Pediatric Cytomegalovirus Pneumonia

　　I. Etiology

　　The pathogen is the cytomegalovirus, a DNA virus belonging to the herpesvirus family, which can be carried by healthy children. The main route of transmission in congenital cases is from the infected mother to the fetus through the placenta. Jaundice, purpura, and enlargement of the liver and spleen may appear at birth. Postnatal transmission mainly occurs through the respiratory tract, contaminated urine, and blood transfusion. It is more common in newborns and premature infants, with onset more than 4 months after birth. Both patients and carriers can excrete the virus from urine and saliva. In recent years, due to the widespread use of hormones and immunosuppressants, there has been an increasing trend in cytomegalovirus pneumonia in older children, especially in patients with malignant tumors, organ transplant recipients, and AIDS children after immunosuppressive therapy. In patients receiving bone marrow transplantation, the incidence of CMV infection is very high, with an infection rate of 60% to 70% after transplantation, and 10% to 50% may develop into interstitial pneumonia. Studies have confirmed that 50% of interstitial pneumonia occurring in patients with immunosuppression or immunodeficiency is caused by CMV.

　　II. Pathogenesis

　　The pathological changes caused by pulmonary infection are divided into three types according to the age of onset:

　　1. Pulmonary infection accompanied by systemic lesions mainly involves widespread involvement of various organs throughout the body, while the pathological changes in the lungs are mild, mostly congenital infections. The pleura, larynx, and trachea are all normal, the chest lymph nodes are not swollen, and there are only a few purple-red infarct-like spots, with blood-like fluid on the cut surface. Under the microscope, the changes in the bronchi are mild, without ulcers or necrosis. The blood vessels in the bronchial wall are congested, the alveoli are congested and edematous, the interalveolar septa are slightly thickened, and the foci of alveolitis are filled with phagocytes. Giant cells are found in the bronchial lumen, in the walls of the small bronchi and mucus glands, and around the alveoli.

　　2. Primary CMV pneumonia primarily affects the lung tissue, which is the main or only pathological change. The lung tissue is congested, with an irregular surface, appearing grayish yellow in appearance, with bloody serous exudation when pressed. Microscopically, the bronchial lumen is filled with inflammatory multinucleated cells and mononuclear cell fragments. The bronchial wall thickens and becomes congested, with cellular infiltration in the pulmonary interstitium. The mucous glands around the bronchioles show mononuclear cell infiltration, and the interalveolar septa are significantly thickened, with hyperplasia of histiocytes, and giant cell inclusions are found at the edges of the alveolar septa. Typical CMV infection cells have significant cell swelling, with a large eosinophilic inclusion (or occasionally basophilic inclusion) in the nucleus, separated by an unstained halo from the nuclear membrane. Enlarged and swollen cell nuclei are visible, and inclusions can also be seen in the cytoplasm.

　　2. Fibrinous pneumonia presents with granuloma-like necrotic foci in lung tissue, appearing as small nodular nodules, firm and elastic with clear boundaries, which can also be scattered or fused. Microscopically, the initial lesions are scattered hemorrhagic necrotic foci, alveoli filled with fibrin, red blood cells, mature granulocytes, histiocytes, and cell fragments. These swollen alveoli all contain inclusions, and the alveoli often show hyaline membrane changes. If CMV infection is a systemic disease, in addition to lung lesions, the liver, brain, kidneys, digestive tract, salivary glands, heart, adrenal glands, reproductive glands, and skin can also be affected. The main changes are interstitial inflammation and focal necrosis, with infected cells being large and containing inclusions. Infants and adults may show different symptoms from the disease, not only due to their different sensitivities but also because of previous contact with the pathogen in adults. In infants, inclusions mainly occur in epithelial cells, while in adults, they are found in mesenchymal components. Patients who have received renal transplantation and isolated CMV from the lungs indicate lung infection. Some believe that the presence of high levels of serum antibodies and immune complexes suggests that hypersensitivity may be involved in the pathogenesis, and the suppression of cell-mediated immunity may also be related.

　　The most common clinical manifestation in children:

　　1. Respiratory tract infection:Rhinitis is the most common symptom of adenovirus infection in infants. This age group can occasionally cause acute bronchitis and pneumonia, and some children may develop whooping cough syndrome.

　　2. Pharyngo-conjunctival fever (APC fever):Adenovirus type 3 and 7 are the most common causes, which can lead to small outbreaks in summer, associated with the spread of swimming pool water. The onset is acute, with fever above 38℃, accompanied by pharyngitis, rhinitis, conjunctivitis, and cervical lymphadenitis. Granular protuberances and redness are visible on the bulbar conjunctiva and palpebral conjunctiva, usually unilateral, with the other side being more severe in bilaterals. Symptoms last for 1 to 2 weeks, without sequelae, and generally do not accompany bronchitis and pneumonia.

　　3, Hemorrhagic cystitis (hemorrhagic cystitis):Mostly caused by adenovirus types 11 and 21, more common in boys, without obvious seasonality, with symptoms such as hematuria, frequent urination, urgency, and difficulty in urination, gross hematuria lasting for about 3-7 days, and microscopic hematuria lasting for about 2 weeks.

　　4, Other:Infantile diarrhea, pericarditis, chronic interstitial fibrosis, rash-like diseases, and congenital malformations have been found to be associated with adenovirus infection. There have been reports that adenovirus infection in organ transplant recipients and immunodeficient individuals can cause not only respiratory and urinary tract infections but also central nervous system infections such as encephalitis.

　　Whether congenital or acquired cytomegalic inclusion disease, pneumonia is often masked by other systemic severe symptoms. Neonatal cytomegalovirus pneumonia can manifest as persistent respiratory distress, but it is often accompanied by hepatosplenomegaly, jaundice, purpura, and central nervous system damage. In those who develop the disease a few months after birth, pneumonia can also be associated with liver and spleen enlargement, and sometimes Kaposi's sarcoma pneumonia may also occur. Pulmonary symptoms are often similar to those of other non-bacterial pneumonias, with symptoms such as cough, dyspnea, cyanosis, and tracheal retraction. Auscultation often shows no abnormalities, and the chest X-ray shows extensive coarse streaky patterns and lobular inflammatory infiltrates, presenting as reticular shadows. When children have viremia, symptoms such as hepatomegaly and decreased liver function, which are manifestations of chronic hepatitis, may appear. Mononucleosis caused by cytomegalovirus is difficult to differentiate from infectious mononucleosis caused by EBV.

　　The key to preventing CMV pneumonia is the prevention of CMV infection. Some have tried to use high-titer immune serum as passive immunization for susceptible children who are CMV antibody-negative or have undergone organ transplantation and immunosuppressive drug treatment, to prevent their onset of disease after exposure to CMV, but this did not achieve the expected results. It also has no therapeutic effect on those already infected. Many attempts have been made to prevent CMV infection with vaccines, and it has been confirmed that it is possible to prepare a human CMV vaccine that can induce antibodies in susceptible individuals without severe reactions and排毒 phenomena. Neff et al. reported that a live vaccine made from the ADL68 strain was produced, and a small-scale inspection showed that all antibodies were positive, the clinical reaction was mild, and the virus could not be detected in throat swabs, urine, and white blood cells. Therefore, it is meaningful to vaccinate normal women who are CMV antibody-negative and are about to become pregnant, and those who are about to undergo organ transplantation. Since CMV can cause intrauterine infection, resulting in congenital malformations, it is also a complication after organ transplantation and massive blood transfusions. As the herpesvirus genus has a potential carcinogenic effect, although there is currently no sufficient epidemiological evidence to show a link between CMV and human cancer, it also affects the widespread development of this work. For fetuses suspected of having congenital infection, therapeutic abortion can be used for control. CMV infected individuals, the virus can exist in urine, saliva, cervical secretions, and breast milk, and can be transmitted through contact, so it is recommended that patients be isolated.

　　1, Early antigen (EA) determination method:A few hours after CMV infection, an early antigen appears before the virus DNA replication, the nature of which is not yet clear, but it can be used as an early indicator of CMV infection for detection. Immunochemistry or enzyme-linked immunosorbent assay can detect the level of EA in serum. Some people believe that the appearance of EA not only indicates an early CMV infection but may also indicate the activation of past latent infection.

　　2, Specific IgM determination method:After CMV infection, the specific IgM in the serum increases first. By using sensitive radioimmunoassay or enzyme-linked immunosorbent assay, this specific antibody response can be detected in the early stage, thus making an early rapid diagnosis. Since IgM cannot pass through the placenta, the detection of CMV-specific IgM in newborns can indicate an active infection.

　　3, Counterflow immunoelectrophoresis preliminary screening test:Place the known antigen (CMV) on the cathode plate, and the serum of the child to be tested on the anode plate. The specific IgM in the serum can be measured by using a counterflow immunoelectrophoresis instrument. This method can produce results in a few hours, is simple, but not very sensitive, and can only detect positive serum with complement fixation antibody titer of 1:128 or higher, which can be used as a preliminary screening test.

　　4, Urine sediment cell detection:Take a drop of urine sediment, fix it after staining, and then observe under a common optical microscope. Special-shaped giant cells can be seen, with an enlarged cytoplasm, expanded nucleus, surrounded by a 'halo', resembling an eagle's eye. Inclusions stained with eosin can be seen in the cytoplasm and nucleus. This type of cell is unique to CMV infection. This method should be checked repeatedly with patience to increase the positive rate. The absence of giant cells does not exclude CMV infection.

　　5, Other:Peripheral blood mononuclear cell增多, sometimes with thrombocytopenia, blood biochemistry examination may show jaundice or metabolic acidosis and hypoxemia, etc.

　　6, Ultrasound examination:Commonly accompanied by splenomegaly and hepatomegaly.

　　Therapeutic diet for pediatric cytomegalovirus pneumonia:
　　1) Braised pork with chestnuts (folk recipe) formula: 250 grams of chestnuts, 500 grams of lean pork, a little salt, ginger, and fermented soybean paste. Usage: Peel the chestnuts, cut the pork into pieces, add salt and other seasonings, and then stew with an appropriate amount of water until tender and well-cooked.
　　2) Job's tears lily soup (TCM recipe) formula: 200g of Job's tears, 50g of lily. Method: Put the two ingredients in a pot, add 5 bowls of water, boil to 3 bowls, take three times a day, finish one day.
　　3) Fish grass egg (TCM recipe) formula: a handful of fish grass, several eggs. Method: Boil the eggs and eat them for several days to recover.

　　Acyclovir (acyclovir) is a nucleoside analog that is activated by viral thymidine kinase and cellular kinase into triphosphate form in the body, competitively inhibiting viral DNA polymerase. Acyclovir (acyclovir), cytosine arabinoside, and interferon prevent CMV infection, which can reduce the virus titer and inhibit viral replication to some extent, but it is not ideal. Ganciclovir (GCV, GCV, propyloxyguanosine) is a derivative of acyclovir (acyclovir), an open-chain analog of deoxyribose nucleoside. It has been confirmed in vitro that its antiviral activity against CMV is 10 times that of acyclovir (acyclovir) and is effective for CMV interstitial pneumonia. GCV is the first-line drug for severe CMV infection in children. There are few large-sample reports on pediatric intravenous medication, and most refer to the treatment plan for adults:

　　1. Induction therapy:Generally, 5mg/kg is used, once every 12 hours (with a constant infusion speed for more than 1 hour), for 2-3 weeks.

　　2. Maintenance treatment:Dose: 5mg/kg, once a day, for 5-7 consecutive days. If the disease progresses during maintenance treatment, consider re-inducing treatment. Patients with renal damage should reduce the dose, and the main side effects are granulocytopenia and thrombocytopenia. During the medication period, blood routine should be monitored, and if platelets and granulocytes decrease to ≤25×109/L and 0.5×109/L, or decrease to 50% of the pre-medication level, the medication should be discontinued.

　　3. Immunotherapy:CMV-Immunoglobulin is currently a commonly used immunoglobulin for the treatment of CMV interstitial pneumonia. It is currently recommended to use combined medication to treat CMV interstitial pneumonia, and the combination of Ganciclovir with high-dose intravenous immunoglobulin has a good effect.