Background (cdc.gov/flu)

Influenza viruses are common respiratory pathogens, with presentation ranging from asx to common cold to life-threatening lower respiratory infection

Influenza-like illness (ILI): Syndrome of fever, respiratory sx which may or may not be 2/2 influenza virus

Epidemiology: Influenza affects between 9 and 36M adults annually, with 140–710K requiring hospitalization, and 12–56K deaths (a further ∼5M cases and ∼71K hospitalizations prevented by flu immunization in 2015–2016 season)

Microbiology: ⊖ ssRNA Orthomyxoviridae; 2 viruses (A & B); A virus undergoes frequent mutations; Antigenic drift: Minor mutations in hemagglutinin or neuraminidase → seasonal epidemics; Antigenic shift: Major antigenic Δ → most of population is susceptible → pandemics (occur every few decades)

Transmission: Primarily spread from person to person via droplets (cough or sneeze); infectious 1 d prior and 5–7 d after onset of sx; incubation period 1–4 d

Natural history: 33% of pts with influenza are asx; usually resolves after 3–7 d but can → serious/life-threatening complications (bacterial upper or lower respiratory infections, dehydration, worsening of other chronic illnesses)

Bacterial pneumonia: Complicates influenza in 0.5% of healthy pts, 2.5% of pts >65 y, obese, or w/ pre-existing medical comorbidities (JAMA 2013;309:275)

Evaluation (CID 2009;48:1003)

History: Distinguishing features vs. URI include high fever & cough, severe myalgia, exhaustion, sudden-onset; ask about vaccination (although does not rule out influenza), known/suspected flu exposure; assess for complication risk (below)

Exam: VS: high temperature, hemodynamic instability, oxygenation; HEENT: coryza; Pulm: ↑ work of breathing, rhonchi, scattered rales

 

High Risk of Influenza Complications (ACIP, MMWR 2011;60:1)
Age ≥65 y Pregnant or <2 wk postpartum American Indians/Alaska Natives BMI ≥40 Nursing home/chronic care residents Chronic lung disease (incl asthma) ASCVD (not HTN alone) CKD	Chronic liver disease Diabetes Hematologic disorders (sickle cell) Neurologic disorders (epilepsy, cerebral palsy, developmental delay, spinal cord injury) Immunosuppressed (including 2/2 medications) HIV

Whom to test: Strategy varies by clinical scenario (below); do not test asymptomatic persons; generally no need to test if presenting w/ ILI and at average risk of complication (regardless of tx decision)

 

Whom to Test for Flu (IDSA guidelines: CID 2009;48:1003)
During Flu Season (Locally)	Outside of Flu Season
High-risk and sx onset <5 d Immunocompromised and still sx (↑ shedding period) Recently hospitalized	Healthcare workers at or residents of institution w/ institutional outbreak Those w/ known/likely risk in setting of larger outbreak

Testing modality (Ann Intern Med 2012;156:500):

Rapid Ag testing: Can detect A vs. B or identify presence of either in

<20 min but poor test characteristics (sensitivity 62.3% and specificity 98.2%); consider PCR testing in pts likely to have influenza on clinical grounds but test negative PCR: Can identify type A or B, H1N1, H5N1; most sensitive

Immunofluorescence: Can distinguish between type A & B

Treatment (ACIP, MMWR 2011;60:1)

Pts who are severely ill or hypoxemic → inpatient admission (see “Pneumonia”); for those considering outpatient treatment, see below General approach: Treatment most effective when started ASAP and w/in 48 h of sx onset (data limited on effectiveness if >48 h); if high clinical suspicion, start Rx immediately (do not wait for test results, if ordered)

 

Whom to treat: Those with suspected or confirmed influenza, regardless of testing decision and results

• all pts w/ ↑ risk of complications
• progressive or severe disease
• consider in pts at avg risk who present w/in 48 h of sx onset

Prophylaxis indications

(1) Pts at ↑ risk pts of complications or healthcare workers <48 h after contact w/ infectious individual (2) SNF residents in an outbreak (>2 lab confirmed cases in <72 h), regardless of pt vaccination status (3) Consider in exposed, unvaccinated pregnant women

Neuraminidase inhibitors: ↓ Duration of illness 1–3 d if given <48 h of sx onset

Oseltamavir first-line; alt: Zanamivir (inh, avoid in COPD/asthma/pregnancy) & peramivir (IV only, $$$); do not use rimantadine or amantadine (resistance) Tx dose: Oseltamavir 75 mg BID × 5 d (30 mg BID if CrCl <30 mL/min) Ppx dose: Oseltamivir 75 mg QD × 7 d (30 mg QD if CrCl <30 mL/min) Institutional outbreak ppx duration: 2 wk or 1 wk after last case diagnosed, whichever is longer

Prevention: Hand-washing, avoid touching mucous membranes, masks; smoking cessation (NEJM 2003;348:1256); annual influenza vaccination (see “Immunizations”)

 

Background (Natl Vital Stat Rep 2012;60:1; Am J Manag Care 2012;18:380)

Classification: Community-acquired pneumonia (CAP): Bacterial pneumonia acquired in community setting; Healthcare-associated PNA (HCAP): PNA acquired in hospital, SNF, HD facility, or within 90 d of hospitalization; HCAP assoc w/ ↑ drug resistance and different organisms

Epidemiology: >2.5M annual visits to PCPs (Vital Health Stat 2011;13:1), prevalence of PNA among pts presenting w/ acute cough to primary care is 5–7% (Ann Intern Med 2003;138:109)

Microbiology: No pathogen detected in ∼60% of cases; among

 

identified pathogens, viral etiology most common (22%; rhinovirus > influenza > metapneumovirus > RSV > parainfluenza > coronavirus > adenovirus) followed by bacterial (11%; Streptococcus pneumoniae >

1. pneumonia > S. aureus and L. pneumophila) (NEJM 2015;373:415) Other etiologies: Fungal (Histoplasma, Coccidioides, Cryptococcus, Pneumocystis), zoonotic (psittacosis, Q fever, tularemia) Pneumonia risk factors: ↑ Age, immunocompromise (HIV, chemotherapy), pulmonary disease (asthma, COPD), smoking (Arch Intern Med 1995;155:1649), EtOH (NEJM 2000;342:681), medical comorbidities (DM, ESLD, CKD, neoplastic disease)

Drug-resistant S. pneumoniae (DRSP) risk factors: Age >65, abx w/in past 3 mos, EtOH, comorbid illness (chronic heart, lung, liver, or renal disease, DM, malignancy), asplenia, immunocompromise, exposure to child in daycare (CID 2005;40:1288; 2006;43:432; Inf Dis Clin North Am

2004;18:993; CID 2007;44:S27)

Potentially severe (50,000 deaths/y in US), but majority of cases can be treated as outpt

Evaluation (NEJM 2002;347:2039; AJRCCM 2001;163:1730)

General approach: Dx requires clinical features + radiographic infiltrate; assess for HCAP criteria (above) or drug-resistant S. pneumoniae risk factors (above)

History: Assess for cough, fever, chills, CP, fatigue, SOB, pleurisy, absence of rhinitis

Past medical history: Comorbidities (including cardiac & pulmonary disease, smoking, EtOH, immune suppression); health care, travel, & animal exposures

Exam: Normal vitals & lung exam → ⊖ LR as low as 0.13 (JAMA 1997;278:1440)

VS: Fever, tachycardia, hypoxia (SaO2   <90% assoc w/ ↑ 30 d morbidity/mortality) Pulmonary: Assess work of breathing; listen for rales (common), egophony, and/or bronchial breath sounds (CID 2011;52:325) Volume: JVP, skin turgor, dry mucus membranes

Neuro: Mental status changes

Imaging: All pts in whom PNA is suspected should receive CXR; varied radiographic presentations—lobar/multilobar consolidation, patchy interstitial or reticulonodular pattern, or cavitation; abnormalities

 

may be minimal at <24 h if dehydration, immunocompromise, or older age (Clin Radiol 1996;51:689; J Clin Oncol 1999;17:796; Am J Med 2004;117:305)

Labs (BMJ 2013;346:f2450; Cochrane Database Syst Rev 2012;9:CD007498):

Severity assessment: Consider CBC w/ diff, lytes, BUN/Cr, glucose, LFTs Dx: CRP shows promise in prediction rules & ↑ procalcitonin may help rule in bacterial illness; optimal use of both tests not yet clear: Further study needed

Microbiologic testing (sputum culture ± serology, urinary Ag, PCR) optional in outpts; identifies causative organism <½ the time & empiric Rx usually effective (JAMA 2000;283:749; Ann Intern Med 2005;142:165); pursue if:

• ↑ Suspicion for epidemiologically important organism (influenza (see “Influenza”), Legionella, TB (see “Tuberculosis”), CA-MRSA)
• Cavitary lesion, pleural effusion, severe underlying lung disease
• Failure to respond to tx
• Unusual presentation

Treatment

First decision for outpatient provider is whether or not to hospitalize:

HCAP: Usually requires admission for IV antibiotics

CAP: Consider PNA risk scores (PSI/PORT, C[U]RB-65, below), pregnant or immunocompromised status (↓ threshold to hospitalize), & also individual social situation (caregivers available, functional status, likely adherence to meds)

 

Pneumonia Severity Index (PSI/PORT Score) (NEJM 1997;336:243; Ann Intern Med 2005;142:165)
To calculate score: Age (+age in y), ♀ (–10), Nursing home residence (+10) Malignancy (+30), liver disease (+20), CHF (+10), stroke (+10), CKD (+10) &ΔMS (+20), RR >30 (+20), SBP <90 (+20), T <35°F or T >40°F (+15), HR >125 (+10) pH <7.35 (+30), BUN >30 (+20), Na <130 (+20), glucose >250 (+10), HCT <30 (+10), PaO2 <60 (+10), pleural effusion (+10)
Class	Score	Mortality (%)	Triage
I	Age <50 & healthy	0.1	Outpt
II	≤70	0.5	Outpt
III	71–90	1	Consider outpt
IV	90–130	9	Hospitalize

 

V	>130	27	Hospitalize
C[U]RB-65 (Thorax 2003;58:377)
Predicts mortality (may use w/ or w/o blood test); cumulative score = 1 pt each for Confusion, BUN >20, RR >30, BP <90/60, Age >65 y → 0–1 points may be safe for outpt; ≥2 points recommend inpt

Outpatient treatment: Empiric regimen based on drug-resistant S. pneumoniae risk (see “DRSP risk factors,” above); treat for minimum 5 d or until afebrile 48–72 h; if ↑ suspicion for unusual organism, may alter diagnostics & tx coverage

 

Empiric Antibiotic Regimens (CID 2007;44:S27)
Risk	Antibiotic Choice
Low DRSP risk	Azithromycin 500 mg × 1, then 250 mg QD × 4 (preferred) Alt: Azithro 500 mg QD × 3, azithro 2 g × 1, or clarithromycin 1 g QD × 5 Assoc w/ ↑ QTc & ↑ CV mortality; use alt or monitor in ↑ risk pts •  If adherence concerns, consider short course w/ single dose or 3 d course of azithro (long t½) (NEJM 2012;366:1881; Eur Respir J 1995;8:398; Int J Antimicrob Agents 2004;24:181)
	Doxycycline 100 mg BID × 7–10 d (Diagn Microbiol Infect Dis 2012;75:107) • Review local resistance patterns; doxycycline preferred if >25% of S. pneumo have high-level (MIC ≥16 μg/mL) macrolide resistance
High DRSP risk	Respiratory FQ (preferred) Levofloxacin 750 mg QD × 5–7 d, moxifloxacin, or gemifloxacin •  If possible TB, avoid FQ use (2nd-line tx for TB)
	(Macrolide or doxy) & (amox/clav 2 g BID or amox 1 g TID or 2nd-gen ceph) • Amox or amox/clav preferred over cephalosporins; cefpodoxime preferred over cefuroxime (CID 2003;37:230)

Follow-up: Sxs should improve soon after abx, but some sxs (cough, fatigue) can linger up to 30 d; repeat CXR usually unnecessary; consider if smoker or ? of malignancy

Symptomatic treatment: Cough suppressants and expectorants do not affectoutcomes

Smoking cessation: Screen all pts, advise to quit, & offer assistance (see “Tobacco”)

Prevention: Administer pneumococcal vaccines per guidelines (see

“Immunizations”) to prevent invasive pneumococcal disease (Cochrane Database Syst Rev 2013;1:CD000422; NEJM 2003;348:1747)

 

 

Background (CDC: STD Surveillance 2016; Sex Transm Infect 2011;87:183)

Epidemiology: 110 M Americans have current (new/existing) infections; half of new dx in pts <24 y

Microbiology: HPV most common (∼14M/y); C. trachomatis most common bacterial infection (∼1.4M cases in US in 2015, majority asx

→ importance of screening, see below), followed by N. gonorrhoeae

(∼700,000 cases/y)

Risk Factors: Young age (15–24 yo), unmarried, MSM (esp ↑ RR of syphilis), new partner in past 60 d, multiple sex partners, hx prior STI, HIV ⊕, illicit drug use, imprisoned, contact w/ sex workers, hx exchanging sex for payment, inconsistent condom use

Screening: Screen or consider testing in groups with risk factors (above) at least annually, be aware of local prevalence patterns and recommendations; complete sexual history helps to identify those at ↑ risk; for specific testing modality see Individual pathogens below

 

Specific STI Screening Recommendations (CDC 2015 guidelines; MMWR 2015;64:1)
Gonorrhea, Chlamydia	Sexually active ♀ <25 y MSM annually at site(s) of contact, q3–6mos if ↑ risk HIV⊕ at first visit, subsequently if ↑risk
Syphilis	MSM annually, q3–6mos if ↑ risk HIV⊕ pts at first visit, subsequently if ↑risk
HIV	All adults 13–64 once MSM annually if pt/partner have had any partners since last test; more frequently in those at ↑ risk Anyone seeking evaluation for STIs (“STD check”) More frequently in those at ↑ risk

General Approach (CDC: STD Treatment Guidelines 2015)

History: Cannot screen/test accurately without obtaining sexual history; respectful, nonjudgmental attitude key to obtaining accurate history; ask about 5P’s (below); “Is there anything else I need to know?”; see “Patient Visit”

 

Partners	“Tell me about any new sex partners you’ve had since your last visit” “Is it possible any of your sex partners in past 12 mos had sex with someone else while still in a sexual relationship with you?”
Sexual practices	“To understand your risks for STDs, I need to understand the kind of sex you have had recently” “When you have sex, who puts what where?”
Pregnancy	“What are you doing to prevent pregnancy?”
Protection	“What are you doing to protect yourself from HIV/STDs?” “When you have [ ] sex, do you use condoms always, sometimes, or never?” If sometimes: “In what situations do you use condoms?” “Some of my patients have difficulty using a condom every time. How is it for you?”
Prior STIs	“Have you ever had a sore or scab on your penis?” “Have you ever had an STD? Has your partner?

STI symptoms: Recall that many STIs are asx

Urethritis: Dysuria > pruritus, burning, or discharge Cervicitis: Pelvic pain, dyspareunia, discharge; early sign of PID (see “PID”) Epididymitis: Pain, swelling, inflammation of the epididymis; may extended to testes Proctitis: Anorectal pain, tenesmus, rectal discharge or bleeding Ulcer: Oral, anal, vaginal, perineal; for hx rash, consider HSV (see “HSV”)

Exam: Skin, LN exam (cervical, inguinal), OP exam

Perineal: Rash, ulcer (Painless: Syphilis, LGV, granuloma inguinale;

Painful: HSV, chancroid), Rectal: Discharge (proctitis)

Male exam: Urethra: Purulent/mucopurulent discharge (urethritis); epididymal/testicular tenderness (epididymitis) Female exam: Cervicitis: Purulent/mucopurulent d/c, bleeding/friable cervix w/ minor trauma (e.g., specimen swab in os, also see “Vaginitis”)

Testing: By symptoms; see specific disease processes below; for urethritis and cervicitis, test (& empirically treat) for GC/CT

 

Causative Organism by Presentation
Urethritis	N. gonorrhoeae or C. trachomatis > M. genitalium > T. vaginalis; also possibly HSV, rarely T. pallidum Dx: GC/CT testing on urethral swab or first-void urine
Cervicitis	N. gonorrhoeae or C. trachomatis >> T. vaginalis or bacterial vaginosis See “Vaginitis” and “Pelvic Inflammatory Disease” Dx: GC/CT testing on cervical swab or first-void urine

 

Epididymitis	Age <35: N. gonorrhoeae or C. trachomatis > E. coli (insertive anal intercourse)   Age ≥35: more likely non-STD (bacteriuria, instrumentation)
Ulcer	Painless: Syphilis, LGV (esp if assoc w/ painful LAN), granuloma inguinale; Painful: HSV, chancroid
Proctitis	N. gonorrhoeae, C. trachomatis (including LGV serovars), T. pallidum, HSV

Treatment

Treatment by organism below; empiric GC/CT treatment for pts presenting w/ urethritis & cervicitis, empiric tx for all women w/ suspected PID (see “PID”)

For all patients who test positive for an STI:

Partner Rx: Recent partners of pts w/ STI should be referred for treatment & testing, EPT (expedited partner testing) or PDPT (partner-delivered partner therapy); local dept of public health can do anonymous partner tracing Reporting: GC, CT, syphilis, HIV all reportable to local health dept Advise rescreening in 3 mos (Ann Intern Med 2006;145:564)

·   For all patients in whom STI diagnosis being considered or at ↑

risk:

Immunization: HPV vaccine for ♀ & ♂ ages 9–26; HAV & HBV vaccines for MSM, injection drug users, & HIV-infected pts; consider HBV vaccine all pts being eval for an STI (see “Immunizations”) Evaluate if appropriate for PrEP (see “HIV”)

Education: Encourage condom use as an effective way to ↓risk; for pts w/ ambivalence, consider motivational interviewing (see “Counseling Pts”) (Ann Intern Med 2008;149:497)

When to refer: Diagnosis uncertain, treatment-resistant disease, 3° syphilis, co-mgmt in HIV ⊕, multiple STIs → infectious disease specialist and/or STI clinic

SPECIFIC DISEASE MANAGEMENT (CDC: MMWR 2015;64:1)

 

Chlamydia (Annals Int Med 2013;158:ITC2)

Microbiology: Causative organism C. trachomatis; specialized intracellular bacteria; can infect genital tract, rectum, oropharynx, &

 

conjunctiva

Symptoms: ♀: If present, can include dysuria, change/↑ in vaginal d/c, sx of PID (fever, pelvic pain, dyspareunia); ♂: (2/3 of men sx) urethral d/c, dysuria, testicular pain

Exam: ♀: Can appear normal or ⊕ cervical friability, purulent d/c, signs

of PID (see “PID”) ♂: Mucoid/purulent d/c (can be ↓ if recently urinated); testicular/epididymal pain

Testing (screening and dx): NAAT (nucleic acid amplification test) most sensitive/preferred; culture also available (but ↓ Se); recommend test all sites of sexual contact to ↑Se; (rectal, oropharyngeal NAAT testing not yet FDA-approved, available at some labs, check cdc.gov/std for ongoing testing updates)

♀: First-catch urine, cervical, or vaginal swab; ♂: First-catch urine, or urethral swab; may perform (not FDA-approved) for eval of rectal infection to ↑Se

Treatment: Urine, urethral, cervical, vaginal: Azithromycin 1 g PO × 1; Rectal, or azithro allergy: Doxycycline 100 mg BID × 7 d (use alt if pregnant)

Partners: From past 60 d should be treated (may be done empirically) Complications: Reactive arthritis (more common in ♂: Conjunctivitis, urethritis, oligoarthritis); PID & Fitz–Hugh–Curtis syndrome (RUQ pain 2/2 hepatic capsular inflammation)

Gonorrhea (MMWR 2012;61:590; Annals Int Med 2013;158:ITC2)

Microbiology: N. gonorrhoeae causative organism; gram ⊖

diplococcus; can infect genital tract, rectum, & oropharynx

Signs and symptoms: Generally indistinguishable from chlamydia (above); ♀: Assess for PID s/sx in ♀, 95% of ♂ are sx

Testing (screening and dx): NAAT as above; culture if concern for resistance, inoculate on appropriate growth media (culture Se for GC > CT)

Treatment: Dual therapy: Ceftriaxone 250 mg IM × 1 and (azithromycin 1 g PO × 1 or doxycycline 100 mg PO BID × 7 d) Alt: If ceftriaxone unavailable → PO cefixime (not first-line 2/2 ↑ resistance); Cephalosporin allergy: azithromycin 2 g PO × 1 & gentamicin 240 mg IM × 1 or gemifloxacin 320 mg PO × 1

Partners: From past 60 d should be tested & treated

 

Complications: Disseminated gonococcal infection (DGI): Rare, more common in ♀ (↑ risk in immediate postmenstrual period); papular rash (<30 lesions on extremities; can → pustular, purpuric/necrotic; oligoarthritis; tenosynovitis; perihepatitis; endocarditis; & meningitis

Trichomonas (see also “Vaginitis”) (cdc.gov)

Microbiology: T. vaginalis, protozoan parasite which can persist w/o sx for mos–y → ↑ prevalence (3 million infected in US), more common in older women

Signs and symptoms: 70% of infections are asx; ♀: Itching, burning, dysuria, vaginal d/c; ♂: Penile itching/irritation ± d/c, dysuria or burning after ejaculation

Diagnosis: Cervical wet prep in ♀, (60–70% Se), cx, urine DNA amp in

♂

Treatment: Metronidazole 2 g PO × 1 or Tinidazole 2 g PO × 1; or metronidazole 500 mg BID × 7 d; reinfection rates high (20% at 3 mos); consider rescreening

Partners: Abstain from sex until both partners are treated

Syphilis (cdc.gov; AFP 2012;86:433)

Microbiology: T. pallidum; spirochete which can → chronic, lifelong infection

Signs and symptoms: Vary by stage; incubation avg 21 d (but ranges from 3–90 d)

Primary: Classic: Firm, painless sore (chancre) on genitals, anus, or mouth; Atypical: Soft, painless, multiple lesions; can last 3–6 wk; only 30–60% of cases dx at this stage as may be subtle or difficult to visualize (vaginal, rectal) Secondary: Occur 2–8 wk after 1° lesion; rash (typically red-brown papules on trunk, extremities, & palms/soles, but many forms) & constitutional sx (fever, LAD, fatigue, wt loss, myalgia), HA, hair loss Latent: Period after 2° sx resolved; classified as early (<1 y) or late (>1 y) Tertiary: Years after 1°infection: May include CV, neuro, ophtho, granulomatous disease Neuro: Any stage disease, various presentations; cog dysfunction, motor/sensory deficit, ophthalmic sxs (uveitis, optic neuritis), auditory sxs, CN palsy, meningitis, stroke s/sxs

Testing: Multiple modalities available

 

Screening: Direct antitreponemal preferred for pts w/o hx infection; if

⊕ may be 2/2 prior infection (treated or not) or current infection, false ⊕ in pts w/ low likelihood also possible; typically confirmed w/ RPR

1°, 2°, or latent: RPR titer; if ⊕, confirm dx with treponemal test (FTA- ABS, TPPA, ELISA); n.b. some labs screen w/ treponemal test and confirm ⊕ w/ RPR titer; can also perform dark field microscopy on chancre (1°) or condyloma lata (2°), but not on oral lesions (other spirochetes are nl oral flora) 3°: As above & CSF testing if neuro sx (LP w/ ↑ lymphocytes, TP; 50% ⊕ VDRL)

 

Syphilis Testing (AFP 2012;86:433)
Testing Modality	Notes
Indirect/nontreponemal: (Measures marker of immune response to syphilis infection) VDRL, RPR	False ⊕ in other infections, pregnancy False ⊖ early in disease or in immunocompromised Follow titers to track tx response; 4× ↑ in titers can indicate reinfection
Direct antitreponemal: FTA-ABS, TP-EIA, TPPA	More specific; more costly; false ⊖ early in disease Remains ⊕ for years after tx → cannot be used to dx reinfection
Direct visualization of organism: Darkfield microscopy	⊕ In early disease; requires technical experience ↑Sp/↓Se

Treatment

1°, 2°, or early latent: Benzathine PCN 2.4 × 106 U IM × 1 (risk of Jarisch–Herxheimer reaction); Alt: doxycycline 100 mg PO BID × 14 d or azithromycin 2 g PO × 1 (less effective) Late latent/3°: Co-mgmt w/ specialist; PCN as above IM weekly × 3 wk, or doxycycline × 4 wk Neuro/Ophthalmic: IV PCN 4 × 106 q4h or ceftriaxone 2 g IV QD (↓ effective) × 10–14 d; monitor RPR titer and repeat LP over 12–24 mos

Other

Chancroid (H. ducreyi): Multiple, painful ulcers & tender LAD; Dx: Often clinical, order gram-stain + special culture; Tx: Azithromycin 1 g PO × 1 or ceftriaxone 250 mg × 1 or cipro 500 mg PO BID × 3 d; partners from past 10 d should be tx; test pt for syphilis

 

HSV, HIV, HBV, HCV—see respective chapters

 

Background (NEJM 1996;335:468; 2012;366:1028; J Urol 1993;149:1046; Ann Epidemiol

2000;10:509)

Classification: Uncomplicated cystitis: Acute (<14 d) infection of the lower urinary tract in an otherwise healthy, nonpregnant woman

Complicated cystitis/UTI: Acute UTI in anyone else (see “Red Flags” below) Pyelonephritis: Infection of the kidneys, usually extension of lower urinary tract infection

Epidemiology: Lifetime incidence in ♀ ≥50%; 11% of ♀ report at least 1 UTI/y; much rarer in young ♂, although after age 65, incidence equal between ♀ & ♂

Microbiology: E. coli causes 80% of uncomplicated UTIs; other pathogens: Proteus mirabilis, Staph saprophyticus, & Klebsiella pneumoniae (CID 1999;29:113); complicated UTIs may be caused by broad variety of organisms

Risk factors: Previous UTIs, sex, spermicide use (alters vaginal flora), BPH, DM2, GU tract surgery/recent instrumentation, bladder dystonia, indwelling catheter

Evaluation (AFP 2002;65:1589; Ann Intern Med 2012;156:ITC3–1; JAMA 2002;287:2701)

History: Dysuria, frequency, suprapubic pain, malodorous urine, & urgency in the absence of vaginal sx argue strongly for UTI; altered mental status or incontinence in the elderly; elicit sexual hx (i.e., new partners) to evaluate for STIs; see “STIs”

Criteria for complicated UTIs: ♂, Childhood UTIs, urinary tract abnormality (incl indwelling catheter or recent instrumentation), DM, hx pyelonephritis, nephrolithiasis, elderly, recurrent UTIs, recent abx, hx multidrug resistant UTIs

Differential diagnosis: Gonococcal or chlamydial urethritis, interstitial cystitis (bladder pain related to filling/emptying w/ frequent voids occurring over mos), irritants (tampons, condoms, detergents), pyelonephritis, vaginal infections (trichomonas, candidiasis), PID; in ♂: Prostatitis, BPH, or epididymitis

 

Exam: VS; GU exam: suprapubic tenderness or fullness (urinary retention), CVA tenderness; pelvic exam if sx suggestive of vaginitis (including atrophic vaginitis) or urinary source unclear

Diagnostics: Uncomplicated UTI may be diagnosed based on sx; telephone diagnosis using established protocols is safe & effective (Wisc Med J 2007;106:326; Am J Med 1999;106:636; Arch Intern Med 2004;164:1026); for those w/ complicating features or pyelonephritis, must obtain urinalysis (midstream) and urine culture

 

Laboratory Testing in Urinary Tract Infection
Urine Dipstick	Urinalysis	Urine Culture
Leukocyte esterase (Se 75– 96%/Sp 94–98% for WBC); nitrite detects Enterobacteriaceae (which incl E. coli) only (Med Clin North Am 1991;75:313)	Pyuria (>10 neutrophils/HPF [95% Se, 71% Sp]) + bacteriuria ± hematuria (>5 RBC/hpf); pH >6.5 suggests urea-splitting organism such as Proteus	>105 cfu/mL used to be the gold standard for dx, but if hx strongly suggests UTI then a lower cut-off (102 cfu/mL) reasonable

Imaging: Not needed for diagnosis of UTI or pyelonephritis; generally only ordered if suspicion of alternative/precipitating etiology (stones, abscess); consider in pts w/ pyelonephritis and: ♂ Gender, DM, renal colic, or no response to abx after 72 h

Treatment (AFP 2000;61:713; AFP 2010;82:638; CID 2011;52:e103; NEJM 2003;349:259)

Asymptomatic bacteriuria: Defined as >105 cfu/mL of a single organism; found in 5% of women; treat if pt is pregnant, undergoing hip arthroplasty or a urologic procedure; pts w/ DM do not need to be screened or treated for asx bacteriuria (NEJM 2002;347:1576) Uncomplicated UTI: Multiple regimens available; note duration varies by Rx

Complicated UTI: Preferred regimen varies by case; review prior culture data; do not use moxifloxacin (even if spectrum appropriate, GU drug concentration is too low to be effective); avoid nitrofurantoin or b-lactams in ♂, as they do not treat occult prostatitis

 

Uncomplicated UTI Regimens
Antibiotic	Duration	Notes
Nitrofurantoin 100 mg PO BID	5 d	Preferred 1st-line agent

 

TMP-SMX DS 1 tab BID Fosfomycin 3 g PO	3 d ×1	Use if no abx use in the past 3 mos, no recent hospitalization and local resistance <20%
Amoxicillin/clavulanate 500/125 mg	7 d	2nd-line agent
Not Fluoroquinolones	Save for complicated UTI – ↑ resistance

 

Complicated UTI regimens
Antibiotic	Duration	Notes
Ciprofloxacin 500 mg BID Levofloxacin 500–750 mg daily	7–14 d	For patients who have not recently received an FQ and are not from a long-term care facility
TMP-SMX 160/800 mg (DS) one PO BID	7 d	Phenazopyridine 200 mg PO TID × 2 d; avoid in pts w/ G6PD deficiency

For dysuria/symptom management: May add phenazopyridine 200 mg PO TID × 2–3 d; avoid in pts w/ G6PD deficiency; caution pts can → orange urine

Pyelonephritis: Dx of UTI + CVA tenderness and/or systemic sx: If pt does not meet ED referral criteria (below), tx guided by local FQ resistance patterns

Empiric if E. coli FQ resistance <10%: Ciprofloxacin 500 mg PO BID

× 7 d: Noninferior to 14 d and ↓s/e (Lancet 2012;380:484) Empiric if E. coli FQ resistance >10%: Consider first-dose IV w/ CTX 1 g or cipro 400 mg IV × 1, then empiric cipro 500 mg BID

Culture-guided subsequent treatment: Narrow regimen if possible; if narrow to TMP-SMX or B-lactam (2nd-line), extend to 14-d course (NEJM 2003;349:259); do not use nitrofurantoin (does not penetrate renal parenchyma); do not use moxifloxacin (ineffective 2/2 low [GU])

Symptomatic candiduria: Fluconazole 200 mg PO QD × 14 d; consider U/S or CT for persistent candiduria in DM pts to assess for hydronephrosis, fungal balls, or abscesses

When to refer: Complicated pyelonephritis: Pts w/ severe systemic sx, hemodynamic instability, altered mental status, pregnant, unable to tolerate PO, inability to confirm close outpatient f/u → ED/inpatient admission

Recurrent UTI

 

Definition: >2 UTI in 12 mos

Pt counseling: Avoid spermicides; unclear whether hydration, postcoital voids, methenamine hippurate, probiotic vaginal suppositories, wiping urethra front-to-back are effective; cranberry juice ineffective (JAMA 2016;316:1879)

Self-treatment: Depends on prior susceptibilities; consider TMP-SMX; instruct pt to call if sx persist >48 h

Postmenopausal: Consider intravaginal estrogen cream

Postcoital ppx: Nitrofurantoin 50–100 mg PO or cephalexin 250 mg PO × 1 postcoitally; TMP-SMX ½ SS tab (40/200 mg) PO if pt has high- efficacy birth control regimen

Prophylaxis: NNT to prevent 1 UTI/y = 2.2; NNH to cause 1 side effect (nausea, rash, candidiasis) = 13.5 (AFP 2005;71:1301)

Initiation: 6 mos trial w/ observation for infection; start after latest infection resolved (confirmed w/ negative UCx) Duration: >12 mos duration not evaluated; not recommended in pts at risk for complicated UTIs; chronic nitrofurantoin associated w/ hepatitis, neuropathy, pulm complications—counsel pt; advise risk & sx of C. diff infection Regimens: TMP-SMX ½ SS tab (40/200 mg) PO QHS if local E. coli resistance <20%, or nitrofurantoin 100 mg PO QHS; may also use cefaclor, cephalexin; FQs & TMP-SMX contraindicated in pts who could become pregnant

 

Background (www.cdc.gov; CID 2008;46:S19; Infect Control Hosp Epi 2010;31:431)

Clostridium Difficile Infection case definition: Clinically significant diarrhea or toxic megacolon without other etiology with (1) stool with positive toxin A-or B-producing organism; (2) pseudomembranes seen on endoscopy; (3) pseudomembranous colitis on histopathology Rapidly increasing incidence in US, including community-acquired infections and community-based recurrence; 500K cases in 2011; most common hospital-acquired infection in US; increasing severity → higher hospital mortality (CID 2012;55:S88)

Microbiology: Spore-forming, toxin-producing, anaerobic gram-

 

positive rod; resistant to alcohol disinfectants; spores are ingested, colonization occurs → protective colonic flora disturbed → C. diff releases toxin A/B which mediates mucosal inflammation and damage

→ necrosis/pseudomembranes

Risk factors: Recent antibiotic use: Fluoroquinolones, clindamycin, penicillins/cephalosporins assoc w/↑ risk, but all abs implicated (CID 2008;46:S19); antacids (Am J Gastro 2012;107:1011), age, chemotherapy, immunosuppression, hospital exposure

Evaluation (CID 2012;55:S88)

Hx/PE: Assess for risk factors (above) and red flags (suggest fulminant colitis): Fever or hemodynamic instability, severe or systemic symptoms, lower or diffuse abd pain, ileus, distention

Labs: CBC, BMP (WBC and Cre used to assess disease severity)

If diarrhea and risk factors, send stool for EIA testing (glutamate dehydrogenase [GDH] antigen test + toxin A/B test); GDH enzyme is present in all C. diff isolates; toxin confirms strain is pathogenic; if indeterminate → PCR for tcdB and tcdC genes to confirm disease; False ⊕ seen in asx carrier or s/p tx

KUB: Typically obtained in setting of ED eval; colonic distention (>7

1. cm) = emergency

Treatment (CID 2012;55:S88; Inf Cont & Hosp Epi 2010)

General approach: Treatment determined by severity: No consensus guidelines for classification of mild, mod, severe illness, relies on clinician judgment; proposed stratification by IDSA/SHEA below

Asx colonization: Toxin or PCR ⊕ and no symptoms → no treatment

required

Acute diarrhea w/ colitis: Watery, rarely bloody ±mucus; spectrum of systemic sxs; only mild and some moderate disease appropriate for outpatient treatment

Mild–moderate disease criteria: T <38.5, WBC <15K, no peritoneal signs, no evidence of sepsis, age <65 y; all others → ED

Treatment regimen: For mild–mod disease, metronidazole 500 mg PO TID ë 10–14 d

Other meds: D/c all antiperistaltics

Other antibiotics: If on antibiotics to treat a different infection, d/c if not essential; if must continue, C. diff tx course should extend 7 d

 

beyond last dose of other abx Reassess: If no improvement after 2–3 d, change to vancomycin 125–500 mg PO QID

Recurrence: 1st – Same regimen as original; 2nd – vancomycin in tapered or pulsed regimen (vanco 125 mg PO q6h for 10–14 d, then 125 mg PO q12h for 1 wk, 125 mg PO QD for 1 week, 125 mg PO every 2 or 3 d for 2–8 wk)

Refractory disease: Fecal transplant appears safe and effective (NEJM 2013;368:407; Open Forum Infect Dis 2015; 2: ofv005)

When to refer: Severe disease, red flags → ED; recurrent or persistent disease or for guidance on continuing preceding antibiotics → ID

 

Background (JAMA 2016;317:3; NEJM 2004;350:904; BMJ 2012;345:e4955)

Definition: Acute, pyogenic inflammation of dermis & subcutaneous tissue 2/2 bacterial infection; ranges from mild infections of the epidermis (impetigo, erysipelas), or hair follicles (folliculitis, furuncles, carbuncles), deeper involvement of the dermis (cellulitis), abscesses or life-threatening infection (necrotizing soft-tissue infection [NSTI]) Presentation: May occur on any part of epidermis, but legs common, followed by face, feet, hands, torso, neck, & buttocks (AFP 2002;66:119) Epidemiology: Incidence estimated as ∼4%/y; >14 million outpt visits/y in US (↑ >50% in past 10 y), in large part 2/2 ↑ in CA-MRSA infection

Risk Factors: Disruption of skin barrier (tinea, atopic dermatitis, trauma, IDU); disruption of vascular/lymphatic system (PAD, venous stasis, prior surgery/trauma), or depressed immune function (DM, HIV) Microbiology: Nearly all cases 2/2 S. aureus or pyogenic Strep spp (GAS >> GCS, GGS); hospital or community-acquired MRSA (CA- MRSA) → 20–50% of SSTIs

1. aureus more common: Abscess, furuncle/carbuncle, impetigo, folliculitis S. pyogenes more common: Erysipelas, cellulitis

Polymicrobial: Abscess 2/2 IVDU, trauma; deep/subacute DM foot infection (see below)

Syndromes (Chest 1996;110(1): 219)

 

Infection by Cutaneous Layer
	Skin/Soft Tissue Layer	Infection
	Epidermis	Erysipelas Impetigo
	Hair follicle	Folliculitis Furunculosis (deep) Carbunculosis (deep)
	Dermis/superficial fascia	Cellulitis
	Subcutaneous and below	Necrotizing STI

Evaluation

History: Inquire re: onset, duration, prior hx of similar presentations, tx (incl topical) risk factors (above) including prior injury to area, prior episodes of infection, shaving (folliculitis), presence/absence of systemic symptoms

History suggestive of specific pathogen: Hot tub (P. aeruginosa folliculitis), animal bites (Pasteurella multocida, Capnocytophaga canimorsus; see “Bites & Stings”), freshwater exposure (Aeromonas, Pseudomonas), salt water (Vibrio, Erysipelothrix), unseen “spider bite” (MRSA), immunocompromised (common pathogens still common, but consider GNR, P. aeruginosa, rarely nontuberculous Mycobacteria, Cryptococcus, other fungi)

Methicillin-resistant S. aureus risk factors: Hx MRSA colonization,

⊕ MRSA household contacts, IVDU, recurrent infection, failure to respond to MSSA/Strep tx, recent healthcare facility exposure, indwelling line, immunocompromised; contact sports, crowded, or unsanitary living conditions, MSM; n.b. many pts w/ MRSA have no risk factors; should consider local endemic rates when deciding on empiric coverage

Exam: Gen: Vital signs, ill-appearing or not; LN: Assess for proximal LAD, look for proximal streaking (lymphangitic involvement); CV: Check distal pulses (PAD)

Lesion: Assess for purulence, well vs. poorly demarcated (superficial vs. deep), indurated, fluctuant (abscess), bright red (infectious) vs. darker (hemosiderin, dependent rubor); if lesion on

 

LE, elevate leg (if redness ↓↓, consider venous stasis), temperature of affected skin relative to surrounding areas; distribution (bilateral suggests other causes), ulceronodular lesions w/ surrounding erythema (Sporothrix, other fungi [soil], mycobacteria, tularemia)

Red flags: Rapid spread, woody feel w/ loss of palpable landmarks, edema & hyper/hypesthesia extending beyond cellulitic border, skin ecchymosis, SC emphysema, necrosis, or e/o sepsis → suspect NSTI

→ immediate referral to ED

Labs: Typically not needed; obtain CBC, BMP if suspect sev/systemic infection

Culture: Indications vary by SSTI; Cellulitis: Tissue/blood cx if suspicion for atypical pathogen, e/o systemic infection; Abscess: If large/multiple abscesses or planned abx use

Imaging: Typically not needed but may obtain if concern for osteomyelitis or NSTI

Differential diagnosis: Up to 1/3 of LE “cellulitis” cases are actually due to another cause: Vascular (DVT, superficial thrombophlebitis, calciphylaxis, stasis dermatitis), inflammatory (drug reactions, contact dermatitis, gout, erythema nodosum), other infections (erythema migrans, zoster), miscellaneous (insect bites/stings); many of these causes are also RF for cellulitis which independently require mgmt (JAAD 2012;67:186) (see “Lower Extremity Edema” for dx & mgmt of venous insufficiency)

Treatment (CID 2014;59:2; AFP 2015;92:474)

Management based on whether infection is purulent vs. nonpurulent General approach to purulent STI: I&D if large enough to drain, with cultures sent from abscess if considering antibiotics; mild SSTI do not require further treatment; for moderate infection, abx as below; for sever infection → inpt/ED

Red flags: Abscess requiring extensive I&D, in cosmetic/sensitive area (face, neck, groin), suspect extension near/into deeper structures, systemically ill, immunocompromise

Furuncles/carbuncles: No evidence abx significantly improve outcomes

1st-line: Moist heat → auto-drainage

 

Alt: I&D if large; systemic abx if significant cellulitis or pt clinically ill Recurrent/interpersonal transmission: Consider staph eradication w/ antibacterial soaps/washes & mupirocin nasal carriage eradication

Abscess: I&D if drainable fluid collection +/- abx (see below) Antibiotic indications: Location (digits, face, genitals, or multiple sites), severity (systemic sx, inability to fully drain), significant surrounding cellulitis/phlebitis, ↑ risk complications (immunosuppressed, elderly), tx failure w/ I&D alone

Antibiotic choices: Empiric coverage for MRSA generally recommended—susceptibilities vary by region & even by hospital; do not use FQ for MRSA even if reported susceptible

 

Antibiotic Regimens for Moderate Purulent SSTI
Empiric tx	Targeted tx
•  TMP-SMX 1–2 DS tabs BID •  Doxycycline/minocycline 100 mg BID •  Clindamycin 300—450 mg PO QID	•  MRSA: See empiric •  MSSA: Dicloxacillin 500 mg QID or cephalexin 500 mg QID

General approach to nonpurulent STI: For mild infection, topical abx, for others coverage of strep infection and MSSA most important; if culture data available, use to guide (but typically none available)

Red flags: Periorbital cellulitis, concern for NSTI (see above), e/o systemic infection, immunocompromised

Impetigo: Most superficial infection, affects face & limbs, red w/ “honey crust.” Topical generally equivalent to systemic abxs; 1st-line: Topical mupirocin TID; preferred to bacitracin/neomycin 2/2 ↑ activity vs. staph; Many lesions or failing topical tx: Oral abx against strep/staph Folliculitis: Inflammation follows hair follicles; usually spontaneously resolves; warm compresses, avoid shaving affected area; consider mupirocin (AFP 2002;66:119)

Erysipelas: Well-demarcated, brightly erythematous; rare in adults but may cause sepsis or deeper infection if not treated early, esp in elderly:

→ Hospitalize if febrile as may progress quickly

Cellulitis: No e/o better outcomes w/ empiric MRSA coverage in pts w/o MRSA risk factors or purulence (CID 2013;56:1754); treat underlying conditions (maceration, edema, venous stasis, tinea, dermatitis) as

 

able to ↓ recurrence

If failing to improve: Consider switch to IV, adding MRSA coverage, skin bx, alternate organisms & diagnoses (above) and/or drain abscess if present, consider ID consult Other: See “Bites and Stings” for animal, human bite pathogens & tx Recurrent cellulitis: For patient with 2 or more episodes of nonpurulent cellulitis in the past 3 y, consider PCN VK 250 mg PO BID for oral suppressive therapy (NEJM 2013;368:1695)

When to Refer (BMJ 2012;345:e4955)

Emergency department: Periorbital cellulitis (ENT eval), abscess requiring extensive I&D, in cosmetic/sensitive area, suspect extension near/into deeper structures (surgical eval), concern for NSTI, meets sepsis criteria or e/o systemic infection

Infectious disease specialist: Failure to improve w/ tx, complex DFI, immunocompromised pt

Dermatology or ID: Dx uncertain

DIABETIC FOOT INFECTION (CID 2012;54:e132)

 

Background

Pathophysiology: Trauma (often minor) or loss of skin integrity → neuropathic wound → impaired healing 2/2 vasculopathy, neuropathy

→ superinfection

General approach: Infection (vs. colonized ulcer) determined by purulence ± inflammation; Ddx includes trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis

Ulcer risk factors: ⊕ PAD or ↓ sensation in affected limb, CKD, hx

walking barefoot; risk of progression to osteomyelitis if ulcer present

>30 d, prior LE amputation

 

Classification: Acute (<2 wk); chronic (>3 wk); Mild: Limited to SC tissue, Moderate: Extending to deeper structures including bone, joints, fascia; severe: Infection + SIRS

Microbiology: Superficial/acute infections → Staph & Strep spp Deep/chronic infections → polymicrobial, incl P. aeruginosa, enteric

GNRs, anaerobes

Evaluation

History: Prior DFI, neuropathy, CKD; lesion history (onset, duration), systemic sx

Exam: Assess for ulcer, local inflammation, vascular exam, neuropathy, tinea; for ulcers, probe for communication to bone Diagnostics: Probe-to-bone test: If ulcer probes to bone, then assume osteomyelitis (no imaging needed); if chronic deep ulcer, eval for osteomyelitis with plain radiograph → insensitive in early infection; if XR ⊖, serial radiograph vs. MRI

Culture: Recommended; 1st cleanse & debride to decrease contamination with wound colonizers, then culture based on ulcer w/ sterile instruments or obtain bone biopsy; if pt stable/minimal inflammation, complete biopsy/debridement prior to abx; no role for superficial wound swab or specimen from clinically uninfected wound

Management

All patients: Behavioral: Offload wt bearing, wound care, glycemic control, proper footwear; also needs vascular evaluation as osteomyelitis not curable in absence of vascular sufficiency to allow healing of overlying skin; Referral: Co-mgmt w/ ID, orthopedics, wound specialists, vascular services optimal

Wound Care: see “Wound Care”

Indications for hospitalization: Severe disease; mod disease & complicating factors (e.g., severe PAD) or unable to adhere to tx regimen as outpt; failing to improve w/ outpt tx

 

Management of Selected DFI
Severity	Antibiotic	Notes/Precautions
Mild	Cephalexin Amoxicillin/Clavulanate	Consider adding Pseudomonas and anaerobic coverage if chronic;

 

Mild + RF for MRSA	Doxycycline TMP–SMX	treat 1–3 wk with final duration   determined by clinical response
Moderate +/- RF for MRSA	ID and surgical consult for management of associated osteomyelitis, abscess, or septic arthritis	Consider for outpatient IV antibiotic therapy if not meeting criteria for admission

Follow-up: If not improving at 3–5 d follow-up, re-eval abx, consider surgical referral

 

Background (JAMA 2006;296:964; 2011;305:1441; 2011;305:1441; JAAD 2007;57:737)

Microbiology: dsDNA herpesviridae; herpes simplex viruses 1 (HSV-

• & 2 (HSV-2) are common causes of mucocutaneous disease, characterized by lifelong infection w/ periods of latency & reactivation HSV-1: Responsible for essentially all cases of clinical orolabial disease & 10–20% of new genital infections in US; can also → skin (e.g., eczema herpeticum), eye (keratitis), & CNS disease (encephalitis) (JAAD 2007;57:737; CID 2013;56:344; JAMA 2016;316:23)

HSV-2: Responsible for anogenital lesions but can also infect oral mucosa; infection in ♀→ ↑ risk of neonatal HSV; can also cause CNS disease (meningitis, including recurrent, assoc w/ Mollaret’s) Epidemiology: 23.6 million new cases/y in persons aged 15–49 y; US seroprevalence of HSV-1/HSV-2 ∼58/17%; of these people, only 10– 25% have ever had clinical disease; acquisition rates higher in ♀ (HSV- 2), prior STI (HSV-2), ↑ number of lifetime sexual partners (HSV-2), uncircumcised men (♂ circumcision ↓ HSV-2 acquisition by 25%) (NEJM 2009;360:1298); African-American (HSV-1 & 2), early acquisition assoc w/

↓ SES

Transmission: Typically via direct contact w/ mucus membranes; oral– oral, oral–genital, genital–genital; can also occur via shared utensils or towels; most transmission occurs during asx periods of viral shedding Natural history: Incubation period 2–20 d (AFP 2010;82:1075); primary infection: Ranges from subclinical to ulcers & ⊕ constitutional signs (pharyngitis, mono-like sx) → latency: In CN V ganglia (orofacial) or

 

sacral (genital) → reactivation: usually 1–6 episodes/y, milder, shorter in duration than primary episode

Risk factors for reactivation: Immunosuppression → more frequent reactivation & dissemination, UV exposure, trauma, fever

Risk factors for transmission: HIV ⊕, <12 mos since 1° infection,

symptomatic disease; viral shedding occurs in 10.2% of seropositive

asx pts (vs. 20% of pts w/ sx disease)

Evaluation

History: Systemic sx (fever, malaise, LAD) + sudden painful lesions, new or HSV ⊕ sexual partner (1° infection), prodromal mucocutaneous burning/tingling → skin lesions in area previously affected (reactivation), dysuria (genital), triggers (UV exposure, topical retinoids, stress, local trauma), hx immunosuppression

Characteristic lesion: Grouped vesicles on erythematous base that progress to scalloped bordered erosions w/ hemorrhagic crust Orofacial: 1° disease usually in childhood (painful oral lesions + systemic sx) Reactivation: Typically milder/shorter duration, often same location as prior episodes; Herpes labialis (“cold sore”): Crusted papule or erosion w/ hemorrhagic crust on outer vermillion of lip; Intraoral herpes: Erosions on keratinized mucosa (hard palate, gingiva, dorsal tongue)

Anogenital: Vesicles of varying sizes; ♀: Labia minora, introitus, urethral meatus, reactivation on buttocks of older women; ♂: Shaft & glans

Other subtypes: Herpetic whitlow (distal phalanx); eczema herpeticum in pts w/ atopic dermatitis or burns; “punched out” monomorphic hemorrhagic vesicles & erosions, + fever/malaise → urgent referral to ED; herpes gladiatorum (multiple lesions) in contact sports; HSV can also be assoc w/ erythema multiforme

Diagnosis: If dx uncertain, unroof vesicle w/scalpel and then swab lesion → direct fluorescent Ab (result 24–48 h), Tzanck smear (most rapid), viral culture (gold std), skin bx

Serologic testing: Given high seroprevalence of HSV-1, ⊕ test not

very useful in dx of specific lesion; cannot distinguish between oral & genital HSV-1; HSV-2 Ab test has low specificity and not recommended for routine screening including during pregnancy (JAMA 2016;316:23); Abs

 

can be ⊖ w/ latent infection; can help est baseline in HIV ⊕, assist in dx when recurrent ulcers & viral cx/PCR ⊖

Management (JAMA 2006;296:964; 2011;305:1441; JAAD 2007;57:737)

Counseling: Pts can expect recurrence (1–6/y); these episodes are typically milder & shorter duration, often ↓ frequency over time; can ↓ risk of recurrence of orofacial disease w/ regular sunscreen use; prevent autoinoculation w/ hand hygiene

Risk of STIs: Genital HSV infection assoc w/ ↑ risk of HIV infection, likely 2/2 impaired mucosal barrier (NEJM 2009;360:1298)

Risk of partner transmission: Risk ↑ when lesions visible; however, majority of infections occur via asx viral shedding; counsel pts to inform partners, use condoms (esp in 12 mos after initial infection) & avoid sexual contact during sx periods (J Infect Dis 2006;194:420; BMJ 2007;334:1048) Pregnancy: Routine screening is not recommended; for women with recurrent genital HSV, offer suppressive therapy at 36 wk gestation; for outbreak at the time of delivery, consider C-section

Pharmacologic tx: May shorten course; start at 1st signs of cutaneous burning/tingling (consider giving pts w/ recurrent disease Rx they can fill to have available at 1st sign of recurrence)

Indications for suppressive treatment: >6 clinical episodes/y, HSV ⊖

partner, pt at ↑ risk for contracting HIV; dose adjustment and consideration of alternate agents in the immunosuppressed

 

Treatment of HSV in Immunocompetent Patients (JAAD 2007;57:737; MMWR 2015;64:1)
Medication	Clinical Context	Dose
Acyclovir	Primary oral or genital	400 mg PO TID × 7–10 d
	Recurrent genital	400 mg PO TID × 5 d; or 800 mg PO BID × 5 d; or 800 mg PO TID × 2 d;
	Suppressive therapy	400 mg PO BID
	Herpes labialis (Arch Intern Med 2008;168:1137)	200–400 mg 5×/d × 5 d 5% crm—apply 5×/d × 4 d
Valacyclovir –  ↑ bioavailability –  FDA-approved for Rx of HSV in HIV	Primary oral or genital	1 g PO BID × 7–10 d
	Recurrent genital	500 mg BID × 3 d; or 1000 PO QD × 5 d
	Herpes labialis	2 g PO BID q12h × 2 doses
	Suppressive therapy	500 mg PO daily

 

 

Background (Arch Int Med 1997;157:1217; JAAD 2007;57:S136; Ann Intern Med

1995;155:1605)

Definition: VZV causes 2 forms of disease: Varicella (“chickenpox,” usually primary infection acquired in childhood) & herpes zoster (“shingles,” reactivation from the sensory ganglia → typically dermatomal distribution)

Shingles risk factors: Age >50 yo, immunosuppression (s/p transplant, autoimmune disease, immunosuppressive medications esp MMF, malignancy, HIV ⊕), ♀ gender, trauma, stress

Complications: Postherpetic neuralgia (pain present >90 d; 5% in

pts <60 yo, 20% in pts >80 yo) that may last mos–y; bacterial superinfection of the skin (2.3%); ocular complications (1–2%); meningitis/encephalitis (0.5%); motor neuropathy (1–3%); GBS (0.03%); stroke syndromes due to cerebral artery involvement (1.5– 4.4% of HIV ⊕ pts) (J Pain Symptom Manage 1996;12:290; CID 2010;51:525; Neurology 2008;70:853; Brain 1994;117:987)

Recurrence: 1–4% of individuals will have a 2nd episode of zoster; ↑ in immunocompromised pts (Mayo Clin Proc 2007;82:1341; Ann Intern Med

1988;108:221)

Evaluation (JAMA 2009;302:73)

History: Prodromal HA & fatigue; skin pain, burning, itching, allodynia often in dermatome where the eruption later develops Physical: Cutaneous findings of grouped (“herpetiform”) erythematous to violaceous edematous papules → vesicles on an erythematous base, which can appear umbilicated or pustular if long- standing → hemorrhagic crusting (usually w/in 1 wk, no longer infectious); usually affects only one dermatome but can affect 2–3 consecutive dermatomes; can occur without rash (zoster sine herpete)

Diagnosis: Determined by morphology & distribution; confirmatory tests are best done in vesicular phase: Unroof vesicle w/scalpel and then swab lesion → direct fluorescent Ab testing (quickest to result, usually within 24–48 h), viral culture, skin bx

 

Management

Acute neuritis: NSAIDs, APAP, ice for mild pain; opioids may be necessary for mod–severe pain; neither glucocorticoids nor TCAs have been shown to help in the mgmt of acute neuritis or in preventing postherpetic neuralgia (JAMA 2009;302:73)

Antivirals in immunocompetent hosts: Valacyclovir 1000 mg PO TID, famciclovir 500 mg PO TID, or acyclovir 800 mg PO 5×/d × 7–10 d; ↓ time to resolution of lesions if given within the first 72 h, lessens acute neuritis & helps prevent postherpetic neuralgia (JAMA 2009;302:73; CID 1996;22:341; Arch Intern Med 1997;157:909; Scand J Infect Dis Suppl 1991;80:62);

consider addition of prednisone taper

Antivirals in immunocompromised hosts: Treat all pts even if they present after 72 h; if disseminated, will need urgent ED referral for admission & IV acyclovir

Postherpetic Neuralgia: See table

 

Treatment of Postherpetic Neuralgia
Medication Class	Examples	Considerations
Anticonvulsants	Gabapentin, pregabalin, divalproex sodium	Dizziness, somnolence, dry mouth, edema, wt gain reported Abrupt d/c may → withdrawal sx
TCAs	Nortriptyline, amitriptyline, desipramine	Anticholinergic effects & lag time (up to 3 wk), can ↑ QTc
Opioids	Codeine, tramadol, oxycodone, morphine	Use cautiously; potential for addiction & diversion
Topical Agents	Capsaicin, lidocaine patch	Topicals not tolerated by up to 1/3 of pts

(Neurology 2004;63:959; Cochrane Database Syst Rev 2011 :CD006866; Ann Pharmacother

2011;45:1483; Clin Pharmacol Ther 1988;43:363; Pain 1988;33:333)

 

Recurrence prevention: Shingles vaccine may ↓ risk of recurrence; is well-tolerated; offer to pts ≥3 mos after zoster episode (booster effect may be greater if further out from zoster episode); see “Immunizations”

(JID 2013;208:559)

When to Refer (NEJM 2005;353:e14)

Herpes zoster ophthalmicus: Reactivation of VZV in CN V1

 

dermatome; accounts for 10–25% of all zoster cases; assoc w/ vesicles & erosions on nasal tip (Hutchinson sign); 71% have ocular complications including keratitis, conjunctivitis, episcleritis, corneal scarring, iritis, vision loss in 15%; also can → acute retinal necrosis or progressive outer retinal necrosis (immunocompromised); requires urgent ophthalmologic eval (JAAD 2007;57:S136; Am J Med 2017;130:1) Herpes zoster oticus (Ramsay Hunt syndrome): Reactivation of VZV in CN VII dermatome, geniculate ganglion; presents w/ ipsilateral facial paralysis, ear pain, occipital HA, vesicles in the auditory canal & auricle; ± numbness over jaw, ↓ taste, vestibular symptoms → ENT referral (Ann Neurol 1994;35:S62; JAMA 2009;302:73)

Disseminated zoster: Prevalence in immunosuppressed pts; defined by >20 vesicles outside of 1 dermatome; requires admission → IV acyclovir

 

Background (www.who.int; Hepatology 2009;50:661; NEJM 2008;359:1486)

Epidemiology: >240 million people worldwide chronically infected with hepatitis B virus (HBV); 850K–2M carriers in US (most asx) Complications of chronic infection: 15–40% will develop serious sequelae (cirrhosis, ESLD, HCC) over their lifetime; HBV → 100× ↑ risk of HCC, even without cirrhosis

Microbiology: HBV is a partially dsDNA retrovirus, primarily infects hepatocytes, difficult to eradicate, transmitted by bloodborne exposure, sexual contact, vertical transmission

HBV Risk factors: Birth in endemic area (Africa, Asia, S. Pacific, due to perinatal transmission); adult transmission: Sexual/household contacts, PWID, MSM, prisoners, ESRD on HD

Risk factors for chronic infection: Progression to chronic HBV (vs. clearance) assoc w/ ↓ age at acquisition: 90% for perinatal, 20–50% for age 1–5; <5% for adult

Natural history of chronic infection: Highly variable, several potential phases, all of which may last several years

• Replicative phase: High HBV viral load, active liver

 

disease/necroinflammation (transaminitis, inflammation on liver biopsies) (2) Low-replication phase: Lower viral load (with or without immune tolerance; can have liver inflammation) (3) Remission phase: Carrier state (remains in hepatocytes)

(4) Reactivation phase: Chronic hepatitis

Risk factors for reactivation: HbSAg positive, immune suppression (anti-CD20 agents > cytotoxic chemo+prednisone, anti-TNF agents > methotrexate, azathioprine, glucocorticoids)

Evaluation (MMWR 2008;57:1)

Screening: Those at ↑ risk of infection or complications, including pregnant ♀, HCV ⊕, HIV ⊕, pts starting immunosuppressants, chemotherapy, chronic ↑ ALT/AST, DM

Diagnosis: Acute infection: HbsAg, Anti-Hbc IgM;

Screening for chronic infection: Anti-HBs, HBsAg, anti-Hbc

 

 

 

 

 

 

 

Diagnosis                                  HbsAg  anti-HBs    anti-HBc  HBeAg  anti-HBe    HBV DNA
Acute hepatitis	⊕	⊖	IgM	⊕	⊖	⊕
Window period	⊖	⊖	IgM	±	±	⊕
Recovery	⊖	⊕	IgG	⊖	±	⊖
Immunization	⊖	⊕	⊖	⊖	⊖	⊖
Chronic hepatitis HBeAg ⊕	⊕	⊖	IgG	⊕	⊖	⊕
Chronic hepatitis HBeAg ⊖	⊕	⊖	IgG	⊖	⊕	±*

*Precore mutant: HBeAg not generated, but anti-HBe can develop due to cross-reactivity w/ HBcAg; assoc w/ high serum HBV DNA levels

(From Sabatine MS, ed., Pocket Medicine, 6th ed., 2017)

 

Prevention

Counseling: Immunization of sexual partners, condom use; cover open cuts/scratches; ineligible for blood/sperm/organ donation; do not share toothbrushes or razors; no other restrictions (day care, contact sports okay)

Immunize: See “Immunizations”; n.b.: If schedule is interrupted after 1st dose, give 2nd dose ASAP, no need to start over; 2nd & 3rd dose should be at least 8 wk apart

 

Postexposure prophylaxis: Recombinant Hep B vaccine should be administered as near to the time of exposure as possible; HBIg ↓ incidence & severity of infection if given w/in 7 d of exposure (Expert Rev Clin Immunol 2011;7:429)

Acute Infection (Hepatology 2009;49:S28; cdc.gov/hepatitis/HBV)

Epidemiology: 2.1/100,000 new cases/y in US, most cases among pts 25–44 y; (↓ 80% from 1987 to 2004 2/2 vaccine availability & universal/needle precautions)

Incubation: Range of 6 wk–6 mos, average 90 d

Presentation: Often mild but wide range of manifestations; only 30– 50% adults develop sx (<1% fatal); typical sx = fatigue, fever, jaundice/dark urine (at bili levels >2.5), pruritus, RUQ pain, N/V, loss of appetite; aminotransferase levels often >1000; ↑ risk of severe disease in elderly; Ddx: CMV, EBV, other viral hepatitis, acute HIV

Diagnosis: For acute infection, initially obtain HbsAg, Anti-Hbc IgM Treatment: Supportive care for mild cases; suspicion of acute lever failure warrants emergent referral → ED, consider antiviral therapy; reportable to CDC/local health dept; IFN gamma NOT indicated as increases mortality

Chronic Infection (NEJM 2004;350:1118; Liver Intl 2017;37:59; cdc.gov; Hepatology

2009;50:661)

Background: Leading cause of cirrhosis and HCC

Risk factors for complications:

Cirrhosis: ↑ Age, genotype C, ↑ HBV DNA, ♂, EtOH, HCV, HDV, HIV⊕

HCC: ↑ Age, EtOH, HCV ⊕, smoking, ♂, ⊕ FHx, cirrhosis

Diagnosis: Chronic HBV defined by ⊕ HBsAg for >6 mos

Hx/PE: Should assess for complication risk factors, s/sx of cirrhosis (see “Cirrhosis”)

Initial Studies: To establish disease activity, hepatic function, and screen for comorbidities & HCC: LFTs, CBC, PT/INR, HBV DNA, HBeAg/anti-HBe, HCV, HIV, HDV for those at ↑ risk, AFP (U/S in ↑ risk pts)

Treatment: Includes both risk reduction and consideration of direct tx (below)

 

Immunization: HAV in all nonimmune pts

HCC screening: U/S (preferred) w/ or w/o AFP q6–12mos Who: Cirrhosis, ⊕ FHx HCC, African descent >20 yo, or Asian

descent ♀ >50 yo, ♂ >40 yo, or anyone >40 yo w/ ALT elevation

or serum HBV DNA >2000 copies/mL

Disease monitoring: See below

 

HBV Serial Disease Monitoring
HbeAg ⊕		HbeAg ⊖
ALT nl	q3–6mos ALT q6–12mos HbeAg	ALT nl, HBV DNA <2000	q3mos ALT × 3, then q6–12mos if still nl
ALT 1–2× ULN	q3mos ALT, q6mos HbeAg Consider bx if >40; if ↑ ALT persistent, consider bx/Rx	ALT 1–2× ULN HBV DNA 2000– 20,000	q3mos ALT & HBV DNA; consider bx or Rx if persistent
ALT >2× ULN	q1–3mos ALT, q3mos HbeAg Tx if persistent or if ↓ liver function	ALT >2× ULN HBV DNA >20,000	Tx if persistent, bx optional

(Hepatology 2009;50:661)

 

Pharmacologic HBV treatment: Rx’ed by specialists; regimens include tenofovir, entecavir, pegylated IFN-α

Goal: ↓ Complications by suppressing HBV replication; not considered curative Indications: E/o liver disease 2/2 HBV infection (jaundice, decompensated liver disease, cirrhosis) ALT persistently >2× ULN and HbeAg ⊕ or HBV >20,000 IU/mL; liver bx may be used if ALT 1–2× ULN & HBV >2000 IU/mL to help guide mgmt

When to refer: Consideration of initiating tx; persistent ↑ of LFTs or HBV DNA; abnl liver bx; evidence of complications (HCC, cirrhosis)

 

Background (Hepatology 2015;62:932; J Hepatol 2014;61:S58; WJG 2014;20:2876;

 

cdc.gov)

Microbiology: ⊕ ssRNA flavivirus, 6 major genotypes w/ assoc subtypes; in US, genotype 1 most common (70% of cases) >>2 (15–

20%) >3 (10–12%) (J Med Virol 2012;84:1744)

Transmission: Via direct blood contact (IDU, transfusions, needlestick); vertical transmission; sexual transmission exceedingly rare except HIV ⊕ MSM; no vaccine, prevention only by ↓ exposure Incubation: Typically 8–12 wk; range 2 wk–6 mos

Natural history: Acute infection typically asx; for those infected →

∼80% chronic carrier state; if untreated → ∼20% cirrhosis over 20– 30 y → 1–5% annual risk of dying from HCC or ESLD

Epidemiology and Risk Factors (cdc.gov; Hepatology 2015;62:932)

Prevalence: Estimated 2.2–3.2M people anti-HCV ⊕ in US; 75% of them born btw 1945 and 1965; leading cause of death from liver disease & leading cause for liver transplantation in US

Risk factors for infection: IDU (30% young users & >70% older uses infected, risk ↑ even w/ single injection), blood tx or organ transplant recipient prior to 1992, clotting factor recipient before 1987, ESRD on HD, HIV

Risk factors for disease progression: EtOH use, older age, ↑ duration of infection, HIV, HBV, obesity

Evaluation (cdc.gov; www.hcvguidelines.org)

Screening: Those w/ risk factors for infection (above) & one-time screening of all adults born between 1945 and 1965, pts w/ unexplained elevated aminotransferases, sexual partners of HCV ⊕ individuals, postexposure, pts receiving regular transfusions (or any blood transfusion before July 1992), HD, transplant candidates/recipients

Symptoms of acute infection (only ∼20% have sx): Jaundice, RUQ pain, fatigue

Symptoms of chronic infection: Many pts asx but fatigue common, later may develop sxs due to hepatitis or cirrhosis; extrahepatic manifestations can include hematologic (cryoglobulinemia), dermatologic (porphyria cutanea tarda), renal (MPGN), endocrine (thyroiditis, DM)

Diagnostic labs

 

Anti-HCV: Current or past infection, ⊕ 1–3 mos postinfection, 97% sens after 6 mos HCV RNA: Active disease; can be quantitative, ⊕ 2–3 wks postinfection; obtain if ⊕ Anti-HCV (often reflexively ordered); may also be ordered to diagnose despite negative Anti- HCV to dx acute infection (before Ab ⊕) or for w/u of ↑ LFTs in immunocompromised pt

Studies in anticipation of Rx: In addition to HCV Ab and RNA

Labs: ✓ LFTs (incl albumin), INR, PLT, genotype

Fibrosis assessment: Indirect: Serum-based commercial fibrosis score (FibroSURE) or vibration-based transient liver elastography; indirect measures ↓ need for liver bx

Management of acute hepatitis: Supportive care (can consider early antivirals); if concern for acute liver failure (rare) → prompt ED referral

Chronic HCV Management (www.hcvguidelines.org; Hepatology 2015;62:932; Ann Intern Med 2010;152:36)

Immunization: HAV, HBV (if not infected), Tdap, influenza annually, PPSV23

Screen for coinfections: HIV, HBV, sexually transmitted infections HCC screening: Indicated only in pts w/ cirrhosis (unlike HBV): U/S every 6 mos

Pt Education:

Prevent infecting others: Discuss modes of transmission, must avoid blood donation or activities that would expose others to blood, advise vaccination of close contacts (HBV); sex between monogamous couples: risk ∼1 in 190,000 acts Prevent disease progression: Avoid other RFs for liver fibrosis (EtOH, tob, obesity), avoid NSAIDs, limit APAP (<2 g in 24 h), vertical transmission in

♀; coffee is protective

Pharmacologic Treatment: All pts w/ life expectancy long enough to expect benefit should be offered treatment for HCV; Rx’ed by provider trained in HCV treatment

 

Treating Hepatitis C (www.hcvguidelines.org)
Regimen	Selected based on genotype, fibrosis score, and, if ESLD, compensated vs. decompensated; also by prior exposure to antiviral therapy; algorithms constantly being updated

 

Duration	Generally 12 wk Rx if no cirrhosis, 12–24 wk for cirrhosis, often combination of agents
Side effects	Direct acting antivirals: Very well-tolerated, excellent safety profile; mild– mod s/e: Headache, fatigue, nausea, insomnia; occ pruritus, rash Ribavirin: May be used as adjunct; s/e fatigue, flu-like sx, depression, N/V, anemia
Safety Monitoring	Check for drug–drug interactions, especially HIV antiretrovirals; screen for and monitor HBV activity (curing HCV can cause HBV flare); safety labs for more toxic med regimens (CBC for ribavirin)
Treatment Monitoring	HCV viral load at 4 wk into treatment to ensure efficacy (should be undetectable) and 12 wk after cessation: If undetectable, sustained viral resistance “SVR12” (>99% cure)
Efficacy	>95% cure rates, incl all genotypes, lower rates for cirrhosis

When to refer: Refer to HCV provider for consideration of treatment; refer to GI/ID provider w/ medical expertise, ideally at liver transplant center, if decompensated cirrhosis or infection w/ multiple genotypes

 

Background (www.unaids.org; cdc.gov/hiv)

Microbiology: Human immunodeficiency virus (HIV) is a ssRNA lentivirus; retrovirus (inserts itself into host genome); 2 types: HIV-1 most common; HIV-2 infections (limited primarily to W. Africa) Epidemiology and risk factors: 37M people infected worldwide, 1.2M in US; 13% are unaware; sexual contact most common transmission route in US; HIV disproportionately affects MSM, PWID, as well as people of African-American > Hispanic race/ethnicity; however, significant transmission occurs among all demographic groups Transmission: Bloodborne pathogen—sexual, vertical, transfusion, or occupational (e.g., needlestick) transmission possible, ↑ risk w/ ↑ viral load

Natural history: Wide variability, usually progresses to sx over 1–10 y if untreated

Acquired immunodeficiency syndrome (AIDS): HIV infection and CD4+ T-lymphocyte count <200 cells/mm3 (normal CD4 count is 500– 1600 cells/mm3) or CD4% <14% or an AIDS-defining opportunistic

 

infection or malignancy (see below)

Acute Retroviral Syndrome (ARS) (http://www.aidsinfo.nih.gov; NEJM

2011;364:1943)

Occurs in ∼40% to 90% of infections, when viral load peaks (∼106 copies/μL) 2–6 wk after viral transmission

Presentation: “Mono-like illness,” w/ fever, viral exanthem (erythematous maculopapular lesions, face, & trunk), LAN, nonexudative pharyngitis, myalgia/arthralgia; often mimics other viral infections and can be easily missed

Diagnosis: HIV RNA (viral load) is most sensitive for acute retroviral syndrome

Treatment: Supportive; prompt referral for antiretroviral tx

Secondary prevention: Pts w/ ARS have very high infectivity 2/2 high viral load; proper dx can → reduction of high-risk behavior → reduced transmission

Diagnosis (cdc.gov/hiv/guidelines/testing.html)

Diagnostic criteria: Presence of any of the following: (1) ⊕ HIV Abs by ELISA w/ confirmation by Western blot; (2) ⊕ 4th generation immunoassay w/ confirmatory testing by HIV-1 and HIV-2 differentiation assay or (3) detectable plasma HIV RNA

Lab tests:

Antibody/antigen testing: 4th generation immunoassay detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen; p24 antigen positive 2–3 wk after infection; confirmatory testing performed w/ HIV-1 and HIV-2 differentiation assay; alternative algorithm at some centers includes western blot as confirmatory test.

Discordant results: If ⊕ screen with negative differentiation assay check HIV-1 VL for acute infection; can consider HIV-2 VL if risk factors (travel to/from W. Africa) Rapid test: Uses oral fluid (also available as home test kit: OraQuick), blood, plasma, or serum; result in 10–20 min; Se & Sp 98.4–100%; must confirm by 4th generation test above (cdc.gov/hiv/topics/testing/rapid/rt-comparison.htm) HIV RNA: Measures by PCR; current detection range 20–10 million copies/mL

If suspect acute infection, must test for HIV RNA (other tests may

 

be ⊖)

Delivering diagnosis: See “Breaking Bad News” section of “Counseling Pts”); can set this conversation up to be more successful w/ counseling prior to testing

• Arrange for in-person meeting (avoid disclosing results over the phone) (2) Assess pt’s understanding of likelihood of HIV dx & their level of anxiety (3) Disclose diagnosis; allow time for pt response
• Emphasize HIV’s transformation to a chronic, manageable disease
• Set up plan for next steps in mgmt; offer access to counselor/peer group/social work Consider initiation of ART on day of diagnosis: Safe, ↓ time to viral suppression, may ↑ retention in care (J AIDS 2017;74:44)

Partner notification/case reporting: Consider timing of exposure for partners to determine appropriate testing; be aware of local dept of public health reporting requirements & resources (many offer anonymous partner notification)

Initial Evaluation of HIV ⊕ Patient

History: Full PMHx, including HLD, CAD, DM, CKD, neuropathy, depression, anxiety, PTSD, TB, hx hepatitis, HSV, VZV, immunizations, prior CA screening

HIV staging: Current viral load, current & nadir CD4, date of dx (& route/date exposure) HIV treatment hx: Prior regimens (including adverse effects), resistance testing (obtain medical records whenever possible), current/prior adherence Substance use: Tobacco, EtOH, IVDU, illicit drugs, Rx drugs Social hx: Occupation, housing, social supports, country of origin, partner stability Sexual hx: Emphasize behaviors (e.g., “do you have sex w/ men, women, or both?”), assess sexual practices (vaginal, oral, anal) & condom use, hx other STIs

Exam: Full PE, including weight, skin exam, OP exam, LN exam

 

Initial Labs/Studies (CID 2014;58:e1)
HIV-specific	CD4 cell count, HIV-1 viral load, HIV genotype, HLA B*5701 (predicts hypersensitivity to abacavir)

 

Medical/Screening	CBC w/ diff, BMP, LFTs, lipids, glucose/HbA1c, U/A, G6PD (for dapsone use), cervical and/or anal pap test based on risk, consider baseline CXR
Other ID	STI: GC/CT (rectal + pharyngeal if risk factors), syphilis, trichomonas in ♀ Hepatitis: HAV IgG, HBV sAb/sAg, HCV Ab (HCV VL if ⊕) TB, CMV + VZV IgG, Toxoplasma IgG (see “STIs,” “TB,” “Hep B,” “Hep C”)

HIV Primary Care

Health maintenance is an important component of HIV care; HIV ⊕ pts are at increased risk of cardiovascular, metabolic, infectious, neoplastic, and psychiatric disease and careful monitoring, prevention, and treatment of these complications is key to their primary care Cardiovascular risk: ↑ CAD mortality, and stroke risk in HIV pts; multifactorial and due to (1) ↑ risk factors (e.g., tobacco), (2) HIV treatment toxicity (can ↑ lipids, ↑ insulin resistance), & (3) HIV itself (inflammation → atherogenesis; risk appears ↑ w/ optimal HIV mgmt)

(JAMA Intern Med 2013;173:614; AIDS 2013;27:973; Neurology 2015;84:1933)

Prevention: Aggressive management of risk factors (BP control, smoking cessation; see “Coronary Artery Disease”) recognize that ASCVD calculators likely underestimate risk in HIV ⊕ patients; monitor closely for development of ↑glucose or ↑lipids, esp in setting of starting or changing antiretroviral therapy regimen Statins: Often indicated to manage HLD; however, caution w/ statins & PIs (PIs can → ↑ serum concentration of statins; pravastatin least affected; NNRTIs can → ↓ serum concentration of statins); requires more frequent monitoring for s/e (LFTs, CK)

Osteoporosis: ↑ Prevalence; screen postmenopausal women (same as general population) and men ≥50 (considered insufficient evidence in general population)

Cervical cancer screening: ↑ risk for cytologic progression and ↑ infection with high-risk HPV; however, if receive appropriate screening, risk of invasive cervical CA = to general population; as of 10/2016 ACOG guidelines; pt should continue screening for lifetime per life expectancy (not stop at 65); baseline recommendation is annual screening

Women <30 y: If 3 annual cytology screens nl → can go to q3y

Women ≥30 y: As above or may cotest w/ HPV; if ⊖ co-test

 

(cytology and HPV nl) → can go to q3y (Obstet Gynecol 2016;128:e89) Anal cancer: Yearly anal pap testing in MSM, pts with anogenital condylomas, woman with abnl cervical histology

Breast, prostate, colon cancer screening: HIV pts at avg risk;

recommendations the same as HIV-negative (see “Screening”) Mental health/trauma: ↑ Prevalence of depression, PTSD; ♀ esp have↑ hx of IPV, childhood trauma; assess at initial visit and periodic mental health assessment thereafter

Sexually transmitted infections: See “Sexually Transmitted Infections”; GC/CT and syphilis if ongoing risk (q3–6mos), Hep C Ab q12mos in pts at risk (MSM, IDU, multiple sex partners) Immunization: CD4 cells affect vaccine efficacy: Defer vaccination in pts w/ CD4 <200 who will soon start ART; live-virus vaccines contraindicated when CD4 <200 (MMWR 2013;62:2); see “Immunizations” HIV monitoring: Frequency depends on CD4 and duration/degree of viral suppression; once suppressed, viral Load q6mos once suppressed

CD4 yearly (optional if CD4 >500 and VL suppressed >2 y) CBC, BUN/Cr, LFTs q6–12mos

 

Immunization Recommendations for HIV ⊕ Patients
Vaccine		Schedule
Inactived	Inactivated Influenza	Yearly (do not use intranasal)
	Tdap	Substitute 1-time dose of Tdap for Td booster, then boost with Td every 10 y
	Pneumococcal 13-valent (PCV13)	1 dose; preferred before PPSV23 (if PPSV23 given first must wait >1 y before PCV13)
	Pneumococcal polysaccharide (PPSV23)	1 dose followed by booster at 5 y (if PCV13 given wait >8 wk)
	HPV series	3 doses up to age 26
	Hepatitis B	3 dose series
	Hepatitis A	If MSM, or other risk factor
	Meningococcal conjugate	2 doses of MenACWY-D or MenACWY-CRM, 8–12 wk apart; booster q5y (MMWR 2016;65:1189)
Live*	MMR	1 or 2 doses

 

	VZV	2 doses
	Zoster	No recommendation
	Yellow Fever	Based on travel risk
	Intranasal Influenza	Do not use

*Live vaccines are contraindicated if CD4 <200

 

Antiretroviral Therapy (aidsinfo.nih.gov 7/2016)

Antiretroviral therapy (ART) should be initiated & managed by a clinician experienced in HIV care; all pts should have HIV genotyping to assess for pre-existing resistance

Indications for ART initiation: Recommended for ALL HIV-infected individuals regardless of CD4 count; ↓ risk of serious events and death

when compared to waiting for CD4 <350 or other indication (INSIGHT START, NEJM 2015;373:795)

 

Common Antiretroviral Agents
Class & Drug		Side Effects & Key Facts
NRTI	Abacavir (ABC; Ziagen)	Hypersensitivity syndrome: fever, myalgia, GI sx & rash (strong assoc w/ HLA B*5701; ✓ HLA B*5701 before starting)
	Emtricitabine (FTC; Emtriva)	HA, nausea, insomnia, palm/sole hyperpigmentation
	Lamivudine (3TC; Epivir)	HA, dry mouth; also active against HBV
	Tenofovir disoproxil fumarate (TDF; Viread)	AKI, Fanconi syndrome, CKD, osteomalacia, GI sx
	Tenofovir alafenamide (TAF; Vemlidy)	Pro-drug of TDF with fewer bone/kidney side effects; can be used in CKD (CrCl >30).
	Zidovudine (AZT; Retrovir)	Cytopenias, fatigue, malaise, HA, GI sx, lipoatrophy myalgia/myopathy, skin/nail hyperpigmentation
NNRTI	Rilpivirine (RPV; Edurant)	Rash, depression, insomnia
	Efavirenz (EFV; Sustiva)	CNS sx (abnl dreams, drowsiness, dizziness; caution w/ driving), ↑ LFTs, ↓ methadone levels, teratogenic
	Etravirine (ETR; Intelence)	↑ LFTs, rash, med interactions (ok w/ methadone), SJS
	Atazanavir (ATZ; Reyataz); also	↑Bili, ↑ LFTs, ↑ PR interval, rash,

 

Protease Inhibitor	coformulated with cobicistat (ATZ/c; Evotaz)	contraindicated w/ PPI, causes less hyperlipidemia than other PIs
	Darunavir (DRV; Prezista); also coformulated with cobicistat (DRV/r; Prezcobix)	↑LFTs, risk for rash in pt w/ sulfa allergy ↑ statin levels except atorvastatin
	Lopinavir/ritonavir (LPV/r; Kaletra)	GI sx, HA, fatigue, dyslipidemia, ↑ LFTs, pancreatitis; med interactions
	Ritonavir (RTV; Norvir)	Med interactions,↑LFTs, GI sx
Integrase Inhibitor (INSTI)	Raltegravir (RAL; Isentress)	GI sx, ↑ LFTs & amylase, CNS sx, myalgia, rash/pruritus/SJS; generally well tolerated
	Dolutegravir (DTG; Tivicay)	GI sx, insomnia, fatigue, HA.; ↑ metformin levels (↓ metformin dose by ∼50%)
	Elvitegravir/Cobi (EVG/c; Vitekta)	Drug–drug interactions due to Cobi; must take w/ food
FI*	Enfuvirtide (ENF; Fuzeon)	Local reaction incl nodules at injection site, neutropenia
EI*	Maraviroc (MVC; Selzentry)	Med interactions, GI sx, ↑ LFTs, hepatitis, liver failure, joint/muscle pain, ↑ URI, HoTN
Recommended Initial ART Regimens in Treatment-Naive Patients please refer to source for updated tx regimens (aidsinfo.nih.gov 7/2016)
INSTI + 2 NRTI	DTG and either TDF/FTC or TAF/FTC EVG/c/TAF/FTC or EVG/c/TDF/FTC DTG/ABC/3TC if HLA-B*5701 RAL and either TDF/FTC or TAF/FTC
PI + 2 NRTI	DRV/r and either TDF/FTC or TAF/FTC

*FI, Fusion inhibitor; EI, Entry inhibitor

 

Infectious and Malignant Complications of HIV/AIDS (aidsinfo.nih.gov 11/2016)

General approach: Pts w/ HIV/AIDS are at ↑ risk of both common and unusual infections (“opportunistic infections,” OI); low threshold for eval of new/persistent complaints; if red flags present, prompt consultation w/ ID specialist vs. ED eval depending on chronicity/severity; all OIs below considered “AIDS-defining conditions”

(MMWR Recomm Rep 2014;63:1)

Selected diseases commonly encountered in ambulatory setting

Mucocutaneous candidiasis: Oral burning/pain, white patches; can be

 

dx clinically or w/ KOH prep: Tx is fluconazole, clotrimazole troches, or pastilles; if suspect esophageal involvement (odynophagia, dysphagia) → referral to ID/GI VZV, HSV: See “VZV,” “HSV”; refer to ID/Derm if severe disease

Red flags: Fever, fatigue, night sweats, wt loss, new HA, vision changes, persistent cough, diarrhea

 

Opportunistic Infections
CD4 Count at Risk	Opportunistic Infections or Malignancies	Recommended 1° Ppx (if none listed, only preventive therapy is ART)
<500 (cells/mm3	Recurrent bacterial PNA/infections, ) MTb infection, mucocutaneous candidiasis (oral thrush, vaginitis) Kaposi sarcoma, oral hairy leukoplakia, cervical CA	If ⊕ latent TB screen (see “Tuberculosis” for Latent Tx regimens) Vaccination as per above (see “Immunizations”)
<100–200 (cells/mm3	PCP, Toxoplasma gondii ) encephalitis, HSV, VZV, Histoplasma capsulatum infection, Cryptosporidium enteritis, Cryptococcus neoformans encephalitis, isosporiasis Visceral Kaposi sarcoma, non-Hodgkin lymphoma, PML	For PCP (when CD4 <200 or CD4% <14): TMP–SMX DS or SS daily or DS 3×/wk (see “PCP prophylaxis” for alternatives) For Toxo (if IgG+ & CD4 <100): TMP– SMX DS daily For histoplasmosis (in hyperendemic areas when CD4 <150): Itraconazole 200 mg daily
<50–100 (cells/mm3	Invasive candidiasis/aspergillosis, ) disseminated MAC, CMV (retinitis, esophagitis, colitis), penicilliosis, CNS lymphoma	For MAC (when CD4 <50): Azithromycin 1200 mg weekly or Clarithromycin 500 mg BID or Azithromycin 600 mg 2×/wk For Penicilliosis (in SE Asia): Fluconazole 400 mg qwk

Discontinuing OI Prophylaxis:

PCP: D/c ppx in pts who respond to ART w/ CD4 counts >200 and CD4% >14% for >3 mos; discontinuation may be safe at CD4+ counts 101–200 cells/μL if suppressed VL, but not currently recommended MAC: D/c ppx in pts who respond to ART w/ CD4 >100 for >3 mos

HIV PREVENTION

 

Background

 

Prevention: HIV prevention takes multiple forms, including; postexposure prophylaxis (PEP), pre-exposure prophylaxis (PrEP), decreases transmission by ∼93%; treatment = prevention of transmission to others (∼0% transmission rate if stably suppressed; (NEJM 2016;375:830), safe sex practices

Risk of transmission (AIDS 2014;28:1509): Sexual (vaginal insertive/receptive ∼0.04/0.08% risk per sexual act, anal insertive/receptive ∼0.1/1.4%), IDU (0.7%), vertical transmission (10– 40% w/o ARVs, ↓↓ if suppressed viral load), transfusion (now in US

<1/2,000,000), occupational (needlestick ∼0.3%); all dependent on viral load (approximates 0% if VL undetectable)

Screening (MMWR 2006;55:1; Ann Intern Med 2013;159:51)

Universal one-time screening: Screen all pts aged 13–64 y once Repeat screening: Pts initiating tx for TB, pts seeking tx for STIs, all pregnant women; see “Screening” “STIs”

Serial screening: Screen at least annually in pts w/ ongoing risk (tailor based on individual risk); typically annually for MSM, IDU

Pre-Exposure Prophylaxis (PrEP) (cdc.gov/hiv/pdf/prepguidelines2014.pdf)

Available for sexually active adult MSM or heterosexually active men or women at substantial risk for HIV acquisition such as HIV ⊕ partner, multiple sex partners, recent bacterial STI, IDU with needle sharing, or recent need for nPEP (below)

Document negative HIV test, normal CrCl, negative Hepatitis B status Follow-up every 3 mos for HIV test, bacterial STIs (including rectal and pharyngeal GC/Chlamydia), renal function, pregnancy test

Once daily TDF/FTC shown to reduce HIV transmission by 44% (by 92% for those who were adherent (NEJM 2010;363:2587;) must take daily, regardless of timing of sexual exposure; on-demand PrEP not currently recommended by CDC (2017)

Non-Occupational PostExposure Prophylaxis (nPEP)

Latest guidelines (2016) at cdc.gov/hiv/pdf/programresources/cdc-hiv- npep-guidelines.pdf

Indications: High-risk sexual exposure, sharing of IV drug equipment, or other high-risk exposures, esp when source is known HIV ⊕ and pt presents w/in 72 h of exposure

 

Dosing: Full nPEP course is 28 d of TDF/FTC QD + either Dolutegravir QD or Raltegravir BID; practices vary by location; often starter pack of 3–7 d given with expedited f/u

Referral: Consult with ID if starting; ED eval may be preferable if allows for earlier start of Rx, as earlier = ↑ effective; if occupational exposure, occupational health services should eval & document agents, or other immunosuppressive meds (Mayo Clin Proc 1996;71:5)

Other infections: Consider other bloodborne diseases: HCV, HBV (see respective chapters); if sexual exposure, consider other STI prophylaxis with ceftriaxone 250 mg IM, Azithromycin 1 g PO, metronidazole 2 g x 1

Follow-up: Ongoing f/u needed for safety labs and repeat HIV testing; consider PrEP after completion of PEP based on individual risk assessment

Pt education: Counsel pt about need for risk-reduction measures until testing excludes HIV

 

Background (Emerg Infect Dis 2002;8:891; aidsinfo.nih.gov; BMC Infect Dis 2004;4:42)

Pneumocystis pneumonia (PJP/PCP) is clinical infection w/ P. jirovecii; clinical disease typically limited to those w/ immunodeficiency, although subclinical infection/colonization likely widespread (Emerg Infect Dis 2005;11:245)

Microbiology: Pneumocystis jirovecii is a fungal organism formerly called pneumocystis carinii but renamed in attempt to distinguish the strain/species which causes human disease; organism cannot be cultured, therefore diagnosed by induced sputum, tissue bx, or BAL Transmission: Airborne transmission; disease occurs by new acquisition, or possibly by reactivation of latent infection; healthy humans likely reservoir (NEJM 2004;350:2487); ∼7/8 healthy adults have antibodies to PCP (J Immunol 1988;140:2023)

Epidemiology: Before PCP ppx & ART, ∼70–80% prevalence in pts

w/ AIDS; now ∼0.8% annual incidence among HIV ⊕ pts in US (AIDS 2013;27:597)

Risk factors for people w/ HIV: CD4 <200 cells/μL or <14% of T cells;

 

prior PCP; oral thrush; recurrent bacterial PNA; unintentional wt loss; ↑↑ plasma HIV RNA; most pts who develop PCP are unaware of HIV status or not receiving HIV care

Non–HIV-infected populations at risk: Transplant recipients (stem cell & solid organ); pts w/ cancer (esp hematologic malignancies); pts receiving glucocorticoids, chemotherapeutic agents, or other immunosuppressive meds (Mayo Clin Proc 1996;71:5)

 

Indications for PCP Prophylaxis
HIV ⊕	HIV ⊖
CD4 <200, Oropharyngeal candidiasis Consider: CD4 <14% of total T cells, Hx of AIDS-defining illness (see “HIV/AIDS”), CD4 200–250 & unable to monitor q1–3mos	>20 mg of prednisone daily (or equivalent) for >1 mo plus another cause of immunocompromise (Rx or disease) 1° immunodeficiency (e.g., hyper-IgM, SCID) Allogeneic SCT, solid organ tx, selected auto-SCT Consider: In pts receiving immunosuppressive biologic agents (monoclonal Abs, TNF-α inhibitors, etc.); no specific guidelines, but e/o ↑ risk

Preventive Treatment (NEJM 2004;350:2487; Eur J Clin Microbiol Infect Dis

2002;21:523)

Prophylaxis is effective: In HIV ⊕ w/ CD4 <200, to prevent 1 case, NNT ≈ 2 (BMJ Clinical Evidence 2010;8:908; JAMA 1988;259:1185); In HIV ⊖, to

prevent 1 case, NNT = 15–19 (Cochrane Database Syst Rev 2007;18:CD005590; 2014;10:CD005590)

 

PCP Prophylaxis Regimens (aidsinfo.nih.gov 2015 guidelines)
Drug	Dosage	Adverse Effects
TMP–SMX (1st line)	1 ds tab daily (preferred in HIV⊕) or 1 ss tab daily	Fever, rash, neutropenia, GI upset, ↑ LFTs
Alternative Regimens (inferior to above)
TMP–SMX	1 ds tab 3×/wk	As above
Atovaquone suspension	1500 mg PO daily	GI distress, rash, high cost
Dapsone	100 mg PO daily or 50 mg PO BID	Fever, rash, GI upset, hemolytic anemia (must check G6PD), methemoglobinemia
Aerosolized pentamidine	300 mg monthly (via Respirgard II nebulizer)	Cough, wheezing, extrapulmonary PCP

 

IV pentamidine

4 mg/kg IV monthly

Nephrotoxicity, ↑ Ca, ↓ glu, HoTN, pancreatitis, arrhythmia, ↑ LFTs

Discontinuing Prophylaxis (NEJM 1999;340:1301; CID 2010;51:1114; aidsinfo.nih.gov)

HIV ⊕: D/c ppx in pts who respond to ART w/ CD4 counts >200 cells/ μL and CD4% >14% for >3 mos; discontinuation may be safe at CD4+ counts 101–200 cells/μL if suppressed VL, but not currently recommended

HIV⊖: CD4 count not shown to be reliable marker; decide on a case- by-case basis when to d/c ppx (JAMA 2009;301:2578)

 

Background (cdc.gov/tb; who.int; MMWR 2012;61:11; NEJM 2013;368:745)

Tuberculosis (TB) infection affects >1/3 of the world’s population, range of disease from lifelong asx infection, to pulmonary or, more rarely, myriad extrapulmonary manifestations (Pleural > lymphatic > bone + joint disease > GU tract > miliary disease, meningitis, peritonitis) Microbiology: Causative organism Mycobacterium tuberculosis (MTb); aerobic, slow-growing rod, acquired via aerosolized transmission of infected droplets, often from close contacts of infected pts (household members, etc.); casual contacts at low risk for infection

Classification: Latent TB: Infection present but no clinical illness, no evidence of active disease, not infectious

Active TB: Illness present, infectious (degree varies by site)

1° disease: Illness occurs <24 mos after infection

2° disease: Occurs >24 mos after infection

Natural history: Once infected, 5% develop 1° disease; 90% have lifelong asx infection (LTBI); 5% go on to develop 2° disease (“reactivation”)

Epidemiology (cdc.gov; MMWR 2012;61:11; Am J Resp Crit Care Med 2000;161:S221)

Incidence/Prevalence: Estimated 4% of US population (up to 13M) has latent TB infection; 9.5K new cases active TB in 2015, annual incidence of 3/100,000 persons

 

Demographics: 66.4% active TB cases in US in 2015 were among foreign-born people (13× ↑ rate than US-born population; particularly ↑ among immigrants from Asia); Mexico, Philippines, India, Vietnam, & China most common; within US-born persons racial disparities exist (↑risk in African-American, Hispanic, Native Hawaiian populations) Risk factors for acquisition: Employees at long-term care facility, hospital, clinic, lab, high prevalence of TB in country of origin, residents & employees of prisons, jails, SNFs, homeless shelters, known close contact w/ person w/ active TB

Risk factors for developing active TB:

Immunodeficiency: HIV, organ transplant, long-term corticosteroids, TNF alpha inhibitors Medical hx: DM, ESRD, gastrectomy/bypass, CA, silicosis, >10% underwt Recent acquisition: Within last 2 y; risk of active TB ↓ w/ time since infected Other: EtOH use d/o, IDU; ↓ BMI; healed TB on CXR, inadequate/incomplete prior tx

HIV: 6% of 2014 US cases of TB w/ known HIV test result were coinfected w/ HIV

Screening (ATS/IDSA/CDC guidelines; CID 2017;64:e1)

Indications: Pts w/ risk factors for acquisition or for developing active infection (above), frequency depends on nature of exposure (e.g., ongoing or one-time), pt-specific risk of infection; screening of those at low risk of infection/low risk of active disease not recommended; healthcare providers screened annually

Prior BCG vaccination: (Given to young children in endemic countries to ↓TB risk) can → false ⊕ but wanes w/ time; hx of BCG should not alter interpretation of TST, but consider IGRA instead

Interferon-gamma release assays (IGRA): E.g., QuantiFERON, T- SPOT; blood test w/ Se/Sp ∼92%/97%; Preferred if (1) likely to be infected and at low-intermediate risk of disease progression, (2) hx BCG vaccination or (3) unlikely to return to have TST read Tuberculin skin test (TST): Uses Mantoux intracutaneous tuberculin

(PPD); dependent on cell-mediated immunity; can be ⊖ in up to 25% of active disease (more common in pts w/ immunosuppression)

Administration: Should be performed by trained personnel; 0.1 mL (5 tuberculin units) injected intradermally on volar surface of forearm Reading: Reaction size determined at 48–72 h; if >72 h,

 

cannot interpret (MMWR Recomm Rep 2005;54:1); based on induration (not redness); cutoff for positive test depends on (1) Pretest probability of being infected (e.g., household contacts: ↑ prob, so

↓cutoff) (2) If infected, probability of developing active disease (e.g., HIV ⊕: ↑ prob, so ↓ cutoff)

 

“Positive” TST (indicates active or latent TB) (MMWR 2000;49(RR06):1)
TST Cutoff	Population
≥5 mm	HIV+, close contact of active TB case, fibrotic changes on CXR c/w prior TB, organ transplant recipients, immunosuppressed
≥10 mm	Recent immigrants, IVDU, occupational or residential risk exposure (prison, nursing home, homeless shelter, health care worker), medical conditions listed above
≥15 mm	No known risk factors (therefore no clear indication for test)

Evaluation (CID 2016;64:e1)

General approach: In patients with positive TB testing, first step in evaluation is to assess for active TB; critical to exclude active disease before beginning tx; determined by hx, exam, & diagnostics History: Systemic sx: Wt loss, anorexia, fever, chills, night sweats, fatigue

Pulmonary sx: Cough >3 wk, pleuritic chest pain, hemoptysis

Extrapulmonary sx: Altered mental status, back pain, abdominal pain Physical exam: Full PE, including careful pulmonary exam, LN exam Chest radiograph: In all cases w/ suspicion for LTBI or active TB

1° TB: Typically, pleural effusion, hilar LAD most common, LL lesions Reactivation/2° TB: UL lesions more common may show atelectasis, consolidation, pleural effusion, cavitation, or miliary pattern

Management

 

Figure 7-3. Management following positive TST/IGRA

 

 

 

General approach: If any of above workup ⊕ → TB precautions (N-95 mask, ⊖ pressure room, resp. isolation) → further eval to r/o active TB (e.g., induced sputum for AFB, cultures) in consultation w/ ID specialist or clinician experienced in TB mgmt

Latent TB Infection (LTBI): See subsection below

Active TB Tx: Initial empiric tx, Rx’ed by experienced clinician, consists of 4-drug regimen (INH, rifampin, PZA, EMB) + B ; see 2016

6

ATS/CDC/IDSA guidelines

When to refer: If any of the above w/u equivocal, high suspicion, or pt pregnant or immunocompromised (including all HIV pts) → ID and/or public health consultation/mgmt

Reporting: Public health dept must be notified of all new dx of TB

(latent or active)

LATENT TB INFECTION (LTBI) MANAGEMENT

 

Evaluation

General approach: Confirm pt does not have active TB (above) or complicating factors, then assess risks/benefits of tx for the individual pt; decision to tx and choice of Rx influenced by pt factors/decisions; pts who undergo tx require regular monitoring to ensure safety/efficacy

 

Appropriateness for PCP management: Exclude active TB (above); pts w/ LTBI who have known exposure to drug-resistant TB, those who are pregnant, immunocompromised, or have HIV should be evaluated by a specialist

Risks/benefits of treatment: Not all pts with LTBI require or desire treatment; calculator such as tstin3d.com/en/calc.html can help assess risk of reactivation & risk of treatment; in general treatment is recommended (benefits > risk) for pts at ↑ risk of reactivation (see above)

Shared decision making: Given duration of most regimens & level of adherence required to eradicate, pt buy-in is key to successful tx; review of risks/benefits, pt & provider assessment of potential barriers to adherence, & assessment of pt commitment should be initiated prior to starting tx

Factors which may ↓ adherence: ↓ Perceived personal risk of progressing to active TB (incl doubts re: LTBI dx), concerns re: frequent venipuncture, cultural, language, or logistical barriers (AJRCCM

2006;174:717)

Treatment (cdc.gov)

Isoniazid (INH) monotherapy (300 mg QD × 9 mos) considered 1st-line

S/e: GI upset (common), hepatotoxicity (avoid EtOH), neuropathy Vit B6: add 50 mg QD pyridoxine while on INH for pts at risk for neuropathy (DM, EtOH, malnutrition, HIV) Labs: Not always

required; baseline + monthly LFTs in pts w/ HIV, liver disease, chemotherapy, pregnancy, or regular EtOH use; for everyone else, only as per sx Monitoring: Monthly eval for hepatitis or neuropathy sx; labs per symptoms

Monthly visits: Recommended for assessing s/e, monitoring adherence

 

LTBI Therapy
Drug	Duration	Notes
INH 300 mg QD (± 50 mg Vit B6 QD)	9 mos (6 mos)	1st-line 6 mos ↓ efficacy, but ↓ cost & may ↑ adherence
INH/Rifapentine weekly	12 wk	Recommended only as directly-observed

 

wt-based dosing: for pts ≥60 kg: INH 900 mg qwk & Rifapentine 900 mg qwk		therapy (DOT)   1.2–1.9× ↑ rate of completing tx compared to std INH regimen (NEJM 2011;365:2155; CID 2016;62:53) S/e: Lightheadedness/orthostasis, flu-like illness
Rifampin 600 mg QD	4 mos	S/e: Orange urine/sweat/tears GI upset, hepatotoxicity, drug interactions (incl warfarin & HIV meds), rash

Completion of treatment: Give pt copy of TST/IGRA, CXR results, regimen used & duration; they should present this if TB testing required in the future; there is no role for future TST screening (will be ⊕ and can develop severe reaction)

Patient information: Including 1-page fact sheets on LTBI medication regimens at cdc.gov/tb/publications/factsheets/treatment.htm

 

Background (Arch Intern Med 1992;152:1869; Lancet 1992;339:135)

Incidence: Estimated at 3–9 cases/100,000 persons annually; significantly ↑ risk in pts w/ valvular disease or IDU (NEJM 2013;368:1425) Rationale for ppx: Bacteremia can → IE if diseased valves; abx ↓ bacterial load → ↓ IE risk

Historical context: Preprocedure ppx used to be recommended more widely, now limited (as of 2007 AHA guidelines) to those at highest risk, as procedures account for very small proportion of IE cases (CID 2006;42:e102); bacteremia likely occurring more w/ daily activities (eating, brushing); poor oral hygiene may contribute more than procedures (Am J

Cardiol 1984;54:797; Pediatr Cardiol 1999;20:317)

Adverse effects of ppx: GI upset, diarrhea, allergic reactions, ↑ resistant organisms

Postimplementation of 2007 AHA Guidelines → ↓ use of ppx → no ↑ incidence of S. viridans IE (Circulation 2012;126:60)

When to Use Prophylaxis: AHA/ACC Guidelines (Circulation 2007;116:1736)

Ppx is recommended in patients w/ high-risk condition undergoing

 

high-risk procedure (must meet both criteria)

 

High-risk Conditions and Procedures (meet 1 criterion from each → ppx)
Conditions	Procedures
•  Prior IE •  Prosthetic cardiac valve or prosthetic material used for cardiac valve repair • Congenital heart disease if: (1)  Unrepaired cyanotic CHD (may have palliative shunts & conduits) (2) Repaired w/ prosthetic material or device w/in past 6 mos (3) Repaired but w/ residual defects near a prosthetic patch or device • Cardiac transplantation recipients who develop cardiac valvulopathy •  Native valve disease not an indication for ppx	•  Dental procedures w/ manipulation of gingival tissue/periapical region of teeth, perforation of oral mucosa • Surgical procedures of infected skin, skin structures, or MSK tissue* •  Respiratory tract procedures that involve incision or bx of the respiratory mucosa (such as tonsillectomy or adenoidectomy) • GI & GU procedures (including EGD & colonoscopy) during active GI/GU infection only (Note: These pts should receive antienterococcal abx [e.g., amoxicillin]; any GI/GU procedures w/o active infection do not require ppx)

*These pts should receive regimen active against GAS and S. Aureus.

 

Prophylactic Antibiotic Regimens (Circulation 2007;116:1747; Surg Infect

2013;14:73)

Antibiotic should be given as a single dose 60 min prior to procedure

Do not use cephalosporins if hx of anaphylaxis, angioedema, or urticaria to penicillin

 

Prophylactic Regimens for Dental Procedures
Scenario	Regimen (all are single doses)
Standard	Amoxicillin 2 g PO
Unable to take oral meds	Ampicillin 2 g IM/IV or (Cefazolin or Cftx) 1 g IM/IV
Allergic to PCN/ampicillin	Cephalexin 2 g PO or Clindamycin 600 mg PO or (Azithromycin or Clarithromycin) 500 mg PO
Allergic to PCN/ampicillin & unable to take oral meds	(Cefazolin or Ceftriaxone) 1 g IM/IV or Clindamycin 600 mg IM/IV or Vancomycin 15 mg/kg max 2 g (vanco should be 120 min before procedure)

 

                 FEVER OF UNKNOWN ORIGIN

 

Background (Arch Int Med 2003;163:545; Medicine 2007;86:26)

Definition: (1) Illness of >3 wk duration; (2) Fever >38.3°C (101°F) on several occasions during that time; (3) Uncertain dx after 1 wk of intensive evaluation (Medicine 1961;40:1; Arch Intern Med 1992;152:21)

Etiology: Usually uncommon presentation of common illness, rather than rare disease; likely cause varies by age, geography, immune status; generally, infectious 25–30%, inflammatory 20–25%, malignant 15%, miscellaneous 5%, no dx in 20–30%; nosocomial, neutropenic, HIV-associated FUO has different Ddx and different considerations

 

Etiologies of FUO (Arch Int Med 2003;163:545; Am J Med 2015;128:1138)
Category	Common Etiologies
Infectious	TB: Most common infectious etiology worldwide; may have ⊖ PPD, CXR, IGRA, blood cx, sputum AFB; bx of nodes, marrow, or liver may → dx (Int J Infect Dis 2008;12:71; J Infect 2006;52:399) Abscess: Usually abd or pelvic (e.g., liver, splenic, renal, prostatic); also retroperitoneal, dental, paraspinal; risk factors include ESLD, immunosuppressants, recent surgery, DM Osteomyelitis: E.g., vertebral, mandibular, DFI; local sx may be min Endocarditis (Cardiovasc Clin 1993;23:139): Culture ⊖ in 5%; consider up to 21 d incubation ± special media to detect fastidious organisms; use serology for Bartonella & Q fever (Coxiella); TTE detects 90% of endocarditis presenting as FUO
Inflammatory	GCA: 15% of FUO cases in the elderly; see “Vision Complaints” Adult Still’s: (Adult JRA, younger adults) fever + macular truncal rash often precede arthritis Also PAN, Takayasu arteritis, RA, SLE, granulomatosis w/ polyangiitis, mixed cryoglobulinemia (Clin Rheumatol 2012;31:1649)
Neoplastic	Leukemia, Lymphoma (esp non-Hodgkin) Renal cell CA: 15–20% of cases have fever (Lancet 1997;350:575) HCC or liver metastases (Heart Lung 2013;42:67)  Atrial myxomas: Rare cause, but fever  in ∼33%, arthralgias, emboli, ↑ IgM
Other	Drug fever: Antimicrobials (PCN, carbapenems, cephalosporins, sulfa, nitrofurantoin, INH), antiepileptics, H1 & H2 blockers, antiarrhythmics, NSAIDs, antihypertensives (hydralazine, ACEI), antithyroid (PTU); Eosinophilia & rash in only 25% (Arch Intern Med 1996;156:618) Endocrine: Hyperthyroidism, thyroiditis, pheo, adrenal insufficiency Other: Hereditary periodic fever syndromes (Familiar Mediterranean Fever); clot (PE, DVT, hematoma); factitious fever

 

Diagnosis (Infect Dis Clin North Am 2007;21:867; Am J Med 2015;128:1138.e1)

Detailed history: Travel, sick contacts, animal exposure, outdoor exposure (forest, lake, ocean), immunosuppression, med & toxin hx unusual foods, localizing symptoms; review of systems could give clues to category of illness (wt loss/early anorexia is hallmark of malignancy) Careful exam: LAD, skin rash or lesions, new murmur, HSM, arthritis, jaw claudication

CT abdomen/pelvis may reveal etiology in up to 20% of cases (Radiology 1980;136:407)

Biopsy (marrow, liver, nodes, temporal artery) as final step or if

localizing symptoms

 

 

Figure 7-4. Diagnostic Approach to FUO

 

 

 

Management (Arch Intern Med 1996;156:618)

Empiric antimicrobials generally unhelpful, except in neutropenic fever

 

Up to 50% of cases remain idiopathic, most of those recover spontaneously

When to Refer: As needed per dx; if dx uncertain, ID consultation

 

Background (cdc.gov/niosh/topics/tickborne; niaid.nih.gov/topics/tickborne)

Tickborne disease can be caused by bacteria, viruses, or parasites; most common in Northeast, but found throughout US; specific pathogens usually have geographic restriction

Presentation: Ranges from mild flu-like illness to fulminant infection; common sx include fever, myalgias, arthralgias, rash, HA, & fatigue Epidemiology: >25,000 cases/y; most common in summer months; outdoor workers & others w/ outdoor activity at ↑ risk

Prevention: Counsel those at ↑ risk to reduce exposure by wearing light-colored long-sleeved shirts & pants, socks & hat when possible; using insect repellent, & performing daily tick checks, including axillae, groin, & scalp; adult tick size ≈ sesame seed, nymphal tick size

≈ poppy seed

Counseling: If tick is found, promptly remove w/ gentle grip of fine- tipped tweezer; grasp very near skin & pull steadily to extract completely; wash area w/ soap & water

LYME DISEASE

 

Background (CDC 2012; CID 2006;43:1089; JAMA 2016;315:16)

Microbiology: Pathogen B. burgdorferi, a spirochete bacterium; vector is L. scapularis (“black-legged tick”/“deer tick,” East/Midwest US) or I. pacificus (West coast); infection typically requires tick to be attached

>24 h; animal hosts include white-tailed deer & rodents Epidemiology: When: Can occur year-round, most cases in summer; Where: NE, Midwest; 96% of cases in CT, DE, MA, ME, MI, NH, NJ, NY, PA, VT, & WI; Who: Adult distribution peaks ∼40–50 y; reinfection can occur

 

Prophylaxis: May Rx doxycycline 200 mg PO × 1 if (1) endemic area,

• confirmed ixodes tick, (3) attached ≥36 h before removal, & (4) ppx can start w/in 72 h of removal

Presentation (NEJM 2001;345:115; JAMA 2016;315:16)

Erythema migrans: Occurs in 70% of pts w/ Lyme disease: Classical appearance is warm, erythematous, nonpruritic/nonpainful expanding (>5 cm) “bull’s eye” lesion at site of tick bite; appearance may also include confluent erythema, vesicles, pustules, purpura; distinct from local bite reaction (self-resolving small papule occurring 1–2 d after tick removal)

Natural history: Untreated disease classically progresses through 3 stages, w/ varying individual presentations; often 1 stage or more is absent; 10% of pts are totally asx

 

Stages of Untreated Lyme Disease (NEJM 2001;345:115; cdc.gov/lyme)
Stage	Manifestations
Early localized (3–30 d after tick bite)	Derm; Erythema migrans (EM) (70–80%) Constitutional: Fevers, myalgias, fatigue, LAD
Early disseminated (days–weeks)	CNS (15%): Bell palsy (8%), meningitis, ataxia, radiculopathy Derm: Additional/multiple EM lesions CV (1–5%): AV block, myocarditis Arthritis: Large joints, esp knee, can be TMJ
Late disseminated (weeks–months)	CNS (5%): Polyneuropathy, subtle cognitive deficits (5%); Arthritis (60%): Recurrent, inflammatory

Diagnosis (JAMA 2016;315:16)

Serology: ELISA & confirmatory Western blot only approved diagnostic tests per IDSA & CDC; Western blot ⊕ if 2 bands for IgM or 5 bands for IgG

Early localized disease (EM): Diagnosed clinically by exam & hx; serology <40% sensitive so not recommended; if suspect early disease, treat

Disseminated disease: ELISA → if ⊕, confirmatory Western blot; if >4 wk of sx, send IgG only (not IgM); serology can remain ⊕ after tx (even IgM, in some cases)

Treatment (CID 2006;43:1089)

 

Treatment: Determined by site/severity of manifestations (below)

 

Treatment of Lyme Disease (CID 2006;43:1089)
Manifestation/Indication	Antibiotics (alternates)	Course
Erythema Migrans Bell palsy 1st-degree heart block	Doxycycline 100 mg PO BID (amoxicillin 500 mg PO TID, cefuroxime 500 mg PO BID)	14–21 d
Arthritis (w/o CNS disease)	Doxycycline 100 mg PO BID (amoxicillin 500 mg PO TID, cefuroxime 500 mg PO BID)	28 d
Meningitis Radiculopathy 2nd-/3rd-degree AV block	Ceftriaxone 2 g IV QD (PCN G 4 million U IV q4h, cefotaxime 2 g IV q8h) Meningitis sx warrant LP; arrhythmia mgmt	14–28 d

Persistent arthritis after PO tx → additional 4 wk of PO abx or 2–4 wk of IV abx

Posttreatment Lyme disease syndrome: 10–20% of pts c/o persistent sx after tx, including cognitive deficits, fatigue, & arthralgias; potentially autoimmune but not 2/2 persistent infection; RCTs have shown no improvement in outcomes w/ prolonged abx (NEJM 2001;345:85;

Neurology 2008;70:992)

OTHER TICKBORNE ILLNESSES

 

Anaplasmosis/Ehrlichiosis (CID 2006;43:1089; JAMA 2016;315:16)

Microbiology: Intracellular bacteria, infect WBCs; Anaplasma phagocytophilum transmitted by Ixodes ticks (often w/ Lyme); in Southeast, Ehrlichia chaffeensis spread by Amblyomma/Dermacentor ticks

Geography: Throughout Eastern US, most in DE, ME, MI, NH, NJ, NY, RI, VT, WI

Presentation: S/sx: Fever, systemic sxs, HA; ± rash (30%); 1–4 wk after exposure

Labs: Leucopenia, thrombocytopenia, elevated LFTs

Diagnosis: Peripheral blood smear showing inclusions, PCR

Treatment: Doxycycline 100 mg PO BID × 10 d; Alt: Rifampin 300 mg

 

PO BID × 10 d

Babesiosis (CID 2006;43:1089; NEJM 366:2397; JAMA 2016;315:16)

Microbiology: Intracellular protozoan, infect RBCs; Babesia microti; transmitted by I. scapularis ticks; often co-transmitted w/ Lyme; can be transmitted by blood transfusion

Geography: Northeast/Midwest US (similar to Lyme), coastal & inland Presentation: S/sx: Fever, systemic symptoms, arthralgias, N/V, rash (rarely)

Labs: Hemolytic anemia ± thrombocytopenia, incl LDH, elevated LFTs Complications: Severe infection possible, w/ hemolysis, renal failure, hepatic failure, ARDS, DIC; ↑ risk if immunocompromised, asplenic, elderly

Diagnosis: Thin smear showing parasites, or Babesia PCR (if low-level parasitemia)

Treatment: Atovaquone 750 mg PO q12h + azithromycin 500 mg PO × 1, then 250 mg PO daily, × 10 d; for severe infection (>5% parasitemia)

→ admission

Rocky Mountain Spotted Fever (cdc.gov/rmsf)

Microbiology and epidemiology: Intracellular bacterial pathogen Rickettsia rickettsii; transmitted by Dermacentor “American dog tick” in eastern US

Geography: Occurs throughout US, highest incidence in MO, AK, OK, TN, NC

Presentation: Fever, then rash: Erythematous, maculopapular, nonpruritic, centripetally distributed, can involve palms & soles; rash present in 90% (but absent in 10%, and absent in 50% in first 3 d of illness (when pts often present); petechial = more severe

Diagnosis: Often made clinically; can also see rise in Ab (2 titers 2–4 wk apart)

Treatment: Doxycycline 100 mg PO BID × 7–14 d

Other (cdc.gov/ticks/diseases)

Other Rickettsia species: R. parkeri in SE US and species 364D on W Coast, both cause fever with eschar at site of tick attachment Tularemia: Gram ⊖ coccobacillus Francisella tularensis transmitted throughout US (more common in south-central US); can also be

 

transmitted by handling infected animal carcass or inhaling aerosolized (“lawn mower” exposure); sx can include ulcers, PNA, ocular, pharyngeal involvement; Dx by serology (notify lab if suspect) Southern Tick-Associated Rash Illness (STARI): Organism unknown, thought to be 2/2 Borrelia lonestari; transmitted in SE, lower Midwest; sx similar to Lyme; suspect if in area w/o endemic Lyme Tickborne relapsing fever: Borrelia hermsii in western US, Borrelia turicatae in SW & central US; sx include high fever lasting ∼3 d after days–weeks of convalescence; can → HoTN, ARDS; dx by blood smear/culture

Other Borrelia species: B. miyamotoi in NE, causes fever but rarely rash; B. mayonii in Midwest, similar presentation to B. burgdorferi Viral tickborne illnesses: Incl Colorado tick fever reovirus in Western US; Powassan virus in NE, Ncentral US; Heartland virus in central US

Tick paralysis: Thought 2/2 tick saliva, not infection; tx is removing tick

When to Refer

If patient has clinical signs of serious medical complications (high- degree heart block, meningitis sx, metabolic derangements, clinically ill)

→ ED; if dx uncertain, tx-refractory, unclear interpretation of results, or other concerns → ID specialist

Reporting: All of the above diseases reportable to local health dept

 

Background (tinet.ita.doc.gov; J Travel Med Infect Dis 2010;17:38)

>60 million international visits by US citizens in 2012; 37 million of these beyond N. America; most have decided on travel plans >60 d in advance, yet few seek travel-related health advice; those who do seek travel advice are most likely to present to PCP

Travelers can be exposed to many health risks, including infection (GI, STI), accidents (incl MVCs), & complications from medical problems occurring in resource-poor or remote settings; however, these risks can be ↓ w/ behavioral & prevention strategies

Visiting Friends and Relatives (VFR): Often used to refer to immigrants from developing countries returning home; broader

 

definitions exist but this focuses on those at ↑ infectious risk during travel; in 2011, >40% of US-based travelers outside N. America listed VFR as purpose of visit

General Approach (Ann Intern Med 2012;156:ITC6; AFP 2009;80:583)

Assess traveler: Immune status, pregnancy, PMHx, medications, mental health, behavioral risk factors

Assess travel: Time until departure, destination, duration, season, food sources, planned activities, transportation (incl cruise ships), altitude

“Universal precautions”: Pretravel counseling for risk reduction Immunizations: Routine & area-appropriate; referral to travel clinic as appropriate

Past medical history: Pts w/ complex or significant hx should carry summary incl meds, allergies, ± ECG; assess for CV/pulm risk factors (see “Preflight Medical Assessment” below)

Air Travel

Hydration/activity: Caution w/ EtOH on flights (hemoconcentration →

↑ intoxication/hangover effect)

Medications: Bring as carry-on, original containers if going through customs; hard copy of Rx/provider note for needles, sharps, or meds problematic w/ airport security

Emergency supply: Carry-on snacks/insulin (DM), rescue inhalers, migraine meds, NTG

Thromboembolic disease: 2–4× ↑ risk w/ prolonged air travel (↑ in flights >4 h): ↑ venous stasis ± hemoconcentration, coagulopathy (Ann Intern Med 2009;151:180);

All patients: Frequent movement, adequate hydration, ankle/knee exercises High-risk pts: Fitted compression stockings or single dose of LMWH; ASA alone ineffective (Chest 2004;126:338; JGIM 2007;22:107)

Medication timing: If time-critical meds, keep dosing at “home” times or for longer trips gradually shift to “local” times; for other meds, ok to dose at “local” times right away; DM: Eastbound travel = shorter day = less insulin, vice versa

Jet lag: Usually develops if time difference >5 h; manifests as insomnia/daytime fatigue (NEJM 2010;362:440); adjustment typically

 

worst eastbound due to “shorter” day, harder to shorten Circadian cycle; natural adjustment takes ∼1 d/time zone; melatonin can be helpful: 0.5–3 mg taken 30 min before local bedtime, helpful to try “test dose” in advance

Safety Counseling (Ann Intern Med 2012;156:ITC6; AFP 2009;80:583; cdc.gov/travel)

Indicated for all patients; attention to each topic will vary based on pt & nature of travel

Emergency preparedness: Know where to find health care (ASTMH, State Dept, embassies have lists); consider evacuation insurance & medical alert tag if indicated

Transportation: MVC the leading cause of preventable death in US international travelers; appropriate levels of caution & attention to rules of the road; use licensed drivers & larger/newer vehicles when possible; seatbelt when in vehicle, helmet when bicycling Security: Be aware of surroundings, esp in unfamiliar areas; avoid displaying expensive items which may make you a target (e.g., jewelry, mobile phone)

Sexual behavior: Pts may have ↑ risky sexual behavior abroad; contacts may have ↑ prevalence of STIs; always use barrier protection (may need to pack)

Food and water: Specific to less-developed regions or countries; adherence often poor among hotel tourists (although still at risk); Water: Boiled, chemically purified, commercially bottled or carbonated, including for tooth brushing; avoid ice in beverages; Foods: Hot, freshly cooked; avoid foods which cannot be boiled or peeled (Lancet 2000;356:133) Hygiene: Frequent hand washing, use of EtOH-based gel if soap & water unavailable

Zika exposure: See cdc.gov/zika for updated maps; territories include Mexico, Caribbean, much of Central/S. America, sub-Saharan Africa, and SE Asia); primary risk is for men or women pregnant or desiring pregnancy

Women: Avoid travel if pregnant or planning pregnancy; avoid pregnancy and use condoms for 8 wk after leaving Zika area Men: Use condoms during travel and for 6 mos after leaving Zika area Prevention: DEET (∼30% concentration) or picaridin (20%) on skin, permethrin on clothing

 

Water safety: Swim in designated areas; caution re: fresh water in developing countries (schistosomiasis), wear shoes on soil/sand w/ potential animal waste (hookworm, strongyloides)

Environmental exposure: Appropriate sunblock, layers, protection to manage heat/cold; see “Sunscreen Pearls” in Prevention/Treatment section of “Melanoma”

Animal avoidance: Steer clear of animals unknown to traveler; urgent care for any bites

Altitude: For rapid ascents to >9000 ft (including via flight), acetazolamide 125 mg BID, starting 1 d before ascent; S/e: Paresthesias, urinary frequency (NEJM 2001;345:107)

Scuba diving: Wait 12–24 h prior to flying if one dive per day, 24–28 h if multiple dives per day (Aviat Space Environ Med 1990;61:1130).

Immunizations (CID 2006;43:1499; CDC “Yellow Book” for Int’l Travel 2012; www.cdc.gov/travel)

Routine vaccines esp advisable before int’l travel (see

“Immunizations”):

Tetanus, diphtheria: q10y Tdap

Measles, mumps, rubella: ⊕ Titers or 2 lifetime MMR doses for travelers born after 1957

Influenza: Year-round if available b/c flu season varies regionally

Required for some travel

Yellow fever: Endemic in parts of equatorial Africa + South America (not Asia); vaccine requirements vary by country; severe adverse events ∼1/100,000 vaccines; benefit > risk for most travelers to high-risk areas; caution if pregnant or elderly; q10y booster not needed per WHO or CDC (MMWR 2015;64:23); check country requirements: www.cdc.gov/travel

Meningococcus: Advised for sub-Saharan “belt” in dry season; required for Hajj

Recommended for some travel

Hepatitis A: All travelers to developing countries; 1 dose → short- term protection in 94–100% of adults; 2nd dose at 6–12 mos for long-term protection; If older, ill, or immunocompromised, consider Ig (administer at separate anatomic site) Typhoid: Vaccinate if ↑ risk country or if expect prolonged unsanitary food/water; IM

 

(booster q2y) or oral (1 tablet QOD × 4, booster q5y; live vaccine; not while on abx or immunocompromised) Polio: Previously vaccinated adults need single lifetime inactivated booster before travel to countries w/ ongoing transmission (incl Afghanistan, India, Pakistan, Nigeria) Hepatitis B: For endemic areas (much of Africa/Asia/S.Am./E.Eur./Iberia/Arctic) or if likely medical/sexual/etc. contact w/ blood/body fluids; see “Immunizations” and “HBV”

Japanese encephalitis: Consider for travel to S & E Asia or Western Pacific during transmission season (summer-fall, rainy season in tropics) if staying ≥1 mo or visiting rural/agricultural areas (MMWR 2010;59:1) Rabies: Consider if caves, rural work, camping, animal exposure or staying >1 mo in endemic area (India, SE Asia, Africa) w/o available postexposure Ig (CMAJ 2008;178:567)

No civilian indications for vaccination against cholera, plague, typhus, or anthrax

Schedule: Multiple vaccines at same visit OK, but space live-virus vaccines 1 mo apart

GI Infection (travelers’ diarrhea) (NEJM 1993;328:1821; IDCNA 2012;26:691; CID

2006;43:1499)

20–90% incidence during first 2 wk of travel in much of S. Asia, Africa, Middle East, Mexico, Central/S. America; nearly all benign, self-limited (3–5 d); most common etiology is enterotoxigenic E. coli (ETEC) Prevention: Sources mostly fecal–oral, include tap water (+ ice), uncooked & unpasteurized foods, condiments, street vendors, food handlers, nonsterile dishes

Consider bismuth subsalicylate (525 mg QID) as short-term ppx in healthy pts; up to 65% effective (counsel pts may cause temporary darkening of tongue/stool) (CID 2002;34:628) Consider prophylactic abx (quinolones or rifaximin) for high-risk pts (IBD, severe comorbidities, immunocompromise, on PPIs) or high-stakes trips

Self-treatment (J Trav Med 2009;16:161): If unresolved at 72 h, seek medical attention

 

Treatment of Traveler’s Diarrhea
Severity	Treatment

 

Mild	Fluid replacement: Ample broth, juice, etc. often sufficient tx; oral rehydration if ↑ watery diarrhea (NEJM 1990;323:891)
Moderate (3–5 stools/d, no fever)	Fluids + antimotility agents: Loperamide for up to 48 h, fluid replacement, ± abx (CID 2008;47:1007)
Severe (fever, blood, mucous, >5 stools/d)	Antibiotics + fluid replacement Cipro 500 mg BID × 1–3 d (↑ resistance in SE Asia; avoid in pregnancy) Alt: Azithro 1000 mg × 1 (s/e: Nausea) or 500 mg QD × 3 d

Malaria Prevention (NEJM 2008;359:603; IDCNA 2005;19:185; CDC Yellow Book 2012)

Risk: See cdc.gov/malaria/map and who.int/malaria/travellers for areas w/ regional endemicity; risk also depends on type of accommodation, season, elevation, & duration of exposure; ↑ risk among pregnant women, military, or immigrants VFR

Self-protection (also ↓ other vector-borne diseases): Insect repellent (DEET 20–30% or picaridin >20%; reapply q8h), long sleeves, pants; screens + permethrin-treated clothing and bednet if sleeping w/o A/C (open windows)

 

Malaria Prophylaxis for Travelers (CID 2006;43:1499)
Medication (Cost)	Dose	Duration	Notes
Atovaquone/Proguanil (Malarone) ($$$-$$$$)	1 tab QD	1–2 d before trip – 1 wk after	Resistance: N/a S/e: GI, HA CI: Coumadin, pregnancy (relative)
Doxycycline ($)	100 mg QD	1–2 d before trip – 4 wk after	Resistance: N/a S/e: Photosensitivity, GI, candida CI: Pregnancy
Mefloquine* (Lariam) ($$$)	228 mg QWk	2 wk before trip – 4 wk after	Resistance: SE Asia S/e: Neuropsych (black box warning), GI, cardiac CI: ψ Disease, cardiac conduction abnormalities
Primaquine ($$$)	30 mg QD	1–2 d before – 1 wk after	Resistance: Used for P. vivax only S/e: GI CI: G6PD deficiency, pregnancy

 

Chloroquine ($$)

300 mg QWk

1–2 wk before – 4 wk after

Resistance: Widespread S/e: GI, HA, visual, insomnia, pruritus CI: Psoriasis (relative)

*Recommended for pregnant travelers

 

Returning Travelers (J Travel Med 2000;7:259; CID 2007;44:1560; BMC Infect Dis

2012;12:386)

Common complaints: Persistent GI illness (10%), skin lesions (8%), respiratory infections (5–13%, depending on season), fever (up to 3%) (cdc.gov)

Exposure history: Insect bites, animal bites, fresh water swimming, bites, sexual contacts, raw meat, seafood, or unpasteurized dairy consumption

Fever: Requires urgent medical attention during & after travel; malaria is most common etiology (∼20%); P. falciparum potentially fatal, often missed; P. vivax or ovale can relapse mos later (dormant hypnozoites), even w/ ppx; also consider dengue, chikungunya, Zika, typhoid, viral hepatitis, acute HIV, leptospirosis, rickettsia, schistosomiasis Gastrointestinal illness: If fever & colitis, send stool culture; if upper GI-predominant sxs, consider Giardia lamblia, Cyclospora; if immunocompromised or diarrhea >10–14 d, O&P × 3

Respiratory illness: If persistent/LRI sxs, consider legionella, influenza, TB

Online References/Resources for Further Info

CDC Travelers’ Health web page and “Yellow Book”: cdc.gov/travel

WHO International Travel and Health: www.who.int/ith/en/

Global TravEpiNet: Tools for clinical decision making: www.gten.travel

When to Refer (AFP 2009;15:583)

When traveler or destination are w/↑ risk or complexity: Travel medicine

Posttravel illness: Travel/ID if significantly ill or any uncertainty in dx/mgmt

PRE-FLIGHT MEDICAL ASSESSMENT

 

 

General Approach: For travel advice re: medical conditions below, much based on expert opinion rather than wealth of evidence; for patients with significant medical conditions, involve their specialists in advising pt on their specific travel risks & measures to ↓ risk

Cardiovascular Disease (Ann Intern Med 2004;141:148)

Contraindications: Recent ACS/PCI (<3 wk), unstable angina, decompensated HF, symptomatic valvular disease (given ↓ PaO in-

2

flight), severe arrhythmias

AICD: Pts should request hand search (theoretical risk screening wands may → firing).

Bring recent ECG for cardiac disease, PPM or ICDs (w/ and w/o magnet) and recent office visit note with summary of medical history (prior interventions etc.).

CV indications for in-flight oxygen: NYHA class III CHF, angina, cyanotic congenital heart disease, pulm HTN/right heart failure (Can J

Cardiol 2004;20:1314)

Pulmonary Disease (Aviat Space Environ Med 2003;74:A1)

Contraindications: Recent PTX, severe hypoxia

 

Indications for in-flight oxygen (Thorax 2002;57:289)
SaO2 at Rest on Room Air	Recommendation
>95%	Supplemental O2 not indicated
<92%	Supplemental O2 indicated
92–95%	With risk factors,* supplemental O2 not indicated
92–95%	Without risk factors,* supplemental O2 indicated
*Risk factors: Hypercapnia, FEV1 <50%, severe cardiopulmonary disease, pulm HTN, recent hospitalization for pulm disease, inability to walk <50 m, cerebrovascular disease

Home O₂: ↑ Flow rate 1–2 L/min (Chest 2008;133:1002)

Asthma: Carry-on β-agonist rescue inhalers, bring a course of steroids Cystic fibrosis and bronchiectasis: May need abx and secretion- clearing medications; stay well hydrated

 

Infectious Disease (Lancet 2005;365:989)

Contraindications: Active/contagious respiratory infections (e.g., TB, PNA, flu) and untreated severe sinusitis (i.e., negative cultures) (Lancet Infect Dis 2010;10:176).

Uncomplicated URI/ mild sinus infections: Consider prophylactic decongestant due to increased risk of pain, vertigo, even TM perforation

Neurologic (Aviat Space Environ Med 2003;74:A1)

Contraindications: Stroke <2 wk, uncontrolled seizure d/o Migraines: Can be triggered by air travel; carry prophylactic and rescue medications

Other

Pregnancy: Air travel safe for uncomplicated pregnancies <36 wk gestation; pts at ↑ risk for DVT → preventive measures (above) recommended (Obstet Gynecol 2009;114:954)

Procedures: Wait 2 wk after open surgery, 1 d for uncomplicated laparoscopic procedures or colonoscopy (Am Fam Physician 1999;60:801)