Cytomegalic inclusion body disease, also known as cytomegalovirus infection, is a congenital or acquired systemic infection caused by human cytomegalovirus infection. It is called cytomegalovirus inclusion disease because human cytomegalovirus inclusion bodies can be found in the nucleus and cytoplasm of many infected organs and tissues. In recent years, with the development of molecular biology techniques, the diagnosis of active cytomegalovirus infection no longer relies on pathological findings of viral inclusion bodies in tissue cells, therefore, cytomegalovirus inclusion disease is mostly referred to as cytomegalovirus infection.
Disease Profile
Human cytomegalovirus (HCMV) infection is widespread in China, with an HCMV antibody positivity rate of about 86% to 96% in the general population and up to about 95% in pregnant women. Although the incidence of HCMV infection is high, HCMV is less pathogenic and is not significantly pathogenic to immunocompetent individuals. The presence of HCMV replication in the body does not always indicate a disease process, and HCMV infection of immunosuppressed individuals or fetuses and infants (physiologically immunocompromised) or immunocompromised individuals is what predisposes to disseminated disease or single organ damage. Therefore, primary cytomegalovirus infections tend to occur in infants and children or in immunodeficient populations.
Classification
Classification according to the source of infection
(1) primaryinfection: initial infection with exogenous HCMV.
(2) recurrentinfection: including endogenous latent virus activation (reactivation) or reinfection (reinfection) with exogenous strains of different viruses.
Classification according to the time of primary infection
(1) congenitalinfection: HCMV infection confirmed within 14 days after birth (including 14 days).
(2), perinatalinfection (perinatalinfection): no infection confirmed within 14 days after birth, but evidence of infection in the third to twelfth week after birth, usually acquired through the birth canal, breast milk or blood transfusion.
(3), postnatal infection (postnatalinfection) or acquired infection (acquiredinfection): acquired after 12 weeks of life through horizontal transmission such as close contact, transfusion of blood products or transplantation of organs.
Classification according to clinical symptoms
(1), symptomaticinfection: when the lesion involves 2 or more organs and systems, it is called systemicinfection, mostly seen in people with congenital infection and immunodeficiency; or the lesion is mainly concentrated in one organ or system.
(2), asymptomaticinfection: there is evidence of HCMV infection but no symptoms and signs, or there are signs and/or functional abnormalities of the diseased organ. The latter is also known as subclinicalinfection.
Pathogenesis
Cytomegalovirus infection is caused by HCMV invading the body, proliferating in the cells and causing tissue lesions. The exact mechanism of transmission of the virus from mother to fetus through the placenta in congenital cytomegalovirus infection is unknown. Cytomegalovirus has a broad cellular and histophilic spectrum, with epithelial cells, endothelial cells, and fibroblasts being its main target cells; peripheral blood leukocytes are susceptible cells; and specific parenchymal cells such as nerve cells of the brain and retina, smooth muscle cells of the gastrointestinal tract, and hepatocytes can also be infected, leading to meaningful cytopathic lesions in some cases. Cytomegalovirus infection in children mainly manifests as hepatic impairment, jaundice, pneumonia, and rarely as hematologic disorders, central nervous system disease, myocardial damage, renal damage, and gastrointestinal damage. Cytomegalovirus infection shows different characteristics with age. In the fetal and neonatal periods, nerve cells and salivary glands are most sensitive to HCMV, and the monocyte-macrophage system is often involved. In immunocompetent older children and adults, the virus is mostly confined to the salivary glands and kidneys in both primary and re-infections. A few primary symptomatic infections may involve lymphocytes; in immunosuppressed individuals, the lungs are most frequently involved and often result in disseminated infections in a wide range of tissues and organs. In addition, salivary glands and the urinary tract are the most common sites of detoxification and the most abundant sites; intraocular and intracranial HCMV infections are mainly seen in intrauterine infected children and immunodeficient individuals due to the protective effects of the blood-brain and blood-eye barriers. [1]
Clinical presentation
Congenital infection
There is often multisystem organ damage or different combinations of 1 or more of the following manifestations Jaundice (predominantly elevated direct bilirubin) and hepatosplenomegaly are most common. There may be thrombocytopenic petechiae, central nervous system involvement such as microcephaly, ventricular enlargement with foci of peripheral calcification, sensorineural deafness, neuromuscular abnormalities, convulsions, and retinal chorioretinitis. There is an increase in peripheral blood anomalous lymphocytes, increased cerebrospinal fluid protein and abnormal liver function. Deformities such as inguinal hernia are common. Sensorineural deafness occurs in up to 25-50% of symptomatic infections and may be late onset or progressive.
HCMV hepatitis
It is most common in primary infections in infancy and childhood and may be jaundiced or non-jaundiced or subclinical. There is mild to moderate hepatomegaly and textural changes, often with splenomegaly; the jaundiced form often has varying degrees of cholestasis; serum liver enzymes are mildly to moderately elevated. Mild cases are self-healing.
HCMV pneumonia
Most often seen in infants under 6 months of age with primary infection. Mostly no fever, may have cough, shortness of breath, intercostal depression, and occasionally lung rales may be heard. Imaging mostly reveals diffuse interstitial lung lesions, which may include peribronchial infiltrates with emphysema and nodular infiltrates. Liver damage may be present.
Post-transfusion syndrome
Most commonly seen in patients with primary infection following a blood transfusion in the neonatal period. Clinical manifestations are varied and may include fever, jaundice, hepatosplenomegaly, hemolytic anemia, thrombocytopenia, and abnormal lymphocytosis. The skin is commonly grayish-white with shock-like manifestations. There may be signs of pneumonia and even respiratory failure. In preterm infants, especially very low birth weight infants, the mortality rate can be more than 20%.
Mononucleosis-like syndrome
(Infectious mononucleosis-like syndrome): Mostly a primary infection in older children, but can also occur in infancy and early childhood. Irregular fever, malaise, myalgia, etc., generalized lymph node enlargement is rare, exudative pharyngitis is rare, and typical blood changes (total leukocyte count of 10×10∧9-20×10∧9/L, lymphocyte ratio >50%, abnormal lymphocyte ratio >5%) occur later in the course of the disease (1-2 weeks after fever); more than 90% have mildly increased serum liver enzymes, only about 25% have hepatosplenomegaly. Jaundice is extremely rare.
Symptomatic infections in immunosuppressed children
Both primary and recurrent infections are likely to occur. Infectious mononucleosis is the most common manifestation, but abnormal lymphocytes are rare. Some have leukopenia with anemia and thrombocytopenia as a result of immunosuppressive therapy. This is followed by pneumonia. Hepatitis often coexists with acute rejection in liver transplant recipients and is characterized by persistent fever, elevated liver enzymes, hyperbilirubinemia, and liver failure. Immune complex glomerulonephritis can occur in renal transplant recipients. Gastroenteritis is common in AIDS and bone marrow, kidney and liver transplant recipients. Neurological disorders such as meningoencephalitis, myelitis, peripheral neuropathy, and polyneuritis may also occur.
Ancillary Tests
Virological evidence
i. Virological evidence is obtained in blood samples (whole blood, single nucleated cells, serum or plasma), urine and other body fluids including alveolar lavage (preferably with exfoliated cells) and diseased tissues as follows.
(1) Viral isolation: the “gold standard” for the diagnosis of active HCMV infection.
(2) Viral particles by electron microscopy and cytomegalic inclusion bodies by light microscopy, but this method has a low positivity rate.
(3), immunolabeling techniques to detect viral antigens: IEA, EA, pp65 antigen, etc.
(4), reverse transcription PCR method to detect virus-specific gene transcription products, positive indicates active infection.
(5), real-time fluorescence quantitative PCR method to detect virus-specific DNA load. Due to the high specificity and sensitivity of the fluorescence quantification method, and the ease of operation, and similar accuracy to pp65 antigenemia, it is now more widely used in clinical practice [4]. HCMV-DNA load is positively correlated with active infection, and a high load or a significantly elevated load during dynamic monitoring suggests the possibility of active infection. Positive HCMV-DNA in serum or plasma samples is evidence of active infection; positive whole blood or single nucleated cells is a possibility of latent infection, and a high load supports active infection. Detection of viral DNA in the neonatal period is evidence of primary infection.
Indirect evidence
Primarily from specific antibody testing. Evidence of primary infection.
(1) dynamically observed change from negative to positive anti-HCMV-IgG antibodies.
(2) Positive anti-HCMV-IgM and negative HCMV-IgG or positive low-affinity IgG. Evidence of recent active infection.
(1) ≥ 4-fold elevated anti-HCMV-IgG titer in both sera.
(2) Positive anti-HCMV-IgM and IgG. Positive anti-HCMV-IgM in the neonatal period is evidence of primary infection. IgG antibodies from the mother need to be considered in infants within 6 months of age; false negatives for specific IgM antibodies may occur in severely immunodeficient individuals or in small infants.
Diagnosis
Clinical diagnosis
A clinical diagnosis can be made with virologic evidence of active infection and clinical manifestations associated with HCMV-associated disease, excluding other common causes of presenting disease. Because of the weak pathogenicity of HCMV, most immunocompetent individuals are clinically asymptomatic after infection. Foreign data show that only 5% of intrauterine infections are systemically disseminated, another 5% have mild symptoms, and 90% are asymptomatic. Therefore, even if evidence of active HCMV infection is found, other common causes of presenting disease must be excluded before the cause of HCMV can be considered.
Determining the diagnosis
The isolation of HCMV virus from biopsied tissue or specific body fluids such as cerebrospinal fluid or alveolar lavage fluid or the detection of viral replication markers (viral antigens and gene transcription products) is conclusive evidence of HCMV disease. [2]
Differential diagnosis
Because of the variety of clinical manifestations of HCMV infection, clinical differentiation from the corresponding disease is often required based on the major clinical manifestations. When HCMV congenital infection has CNS involvement as its main manifestation, it often needs to be differentiated from other causes of perinatal brain injury (e.g., neonatal hypoxic-ischemic encephalopathy, congenital CNS infection due to other viruses or Toxoplasma gondii) and genetic disorders (e.g., chromosomal disorders and genetic metabolic diseases). When HCMV congenital infection is mainly manifested by jaundice and hepatosplenomegaly, it needs to be differentiated from other diseases that cause similar clinical symptoms, such as hemolytic anemia, other congenital viral infections, and hematologic malignant diseases. When HCMV infection has hepatitis in infancy as the main clinical manifestation, it should be differentiated from liver injury caused by other pathogens, such as liver injury caused by hepatitis B, C, and D viruses, and congenital biliary tract developmental abnormalities. When HVMV infection has mononucleosis-like syndrome as its main manifestation, it should be differentiated from infectious mononucleosis caused by EBV infection and infectious mononucleosis-like syndrome caused by other viruses such as enterovirus. The basis for differentiation should be based on the onset of the disease, the rapidity of disease progression, other concomitant symptoms, and ancillary tests. Pathogenic tests for HCMV infection can help clarify or exclude the diagnosis of the disease. Treatment
Indications for the application of anti-HCMV drugs
(1), HCMV disease that meets the criteria for clinical diagnosis or definitive diagnosis and is more severe or disabling, including interstitial pneumonia, jaundiced or bilious hepatitis, encephalitis and retinal chorioretinitis (which can involve the macula and cause blindness), especially in immunosuppressed individuals such as children with AIDS.
(2), post-transplant prophylactic medication.
(3), congenital infections with central nervous system damage (including sensorineural deafness), early application can prevent the deterioration of hearing and central nervous system damage.
Commonly used drug application regimen
i. Ganciclovir (GCV): currently the drug of choice for treatment. Induction therapy: 5mg/kg, q12h, for 2~3 weeks; maintenance therapy: 5mg/kg, 1 time/d, for 5~7 days, total course of treatment is about 3~4 weeks. If the disease remits during the induction period or the viremia or viremia is cleared, the maintenance phase can be advanced; if the induction treatment is ineffective for 3 weeks, primary or secondary drug resistance should be considered, or the present disease is due to other etiologies; if the disease progresses during the maintenance phase, another induction treatment can be considered; if the immunosuppressive factors are not eliminated, the maintenance course should be extended by using (1) 5mg/kg once/d, or (2) 6mg/kg 5 days per week, or (3) sequential valganciclovir orally to avoid relapse of the disease.
Blood count and liver and kidney function should be monitored during the drug administration, and the drug should be discontinued if liver function deteriorates significantly, platelets and granulocytes drop ≤ 25×109/L and 0.5×109/L) or to 50% of the pre-drug level. Granulocyte colony-stimulating factor may be given to reduce myelotoxicity in severe granulocytopenia. The dose should be reduced in the presence of renal impairment.
Valganciclovir (VGCV): Valganciclovir is the valine ester of ganciclovir and was approved in 2000 for the treatment of CMV retinitis in patients over 18 years of age with AIDS and as a prophylactic agent in transplant patients.
iii. Phosphonic acid (foscarnet, FOS or PFA): generally used as an alternative in children, especially alone or in combination with ganciclovir when disease progression still occurs with GCV alone. Induction therapy: 60 mg/kg q8h for 2-3 weeks; maintenance therapy for immunosuppressed patients: 90-120 mg/kg once/d. If disease progresses during maintenance, re-induction or combination with ganciclovir is indicated.
Evaluation of antiviral efficacy
i. Clinical assessment: improvement in symptoms, signs and organ function of HCMV disease.
ii. Virological assessment: quantitative analysis of virus-specific antigens and viral titers is useful to assess antiviral efficacy. Monitoring of dynamic changes in serum or plasma or whole blood HCMV-DNA load can be used to determine antiviral efficacy and to further identify resistant strains. Because HCMV-DNA in urine and saliva can persist for long periods of time after the child’s symptoms have resolved, viral DNA testing of these samples is not appropriate for assessing antiviral efficacy.
Disease prognosis
The rate of visits for cytomegalovirus infection decreases with age, suggesting that symptomatic cytomegalovirus infection decreases as immune function gradually improves. Some studies have found that the prognosis is good in the acute jaundiced form, while some children with acute brucellosis are prone to persist and require treatment and longer follow-up to determine prognosis. Therefore, the clinical treatment of HCMV hepatitis in infants is prone to different treatment regimens for different subtypes, and the course of treatment should be individualized. The course of treatment should be determined based on liver function.
Prevention or care
General prevention
Avoidance of exposure is the primary method of prevention. It includes.
(1) Care of HCMV-infected infants by health care providers according to standard precautions, with hand hygiene as the primary measure of prevention.
(2) Use of HCMV antibody-negative blood products or washed red blood cells.
Interruption of mother-to-child transmission
(1) Susceptible pregnant women should avoid contact with the secretions of known detoxifiers; observe standard precautions, with special attention to hand hygiene.
(2) Handling of viral breast milk: Infants already infected with HCMV can continue breastfeeding without treatment; premature and low birth weight infants require handling of viral breast milk. -(2) Treatment of breast milk with virus: Infants already infected with HCMV can continue breastfeeding without treatment.
Drug prophylaxis
(1) Prophylaxis in bone marrow transplant and organ transplant patients: ganciclovir, valganciclovir and valacyclovir (VACV) may be used.
(2) There are recommendations for prophylaxis of HCMV disease in certain high-risk transplant patients with antivirals plus intravenous immunoglobulin or highly effective HCMV immunoglobulin, 100-200 mg/kg, given 1 week prior and every 1-3 weeks after transplantation for 60-120 days.
(3) It has been suggested that GCV or VGCV prophylaxis should be considered for HCMV-infected preterm infants with severe bronchopulmonary dysplasia requiring hormonal therapy.
HCMV vaccine
Although vaccine research for HCMV has been conducted for more than 30 years, no effective vaccine formulation has been put into clinical use, and there is a large gap especially in blocking mother-to-child transmission.