Cytomegalic inclusion disease, also known as cytomegalic inclusion body disease, giant cell inclusion disease, or human cytomegalovirus infection, is caused by the cytomegalovirus (CMV), mainly in infants, which is manifested in hepatosplenomegaly, jaundice, and intradermal hemorrhage. Intrauterine infections are most common, but acquired infections can also be seen.
Cytomegalovirus, also known as salivary gland virus, is a kind of herpes virus, a DNA virus with 2 layer of capsid and with a diameter of 150 – 200nm, very similar in morphology to herpes simplex virus and varicella zoster virus, so it is not easy to distinguish. However, cytomegalovirus can only grow in the in tissue culture of fibroblasts slowly.
Figure 1, cytomegalovirus and structure
Humans have common susceptibility to cytomegalovirus. Most people have been infected with cytomegalovirus during their lifetime, mostly asymptomatic subclinical infections. Once infected, the infected patients carry the virus throughout their life and intermittently shed the virus. The reactivation of latent virus is caused by the imbalance of host immune system. When the physiological conditions of the body are changed as a result of pregnancy or suppressed immune function while AIDS and organ transplantation, the viral shedding is increased. Its transmission modes include intrauterine transmission, puerperal transmission including breast milk transmission, contact transmission, and blood transmission. This virus is present in genitourinary secretions or semen, so the infection in adults is associated with sexual contacts. Serologic investigations show that 40% - 100% of adults have circulating antibodies to the virus, but the viral shedding can still occur from the urine or salivary gland, suggesting that it is related to the persistent infections or reactivation or latent viruses.
Signs and symptoms
The clinical symptoms vary widely with the age and condition of patients.
Intrauterine infection is caused by the viral invasion through the placenta. Patients may not have clinical symptoms, but if symptoms occur, it is generally more obvious than the acquired infections. Viremia can occur, causing systemic visceral lesions, manifested in jaundice, hepatolienomegaly, interstitial pneumonia, chorioretinitis, spasm, brain calcification, acephalus, bradykinesia, and mental retardation. Due to anemia and thrombocytopenia, ecchymosis can occur on the skin, and sometimes systemic maculopapulae can occur, with systemic papulotubercular rashes occasionally. Most patients die or leave severe neurological disfunction within 2 months, and nervous deafness is the most common.
Acquired infections often occur at birth and are generally asymptomatic. However, dyshepatia, spider nevus, pertussoid cough, bronchopneumonia can occur, and sometimes erythema and maculopapular rash can occur. Children and adults can also develop the disease, mostly in patients with hematopoietic and lymphoreticular malignant tumors or multiple blood transfusions, which is characterized by 3 to 6 weeks of persistent fever, follicular or maculopapular or morbilliform rashes mainly on the lower limbs, as well as urticaria, livedo reticularis, and lymphocytic vasculitis. Unlike infectious mononucleosis caused by Epstein-Barr virus, CMV-infected patients have no exudative tonsillitis and significant hepatosplenomegaly and lymphadenopathy, and negative result is present in the heterophile agglutination test.
CMV infection is also associated with cutaneous sclerosis, Gianotti Crosti syndrome, and papular purpuric gloves and socks syndrome. In patients with impaired or suppressed immune function, CMV infection can present with severe even fatal symptoms, manifested in pneumonia, hepatitis, gastrointestinal ulcers, retinitis, encephalitis, myelitis, and various opportunistic infections. Skin lesions are characterized by papules, purpura, blisters, bullae, pustules, persistent pigmented nodules or plaques, and steep ulcers in the perianal area and buttocks.
In all organs and tissues, giant cells with intranuclear eosinophilic inclusion bodies or cytoplasmic basophilic inclusion bodies can be seen, the giant cells in the vascular endothelial cells are characteristic, and focal monocyte cell infiltration is present. Chronic interstitial nephritis is present in the kidney, patchy pneumonia is visible in the lungs, and gangrenous granuloma may be in the brain.
Figure 2, positive cytomegalovirus (CMV) inclusion bodies in ulcer tissues in anti-CMV monoclonal antibody staining
Figure 3, intradermal leukocytoclastic vasculitis and neutrophils and fibrin infiltration in the subepidermal blisters in the histopathology
Figure 4, cytomegalovirus inclusion bodies in endothelial cells in immunohistochemical staining
Figure 5, cytomegalovirus inclusions in colon cells in immunohistochemical staining
The diagnosis of cytomegalic inclusion disease mainly relies on giant cells with specific inclusion bodies found in the histological examination. The specimens can be taken from urinary sediment, pharyngeal secretions, and skin lesions, but low positive rate is present. Nevertheless, the positive rate can be improved by immunohistochemical staining. The most reliable diagnostic method is to isolate and culture cytomegalovirus from urine, blood, bronchoalveolar lavage fluid, or other body fluids and secretions. The viral culture requires tissue culture of human fibroblasts, but it takes a long time of about 5 – 28 days. The detection of CMV virus early antigen pp65 in 24 to 48 hours of culture can reduce the culture time and speed up the examination. Quick and sensitive methods are PCR and CMV antigen detection in the blood. Detection of specific IgG and IgM antibodies in the blood is also helpful in diagnosis, but pathogenicity determination requires an increase in antibody titer. Neonatal specific IgM antibodies within 3 weeks after birth can help determine the diagnosis.
In general, cytomegalic inclusion disease does not require special treatment. However, when the severe CMV infection is life-threatening or CMV retinitis affects vision, the antiviral drugs ganciclovir and foscarnet sodium are effective. Cytarabine, vidarabine, interferon, and transfer factor are ineffective. There is currently no effective vaccine available.
The recommended treatment regimen is ganciclovir intravenously 6mg/kg twice a day for 6 weeks. Ganciclovir can only be administered intravenously, so it is difficult for patients to adhere to a long-term treatment. At present, there is an oral preparation, known as valganciclovir, which is a prodrug to ganciclovir and can be quickly converted into ganciclovir after oral absorption.