Cytomegalovirus
B. Denise Hemby and Theresa M. Campo
Definition
A.Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpesviridae family. It has the largest genome of the herpes viruses, grows only in human cells, and replicates best in human fibroblasts. Multiple genetically distinct strains exist; the differences in CMV genotypes are associated with differences in virulence. CMV usually causes an asymptomatic infection and remains dormant throughout life but can be reactive. CMV frequently reactivates in critically ill persons.
B.CMV is one of the TORCH infections (Toxoplas mosis, Other infections including syphilis, Rubella, CMV, and herpes simplex virus [HSV]).
C.CMV is primarily asymptomatic or produces mild flulike symptoms and can develop 9 to 60 days after primary infection. The lymph nodes and spleen may be enlarged, and they may have extreme fatigue that can last even after normalizations of lab values
Incidence
A.In the United States, as many as 60% of the population has been exposed to the virus. However, the number is more than 90% in high-risk groups such as those with HIV and unborn babies whose mother got infected during pregnancy. The age of prevalence varies worldwide but in developing countries it is generally acquired during childhood and the risk increases with age
B.Milk ingestion. Preterm infants are at the greatest risk to acquire CMV from breast milk.
Pathogenesis
A.CMV is a lytic virus that causes cytopathic effect in vitro and in vivo. Its hallmark is enlarged cells with inclusion bodies. The cells are described as owl’s eye.
This virus is transmitted both horizontally (by direct person-to-person contact with virus-containing secretions) and vertically (from mother to infant before, during, or after birth). When a person is infected, the CMV DNA can be detected with PCR in all different cell lineages and body systems. Once infected, CMV effects the epithelia cells of the salivary gland causing persistent infection and shedding of the virus.
B.The incubation period for horizontally transmitted CMV infections in households is unknown. CMV antibodies can be found as early as 4 to 7 weeks after initial infection and may persist as long as 16 to 20 weeks.
C.Symptomatic CMV disease can affect almost all organs of the body, resulting in unknown origin of fever, pneumonia, encephalitis, myelitis, hepatitis, colitis, retinitis, and neuropathy. In very rare cases, especially in immunocompetent people, the manifestations can include Guillain–Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia:
1.Congenital CMV disease—most common clinical findings include petechiae, jaundice, microcephaly, small size for gestational age, and hearing loss in children.
2.CMV pneumonia—detected via culture, chest x-ray, histopathology, 6% of patients with CMV infection develop pneumonia. Immunosuppressed patients can develop life-threatening CMV pneumonia and the higher rate and greatest severity are among lung transplant recipients.
3.CMV retinitis—most common with AIDS patients and typically progresses to decreased visual acuity or even blindness if untreated. Retinitis must be confirmed by an ophthalmologist.
4.CMV gastritis and colitis—there is a combination of symptoms of upper and lower gastrointestinal (GI) tract, mucosal lesions seen by endoscopy; detection is by culture, histopathology, immunohistochemistry, or in situ hybridization. It can infect from the mouth through the colon, causing ulcerative lesions, abdominal pain, hematemesis, colitis, and diarrheal illness.
Predisposing Factors
A.Exposure to young children, especially those in day care centers.
B.Sexual contact (cervicovaginal secretions and semen).
C.Blood transfusions.
D.Hospital or occupational exposure.
E.Pregnancy.
F.Transplacental transmission.
G.Breast milk.
Common Complaints
A.Mild flu-like symptoms.
B.Fever.
C.Overwhelming fatigue.
D.Pharyngitis.
E.Ulcerative lesions in the mouth.
Other Signs and Symptoms
A.Visual changes.
B.Retinitis.
C.Arthralgias.
D.Nausea, abdominal cramping, and vomiting (includes hematemesis).
E.Prolonged fever.
F.Mild hepatitis.
G.Headache.
H.Immunocompromised persons:
1.Bacterial: Pneumonia, retinitis, myocarditis, and aseptic meningitis.
2.Anemia.
3.Thrombocytopenia.
Subjective Data
A.Review onset of presenting signs, symptoms, and their duration.
B.Review the patient’s history for recent upper respiratory infection (and mononucleosis-like symptoms).
C.Elicit information concerning contact with any person known to be CMV infected.
D.Review history for other family members with similar symptoms.
E.Ask the patient about any occupational exposure.
F.Review the patient’s exposure to children in day care centers.
G.Review recent blood transfusions and/or organ transplantation.
H.Determine the patient’s history for risk factors or presence of HIV:
1.If known HIV, does the patient know his or her last viral load CD4 count?
2.Is the patient taking antiretroviral treatment (ART)? When were the antivirals started?
I.Ask family members if the patient has been confused, lethargic, or withdrawn, or has exhibited personality changes (CMV encephalitis, dementia).
Physical Examination
A.Check temperature, pulse, respirations, blood pressure, and weight (document serial weight loss).
B.Inspect skin for jaundice and petechiae.
C.Conduct a detailed eye exam:
1.CMV infection may appear as yellow-white areas with perivascular exudates and hemorrhage, having a cottage cheese and ketchup
appearance at either the periphery or the center of the fundus:
a.Differentiating suspected CMV retinitis and cotton wool spots is essential. Cotton wool spots appear as small, fluffy white lesions with indistinct margins and are not associated with exudates or hemorrhages.
2.Evaluate field of vision.
3.Perform ear and nasal exam.
4.Perform an oral/throat exam.
5.Conduct hearing test.
6.Evaluate thoroughly for lymphadenopathy.
D.Auscultate heart and lungs.
E.Palpate abdomen:
1.Note organomegaly.
2.Mild to moderate abdominal pain and tenderness associated with GI colitis.
3.Pregnancy: Palpate fundal height and evaluate for suspected intrauterine growth restriction (IUGR).
F.Neurologic exam:
1.Assess all cranial nerves.
2.Sensation (deficits may occur without loss of vibratory sense and proprioception).
3.Deep tendon reflexes.
4.Motor skills and coordination.
5.Gait.
Diagnostic Tests
A.Viral culture of specimen from urine, cervix, vagina, nasopharynx, and saliva:
1.Viral culture is the best means of diagnosing acute CMV infections, although it does not distinguish between primary and recurrent disease. Urine contains high titers of the virus because CMV is relatively stable in urine.
B.Complete blood count (CBC) with differential.
C.Complete metabolic panel (CMP)—total direct and indirect serum bilirubin.
D.Colonoscopy with biopsy.
E.Serology for CMV immunoglobulin G (IgG) and M (IgM): Only the recovery of the virus from a target organ provides unequivocal evidence that the disease is caused by CMV infection. However, a four-fold or greater rise in IgG-specific antibody titer is usually considered evidence of acute infection.
F.Amniocentesis for PCR to detect CMV DNA is the preferred diagnostic approach for detecting the infected fetus.
G.Immunocompromised patients, especially transplant recipients, may be monitored for viral surveillance weekly using surrogate markers for viremia-PCR.
H.Chest x-ray if indicated.
I.CT scan if indicated to evaluate abnormalities of the brain in the presence of an abnormal neurologic examination, seizures, and microcephaly.
J.Sensorineural hearing evaluation.
K.Routine maternal screening for CMV infection is not recommended during pregnancy. Lab tests that are currently available generally cannot conclusively determine whether a primary CMV infection has occurred during the pregnancy.
Differential Diagnoses
A.CMV.
B.Autoimmune hepatitis.
C.Human HSV 6 infection.
D.Epstein–Barr virus (EBV; Mono).
E.Other TORCH infections.
F.HIV/AIDS.
G.Viral hepatitis.
H.Enteroviruses.
I.Fever of unknown origin (FUO).
Plan
A.General interventions:
1.Provide support for the patient and family.
2.Contact social services if long-term support will be required for these infants/families.
3.Rest is vital.
B.Patient teaching:
1.Patients with splenomegaly should avoid activity that may increase the risk of injury to the spleen, such as contact sports and heavy lifting.
2.Mothers infected with CMV should be discouraged from breastfeeding because CMV is secreted in breast milk
3.Isolation is not required.
4.Use universal precautions, especially good handwashing.
5.Do not share eating or drinking utensils, drinks, or food with toddlers or young children.
6.Educate about the importance of ART in treating CMV:
a.Patients with CMV retinitis may require lifelong suppressive therapy to prevent blindness.
b.Report visual deterioration immediately.
C.Pharmaceutical therapy.
The goals of pharmacotherapy are to prevent outbreaks and complications and to reduce morbidity:
1.Valganciclovir (Valcyte)—drug of choice for prevention of CMV in solid-organ transplant patients:
a.Retinitis with AIDS—start 900 mg PO q12h for 21 days; maintenance—900 g PO qd.
b.Transplant start 900 mg qd within 10 days of transplant for 200 days.
2.Ganciclovir (Cytovene)—a mainstay except in CMV retinitis, treatment of CMV, HSV, human herpesvirus (HHV)-6, HHV-7, and HHV-8. Major adverse reactions include fever, rash, diarrhea, neutropenia, anemia, and thrombocytopenia:
a.Colitis—start 5 mg/kg intravenous (IV) q12h, once tolerated change to valganciclovir 900 mg PO q12h for 21 to 42 days.
3.Cidofovir (Vistide)—approved for CMV retinitis:
a.Retinitis—start 5 mg/kg IV q week for 2 weeks; maintenance 5 mg/kg IV every 2 weeks.
4.Foscarnet (Foscavir):
a.Retinitis—start 60 mg/kg IV q8h for 14 to 21 days; maintenance 90 to 120 mg/kg IV qd.
b.HSV—40 mg/kg IV q8h for 14 to 21 days.
5.CMV vaccines are currently in clinical trials.
Follow-Up
A.Because retinitis is the most common manifestation of CMV disease, patients with central nervous system (CNS), GI, or pulmonary disease should be assessed with a dilated retinal examination to detect subclinical retinal disease.
B.Monitor CBC, serum creatinine, and electrolytes (especially calcium and magnesium) every week.
C.The patient should be seen for reports of excessive bruising or bleeding, jaundice, or abnormal CNS functioning.
Consultation/Referral
A.Consultation with an infectious disease specialist is indicated for acute infection, especially for immunocompromised patients.
B.Antivirals have many adverse effects and are best managed by the physician who has experience using these drugs.
C.Consultation with a hematologist is needed in severe cases, especially with hemolytic anemia and thrombocytopenia.
D.Consultation with a neurologist is indicated for meningitis, encephalitis, polyneuritis, and Guillain–Barré syndrome.
E.Consultation with an ophthalmologist is needed on an emergent basis for a dilated retinal examination due to the risks of blindness. Serial dilated retinal examinations should be done after ART induction therapy and monthly thereafter.