Cytomegalovirus Case File

Cytomegalovirus Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 25

You are called to examine a 1-day-old male because the nurse is concerned that he is jaundiced. He was born by spontaneous vaginal delivery to a 19-year-old gravida1 para1 after a full-term, uncomplicated pregnancy. The mother had no illnesses during her pregnancy; she did not use tobacco, alcohol, or drugs; and the only medication that she took was prenatal vitamins. She denied any significant medical history, and there is no family history of genetic syndromes or illnesses among children. The infant is mildly jaundiced but has a notable abnormally small head circumference (microcephaly). His cardiovascular examination is normal. His liver and spleen are enlarged on palpation of the abdomen. Neurologic exam is notable for the lack of a startle response to a loud noise. CT scan of his head reveals intracerebral calcifications. The pediatrician explains to the child’s mother that the virus involved is the most commonly transmitted transplacental viral infection in the United States.

◆ What is the most likely cause of this infant’s condition?

◆ How did he likely acquire this?

◆ What is the test of choice to confirm the diagnosis?

ANSWERS TO CASE 25: CYTOMEGALOVIRUS

Summary: A 1-day-old male with microcephaly, jaundice, hepatosplenomegaly, and deafness caused by a viral infection.

◆ Most likely cause of this infant’s condition: The infant is most likely suffering from a congenital infection with cytomegalovirus (CMV).

◆ Likely acquisition of this infection: Transplacental spread of the virus during a primary CMV infection of the pregnant mother.

◆ Test of choice to confirm the diagnosis: The definitive diagnostic test to confirm CMV infection in this patient is to demonstrate the presence of CMV in the infant’s urine.

CLINICAL CORRELATION

Human cytomegalovirus (CMV) is the largest member of the human Herpesviridae family. It is lymphotrophic and commonly produces asymptomatic infections in immune competent hosts. However, it can cause serious primary and recurrent infections in immunosuppressed individuals and neonates. CMV is the most common transplacentally transmitted infection in the United States.

APPROACH TO SUSPECTED CMV INFECTION

Objectives

1. Be aware of the genomic characteristics of CMV.
2. Be able to describe how CMV causes infection, including transplacental infection.

Definitions

Lymphotrophic: Having a specific affinity for lymph cells or their precursors.

Microcephaly: Abnormally smaller sized head, which may be associated with mental retardation.

Hepatosplenomegaly: Enlargement of the liver and spleen.

Subclinical infection: Without the presence of noticeable clinical disease.

DISCUSSION

Characteristics of CMV That Impact Transmission

CMV belongs to the Betaherpesvirinae subunit of the Herpesviridae family and is the largest known virus to infect humans. The genome of linear, double-stranded DNA is housed in an icosadeltahedral capsid. Between the envelope and the capsid is a layer called the tegument, a phosphoproteincontaining matrix that plays a role in initiating replication. CMV, like other herpesviruses, has a lipid envelope that contains glycoproteins that facilitate attachment and entry into host cells. The virus often establishes latent infection in lymphocytes, leukocytes, and organs like the kidney, heart, and lung. Cell-mediated immunity is required for the control of CMV infections. Suppression of the immune system by medications or infection, such as AIDS, can result in reactivation of the virus and severe, symptomatic disease.

CMV has a ubiquitous distribution and approximately 10–15 percent of children are infected before the age of 5. Most CMV infections in immune competent hosts are asymptomatic, although occasionally a mononucleosis-like syndrome can occur. Yet, even in subclinical infections, CMV can be isolated from saliva, cervical secretions, semen, urine, and white blood cells for months to years following infection. Although CMV is found in many host secretions, its major routes of transmission are via contact with blood, oral secretions, sexual contact, organ transplant, or congenital infection. CMV is the most common viral cause of congenital disease and infection, and its spread is thought to occur via transplacental transfer. The risk to the fetus is particularly high when the mother has a primary infection during her pregnancy.

Diagnosis

Although most CMV infections during childhood and in adults are asymptomatic, infants and immunocompromised patients can develop severe clinical symptoms from either primary infection or reactivation. Of the 1 percent of infants infected in utero or during delivery, 90 percent will develop asymptomatic infections, while the other 10 percent will develop symptomatic infections with congenital defects or disorders. Nearly all of the infants with symptomatic infections are born of mothers with primary infections during their pregnancies. Congenital CMV can cause a devastating syndrome that includes microcephaly, intracerebral calcifications, hepatosplenomegaly, thrombocytopenia, chorioretinitis, deafness, mental retardation, jaundice, and rash. Many of the infants with severe CMV congenital syndrome die within a short time, and those who survive have been shown to have persistent neurologic deficits. Reactivation of a latent infection during pregnancy confers a much lower risk, as the fetus is protected by the maternal immune response.

In addition to assessing the clinical symptoms, more definitive approaches to diagnosing CMV infection include direct detection of CMV antigen or DNA in tissues or fluids via immunoassays or quantitative PCR. Diagnosis of CMV infection can be confirmed by identification of the virus in the infant’s urine during the first week of life. Histologically, CMV infection can also be detected by its ability to produce characteristic enlarged cytomegaly of infected cells with pronuclear inclusions, or “owl’s eyes.”

Treatment and Prevention

CMV infections are primarily treated with ganciclovir, immune globulin plus ganciclovir, or foscarnet. Treatment with ganciclovir has been used to prevent CMV disease in AIDS patients and transplant recipients. Use of this agent also reduces the severity of CMV syndromes such as retinitis and gastrointestinal disease. Treatment with both immune globulin and ganciclovir has been used to reduce the high mortality of CMV pneumonia in bone marrow transplant patients.

Unfortunately, congenital and perinatal transmission of CMV cannot be prevented once acquired by the pregnant woman. Thus, hygiene and handwashing may play a role in prevention. Isolation of infants with CMV infections can prevent spread to other infants. Prevention of transplantation-acquired CMV infection can be obtained by transplanting organs and blood products from seronegative donors into seronegative recipients. In situations where it is not possible to use organ or blood products from seronegative donors, prophylactic treatment of all transplant patients or preemptive therapy of those patients with evidence of active CMV infection should be used. Such therapies include the use of hyperimmune CMV globulin, anti-CMV agents or a combination of both. Additionally, safe sex practices also reduce transmission of new CMV infections. CMV vaccines are currently under development; however, none are currently available.

COMPREHENSION QUESTIONS

[25.1] An 18-year-old female presents to her physician with a 1-week history of fever, sore throat, fatigue, and myalgia. Physical examination reveals enlarged tonsils and exudative pharyngitis. Based on her clinical presentation, her physician diagnoses her with infectious mononucleosis. Because there are multiple causes of infectious mononucleosis-like illnesses, which of the following diagnostic assays would rule out CMV as the causative agent of this patient’s infection?

A. A negative Gram stain of a throat swab

B. A lack of atypical lymphocytes in the patient’s blood

C. A positive histological finding of cytomegaly

D. A positive Monospot test

[25.2] A previously healthy 8-year-old boy develops a classic childhood illness as a result of a primary viral infection. Which of the following agents would most likely produce symptomatic disease in a boy of this age?

A. Cytomegalovirus

B. Epstein-Barr virus (EBV)

C. Herpes simplex virus 2 (HSV-2)

D. Poliovirus

E. Varicella-zoster virus (VZV)

[25.3] A 32-year-old HIV infected male is noted to have acute CMV infection causing acute gastrointestinal symptoms. The treating physician has ordered that antiviral therapy be administered. Which of the following is most likely to be targeted by the antiviral agent?

A. Protease cleavage

B. Nuclear transport of virus

C. Synthesis of viral DNA

D. Transcription of viral proteins

E. Viral-cell fusion

Answers

[25.1] D. Both CMV and EBV infections can cause infectious mononucleosis disease; however, only EBV produces heterophile antibodies that would result in a positive Monospot test; answers A, B, and C, incorrect: A negative Gram stain of the patient’s throat culture would rule out group A Streptococcus; atypical lymphocytes are commonly present in EBV infection but not CMV-related infections; and cytomegaly is typically present in CMV infections.

[25.2] E. VZV is a classic childhood disease that produces symptomatic primary infections; answers A, B, C, and D are incorrect: Most primary CMV, EBV, and poliovirus infections are asymptomatic, whereas HSV-2 infections would rarely occur in a child of this age.

[25.3] C. Ganciclovir has been used primarily to treat severe CMV infections, and its method of action involves inhibition of DNA synthesis; answers A, B, D, and E are incorrect methods of antiviral therapy for CMV infection.

MICROBIOLOGY PEARLS ❖ CMV is the most common viral cause of congenital infection in the United States with the mechanism being primarily transplacental infection. ❖ CMV establishes latent infection in lymphocytes and leukocytes. ❖ CMV can be excreted in saliva, semen, urine, blood, and cervical secretions for months to years following infection. ❖ Clinical manifestations include a mononucleosis-like disease in immune competent individuals; microcephaly, hepatosplenomegaly, deafness, neurological deficits, and jaundice in congenital infections. ❖ CMV cytopathology involves cytomegaly or enlargement of infected cells with pronuclear inclusions, or “owl’s eyes.”

REFERENCES

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, 5th ed. St. Louis, MO: Mosby, 2005:558–62. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:566–9. 

Sia IG, Patel R. New strategies for the prevention and therapy of Cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000;13:83–121.

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