infection (miliary or meningitis)
• Concurrent infection: Measles, varicella, influenza, HIV, EBV, mycoplasma, mumps, rubella Children who are on immunosuppressive medications, who suffer from malnutrition or an
immunodeficiency may also have false-negative results.
289. How does BCG immunization influence TB skin testing? Generally, the interpretation of PPD tests is the same in BCG recipients as it is in nonvaccinated children. If positive, consideration should be given to several factors when deciding who should receive antituberculous therapy. These factors include time since BCG immunization, number of doses received, prevalence of TB in the country of origin, contacts in the United States, andradiographic findings. Asdiscussedbelow, interferon- γ release assay testing may be helpful in children who have received the BCG vaccine.
290. What is the role of interferon-γ release assays (IGRAs) in the diagnosis of TB in children?
IGRA assays rely on interferon-γ produced by lymphocytes sensitized by antigens specific to M. tuberculosis. These antigens are not found in the BCG vaccine or in nontuberculous mycobacteria, such as M. AVIUM infection. A whole-blood ELISA can measure the interferon-γ concentration after incubation with antigen. IGRAs are preferable to TST in the following circumstances:
• Children 5 years of age who have received BCG vaccine
• Children 5 years of age who are unlikely to return for TST reading
The test is an acceptable but not preferable alternative to the TST in children <5 years of age. In children <2 years of age, there are limited data on the validity of the test.

American Academy of Pediatrics: Tuberculosis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, p. 744.

291. How are IGRA results interpreted? In general, the sensitivity of IGRAs is similar to TSTs in children 5 years. The specificity is higher because antigens found in the BCG vaccine and some nontuberculous mycobacteria do not react with the assay.
• A child with a positive IGRA should be considered infected with M. tuberculosis.
• A child with a negative IGRA result cannot be interpreted as definitively free of infection.
• Indeterminate IGRA results do not exclude TB infection.
• In the case of an indeterminate test, a repeat IGRA should be performed.
• If the repeat is still indeterminate, a TST may be performed.
292. How should a patient with a positive TST or IGRA be evaluated?
History should search for clues that are suggestive of active infection, such as recurrent fevers, weight loss, adenopathy, or cough. A history of recurrent infections in the patient or a family member may be suggestive of HIV infection, which is a risk factor for infection with M. tuberculosis. Information from previous tuberculin skin testing is invaluable. Epidemiologic information includes an evaluation of possible exposure to TB. A family history is obtained, including questions pertaining to chronic cough or weight loss in a family member or other contact. Travel history and current living arrangements should be elucidated. If the patient has immigrated to North America, a history of BCG vaccination should be ascertained.
Physical examination should focus on pulmonary, lymphatic, and abdominal systems.
Examination should corroborate a history of BCG vaccination.
Laboratory evaluation, including a chest radiograph with a lateral film, is the next stage. Family members and close contacts should undergo skin testing. In certain circumstances, chest radiographs should be performed on the child’s contacts. If any of the preceding evaluations suggests active infection, sputum, gastric aspirates, and other appropriate specimens (e.g., lymph node tissue) should be obtained for mycobacterial culture and NAAT.
293. How common is HIV and TB coinfection?
Approximately 1 million people worldwide are coinfected with HIV and TB. In the United States, it is estimated that 10% of patients with active TB also have HIV. There is a 5% to 15% annual risk of acquiring TB in HIV-positive populations, and the risk of progression from latent to active disease
is much greater. Children with HIV infection are considered at high risk for contracting TB, and annual TST beginning at 3 to 12 months of age, (or at the time of HIV diagnosis) is recommended. Children who are diagnosed with TB disease should be tested for HIV infection.

Zumla A, Ravliglione M, Hafner R, et al: Tuberculosis. N Engl J Med 368:745–755, 2013.

294. What is latent tuberculosis infection (LTBI) and why is it treated?
A patient with a positive TST who has no clinical or radiographic abnormalities suggesting TB disease is thought to have LTBI. If a patient has never received antituberculous medication and has not had a known exposure to a person with isoniazid-resistant TB, treatment for LTBI has an efficacy near 100% in preventing progression to disease.
295. In a younger child suspected of having TB disease, what is the utility of gastric aspirates? In infants and young children, a cough may be absent or nonproductive. Hypertonic saline may be used in many children to successfully induce sputum for diagnosis. If this is not possible, gastric aspirates may be used as source for the culture or PCR identification of mycobacteria. The aspirate should be obtained early in the morning as the child awakens to sample the overnight accumulation of respiratory secretions. The first day’s collection generally has the highest yield.
296. What is the role of nucleic acid amplification testing (NAAT) in the diagnosis of TB? NAAT/PCR-based technology is now commercially available for the detection of TB. The Xpert MTB/RIF assay also tests for rifampicin resistance. A recent Cochrane review indicates this assay has an overall sensitivity of 88% and a specificity of 98% in adults. Additionally, it has been shown to have a sensitivity of 68% in patients who are acid-fast bacilli (AFB) smear negative. Additional studies have shown a sensitivity of 80% in extrapulmonary specimens and a CSF sensitivity and specificity of 64% and 98%, respectively.

This is a hopeful development for timely diagnosis, given the limitation of obtaining cultures in children, as well as the generally low mycobacterial burden in many specimens in children.

Steingart KR, Schiller I, Horne DJ, et al: Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults, Cochrane Database Syst REV 1:CD009593, 2013.

297. How do the manifestations of active pulmonary TB on chest radiograph differ between adults and children? Adults and adolescents more commonly present with caVItary disease and pleural effusions. The hallmark of pulmonary TB in children has classically been described as hilar adenopathy. Both adults and children, but more commonly adults, may present with lobar infiltrates. Classically, the right upper lobe has been implicated because the right main stem bronchus provides the most direct route for inhaled mycobacterium. A caveat is that TB may be heterogeneous in radiographic appearance and should never be “ruled out” given appropriate clinical suspicion based on x-ray alone, in either children or adults.

Janner D: A Guide to Pediatric Infectious Disease, Philadelphia, 2005, Lippincott Williams & Wilkins, p 126. Agrons GA, Markowitz RI, Kramer SS: Pulmonary tuberculosis in children, Semin Roentgenol 28:158–172, 1993.

298. How are children with active pulmonary TB treated?
Recommendations for the treatment of active TB in children have evolved over the past several years. Previously, therapy for at least 9 months was suggested for uncomplicated pulmonary disease. Studies in adults and children have demonstrated that 6 months of combined antituberculous therapy (short- course therapy) is as effective as 9 months of therapy. To date, the combined results of multiple studies in pediatric patients have demonstrated the efficacy of 6 months of therapy to be more than 95%. The current standard regimen for active pulmonary TB in children consists of 2 months of daily isoniazid, rifampin, and pyrazinamide followed by 4 months of isoniazid and rifampin (daily or twice weekly).
If drug resistance is a concern, either ethambutol or streptomycin is added to the initial three-drug regimen until drug susceptibilities are determined.

American Academy of Pediatrics: Tuberculosis. In Pickering LK, editor: 2012 Red Book: Report of the Committee on Infectious Diseases, ed 29. Elk Grove Village, IL, 2012, American Academy of Pediatrics, p 745.
Perez-Velez CM, Marais BJ: Tuberculosis in children, N Engl J Med 367:348–361, 2012.

299. Why are multiple antibiotics used for the treatment of TB disease?
Compared with a patient with a positive test but no disease, two features of M. tuberculosis make the organism difficult to eradicate after infection has been established. First, mycobacteria replicate slowly and may remain dormant for prolonged periods, but they are susceptible to drugs only during active replication. Second, drug-resistant organisms exist naturally within a large population, even before the initiation of therapy. These features render the organism—when it is present in significant numbers—extremely difficult to eradicate with a single agent.

300. What are the signs of TB meningitis?
Tuberculous meningitis is a tragic form of the disease. It has a peak incidence in young children (<5 years of age) and is the most common extrapulmonary manifestation of TB in this age group, especially in HIV coinfected children. The symptoms are insidious and nonspecific. These include decreased level of consciousness and lethargy, cranial nerve palsies, poor weight gain, and low grade fever that persists, typically for >5 days. It can be difficult to clinically differentiate from
other forms of meningitis once it is recognized because CSF AFB smears and cultures are often negative. Mortality approaches 30% and >50% of survivors have neurodevelopmental sequelae.
Chiang SS, Khan FA, Milstein MB: Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta- analysis, Lancet Infect Dis 14:947–957, 2014.

301. What is the importance of DOT in the treatment of TB?
Directly OBSERVED therapy (DOT), administration of medication by a third party (either a health-care professional or a trained unrelated individual), has been found to be a valuable approach to the treatment of children and adolescents with TB disease. Failure to properly take chronic medications increases

the likelihood of relapse and the development of resistance. DOT increases adherence and thus lowers rates of relapse, treatment failures, and drug resistance.
302. Why is pyridoxine supplementation given to patients who are receiving isoniazid? Isoniazid interferes with pyridoxine metabolism and may result in peripheral neuritis or convulsions. The administration of pyridoxine is generally not necessary for children who have a normal diet because they have adequate stores of this vitamin. Children and adolescents with diets deficient in milk or meat, exclusively breast-fed infants, symptomatic HIV-infected children, and pregnant women should receive pyridoxine supplementation during isoniazid therapy.
303. Why do children with TB rarely infect other children?
TB is transmitted by infected droplets of mucus that become airborne when an individual coughs or sneezes. As compared with adults, children with TB have several factors that minimize their contagiousness:
• Low density of organisms in sputum
• Lack of cavitations or extensive infiltrates on chest radiograph
• Lower frequency of cough
• Lower volume and higher viscosity of sputum
• Shorter duration of respiratory symptoms

Starke JR: Childhood tuberculosis during the 1990s, Pediatr REV 13:343–353, 1992.

304. In addition to TB, what other airborne microbes can cause respiratory disease?
See Table 10-8.

Table 10-8 Airborne Microbial Diseases
DISEASE AIRBORNE SOURCE
Aspergillosis Conidia spores from decaying vegetation and soil
Brucellosis Aerosolized from carcasses of domestic and wild animals
Chickenpox Aerosolized from respiratory secretions
Coccidioidomycosis Arthroconidia from soil and dust
Cryptococcosis Aerosolized from bird droppings
Histoplasmosis Conidia spores from bat or bird droppings
Legionnaires disease Aerosolized contaminated water, especially from air-conditioning towers cooling
Measles Aerosolized respiratory secretions
Mucormycosis Spores from soil
Psittacosis Chlamydia psittaci from birds
Q fever Coxiella burnetii from a variety of farm and other animals
Tularemia Aerosolized from multiple wild animals, especially rabbits

305. Which famous U.S. First Lady died of TB?
Eleanor Roosevelt, for whom immunosuppressive therapy for aplastic anemia activated dormant TB, died of the disease. Historically, TB has been called “consumption” (as the disease “consumed” the individual with drastic weight loss). Other noteworthy historical and literary figures who died from TB include Thomas Wolfe, George Orwell, Fredrick Chopin, Anton Chekov, and the entire Brontë family (Maria, Elizabeth, Charlotte, Emily, Anne, and brother Branwell).
Acknowledgment
The editors gratefully acknowledge contributions by Drs. Alexis M. Elward, David A. Hunstad, and Joseph W. St. Geme III that were retained from previous editions of Pediatric Secrets.