What is Cytomegalovirus Pneumonia?
Cytomegalovirus pneumonia due to cytomegalovirus, a member of the Herpesviridae family, often occurs in newborns and children of the first year of life, in patients undergoing bone marrow, kidney, liver, lung and heart transplant surgery, in patients suffering from hemoblastosis, in adults, reduced immunity (HIV infection).
With CMV infection, pneumonia is often only one of the manifestations of a generalized disease.
Causes of Cytomegalovirus Pneumonia
The causative agent of cytomegalovirus infection is the DNA genomic virus of the genus Cytomegalovirus (Cytomegalovirus hominis) of the subfamily Vetherpesvirinae of the family Herpesviridae. There are 3 known strains of the virus: Davis, AD-169 and Kerr. Slow reproduction of the virus in the cell is possible without damaging it. The virus is inactivated by heating and freezing, is well preserved at room temperature. At – 90 ° C, it remains for a long time, is relatively stable at pH 5.0–9.0 and rapidly degrades at pH 3.0.
The reservoir and source of infection is a person with an acute or latent form of the disease. The virus can be in various biological secrets: saliva, nasopharynx, tears, urine, bowel movements, seminal fluid, cervical secretions.
The transmission mechanisms are diverse, the transmission methods are airborne, contact (direct and indirect through household items) and transplacental. Possible infection through sexual contact, during transplantation of internal organs (kidney or heart) and blood transfusion of an infected donor. Intranatal infection of the child is observed much more often than transplacental. The most dangerous for the fetus infection of the mother in the first trimester of pregnancy. In such situations, the highest frequency of intrauterine developmental disorders.
The natural susceptibility of people is high, but latent infection is widespread. Clinical manifestations of infections attributable to opportunistic diseases are possible in conditions of primary or secondary immunodeficiency.
The main epidemiological signs of cytomegalovirus infection. The disease is registered everywhere, antiviral antibodies detected in 50-80% of adults testify to its widespread distribution. The variety of CMV infections and the polymorphism of the clinical picture determine the epidemiological and social significance of CMV infection. This disease plays an important role in transplantology, blood transfusion, perinatal pathology, can be the cause of prematurity, stillbirths, congenital defects of development. In adults, CMV infection is seen as a concomitant disease in various immunodeficiency states. Ongoing environmental pollution, the use of cytostatics and immunosuppressants contribute to an increase in the frequency of CMV infection. In recent years, its exacerbation in HIV-infected people has become especially relevant. In pregnant women with latent CMV infection, fetal damage does not always occur. The probability of intrauterine infection is significantly higher during the initial infection of a woman during pregnancy. No seasonal or occupational morbidity features have been identified.
Pathogenesis during Cytomegalovirus Pneumonia
For various transmission routes, the mucous membranes of the upper respiratory tract, gastrointestinal tract or genitals can be the gates of infection. The virus enters the blood; short-term viremia quickly ends with the localization of the pathogen when introduced into white blood cells and mononuclear phagocytes, where it is replicated. Infected cells increase in size (cytomegaly), acquire a typical morphology with nuclear inclusions, which are accumulations of the virus. The formation of cytomegal cells is accompanied by interstitial lymphohistiocytic infiltration, the development of nodular infiltrates, calcifications and fibrosis in various organs, glandular structures in the brain.
The virus is able to persistently and latently persist in organs rich in lymphoid tissue, being protected from the effects of antibodies and interferon. At the same time, it can suppress cellular immunity by a direct effect on T-lymphocytes. In various immunodeficiency states (in early childhood, during pregnancy, the use of cytostatics and immunosuppressants, HIV infection) and, above all, with cellular immunity disorders, additionally aggravated by direct exposure to the virus, pathogen reactivation and hematogenous generalization with damage to almost all organs and systems are possible . In this case, the epitheliality of the virus is of great importance. It is especially pronounced in relation to the salivary gland epithelium, which, under the influence of the virus, turns into cytomegal cells.
Irreversible lung damage associated with immunopathological reactions precedes the clinical manifestation of the disease. Due to the excessive immunopathological reaction to CMV antigens expressed on infected lung cells, the cells undergo immune destruction by specific cytotoxic lymphocytes, which leads to functional damage to the alveoli, the development of a partial deficiency of alveolar diffusion. Only in the future, with severe inhibition of immunity, does the virus begin to replicate, seeding of the lungs, the development of severe damage to the pulmonary vessels, alveoli, bronchioles. The indirect evidence of an immunopathological process in the lung tissue is the efficacy of CMV immunoglobulin cytotect in combination with ganciclovir in the treatment of interstitial cytomegalovirus pneumonia in bone marrow recipients.
Symptoms of Cytomegalovirus Pneumonia
When analyzing the course of cytomegalovirus infection in various groups of patients, first of all, it is necessary to note a similar clinical picture of the disease. Its gradual development with the presence of precursor symptoms, which are several weeks ahead of expressed organ pathology, is characteristic.
Most adult patients have a prolonged wave-like fever of the wrong type with rises in body temperature above 38.50 ° C, weakness, fatigue, loss of appetite, significant weight loss, less often – sweating at night, arthralgia, myalgia. These symptoms are joined by a gradually intensifying dry or sparse cough.
In young children, the onset of the disease can occur without a pronounced initial toxicosis at normal or subfebrile temperature and manifest only a slight “causeless” cough. A child can persistently cough persistently for a relatively generally satisfactory condition. The existing pathology is often mistaken for banal tracheitis or tracheobronchitis. According to some pediatricians, children of the first months of life who suffer from persistent paroxysmal cough should be examined for exclusion of active CMVI. At this stage of the disease, in both adults and children, pathological changes in the lungs during physical and radiological studies are absent or limited to a slight increase in the pulmonary pattern, a decrease in the transparency of the pulmonary fields in the form of “frosted glass”.
In the future, the condition of patients worsens significantly. Symptoms of intoxication become pronounced, peaks in increasing body temperature reach 39-40 ° C, extremely severe weakness, anorexia, moderate sweating, weight loss are noted.
The main clinical symptom of cytomegalovirus pneumonia, present in almost 100% of patients, is a strong paroxysmal dry or unproductive pertussis-like cough. One of the earliest and most constant signs of the disease is shortness of breath, which is inspiratory or mixed in nature, initially appears only during physical exertion, and then at rest. Shortness of breath is constant, moderate (in contrast to pneumocystic pneumonia), but significantly increasing at a minimum load.
The auscultatory picture in the lungs, despite the severity of the lesion, is characterized, first of all, by the “inexpressiveness” of the signs: vesicular or hard breathing is heard with weakening in the lower parts and diffuse crepitating or moist small-bubbling rales in the middle and lower parts of the lungs. There are laboratory signs of hypoxia with a decrease in the partial pressure of oxygen in arterial blood to 75 mm or less. Hg. Art. Hypoxemia often precedes clinical symptoms and radiological changes. With CMV infection, pneumonia is often only one of the manifestations of a generalized disease. Often, lung damage is accompanied by pathology of other organs in the form of enterocolitis, esophagitis, hepatitis, retinitis, adrenalitis, and polyradiculopathy.
CMV pneumonia is characterized by a long recurrent course with a gradual increase in the severity of the disease. In case of untimely making an etiological diagnosis, the absence of etiotropic therapy, the attachment of a bacterial infection, the development of symptoms of respiratory failure, increasing respiratory distress syndrome with a high probability of a fatal outcome is possible.
Diagnosis of Cytomegalovirus Pneumonia
Changes in laboratory parameters include thrombocytopenia, anemia, leukopenia, lymphocytosis, increased activity of AlAT, AsAt, alkaline phosphatase, and GGT.
X-ray signs of cytomegalovirus lung pathology are variable and nonspecific. During the height of the disease, bilateral polymorphic small focal and infiltrative shadows located mainly in the middle and lower parts of the lungs are determined on the chest radiographs on the background of a deformed enhanced pulmonary pattern. Changes occur in the peripheral parts of the lower lobes and spread towards the roots. The foci can be migratory in nature. The X-ray picture of CMV lung lesion is similar to changes in pneumocystis pneumonia, disseminated pulmonary tuberculosis. At the same time, only mesh reconstruction of the pulmonary pattern (“cellular” lungs), the formation of limited dimming, pleural effusion, disk-shaped atelectasis, cystic changes are possible.
During computed tomography, signs of CMV lesion include changes in the lung tissue of the type of “frosted glass”, its compaction, thickening of the walls of the bronchioles or bronchiectasis, interstitial retina without emphysema, the presence of focal and small-focus changes.
The clinical diagnosis of CMV infection requires mandatory laboratory confirmation. Cytomegalovirus in the human body can be in a latent state, in the stage of active replication without the development of organ lesions and be the cause of severe clinically severe pathology. Therefore, the purpose of laboratory confirmation of manifest CMVI is not to establish the fact of the presence of cytomegalovirus in the patient’s body and not even to identify indirect signs of its activity, but to prove the etiological role of CMV in the development of organ pathology. It is extremely difficult to make a lifetime diagnosis of CMV pneumonia for the following reasons: its clinical picture is not pathognomonic, the virus can be isolated from pulmonary secretion in the absence of clinical manifestations of infection and histological signs of the disease, in immunosuppressive patients, CMV often coexists with other pathogens of infectious pulmonary pathology.
Currently, it can be considered proven that the determination of specific IgM antibodies in the patient’s blood and / or a significant increase in IgG antibody titers, the detection of CMV in saliva, urine, sperm, and vaginal secretion is neither sufficient to establish the fact of active replication of cytomegalovirus, nor to confirm the diagnosis manifest CMV infection. On the contrary, the detection of the virus (its antigens or DNA) in the blood is of great diagnostic value. It was shown that the determination of the viral antigen in blood leukocytes (pp65) indicates an active infection, which in turn indirectly indicates the cytomegalovirus nature of the existing organ lesions. The appearance of pp65 viral protein in the blood precedes the clinical symptoms of CMVI, therefore this marker also has a certain prognostic value. The detection of viral antigens by the rapid culture method in biological materials by analyzing infected culture cells is considered to be a specific and sensitive method, proving the presence of an infectious active virus in a patient.
Today, in the practice of laboratory diagnostics of active CMV infection, more and more attention is paid to methods based on polymerase chain reaction (PCR), which allows direct qualitative and quantitative detection of pathogen DNA in biological fluids and tissues. Recent years have been marked by confirmation of the advantages of the PCR method in laboratory diagnosis of many infectious diseases.
A reliable criterion for the high activity of cytomegalovirus, which proves its etiological role in the development of various clinical syndromes, is the CMV DNA titer of 1: 1000 or more in 105 blood leukocytes.
Determination of CMV DNA in the blood by PCR is also of great prognostic value. A gradual increase in the level of CMV DNA in blood leukocytes and plasma is ahead of the development of clinical symptoms. With each increase in the concentration of CMV DNA in plasma by 1 log10, the risk of developing CMV disease increases by 3 times. The identification of a high concentration of CMV DNA in blood leukocytes or plasma requires the onset of etiotropic therapy.
Unconditional confirmation of the cytomegalovirus nature of the patient’s clinical symptoms and pathological changes in the organs is the detection of histological studies of biopsy or autopsy materials of cytomegalocytes.
Cytomegalovirus Pneumonia Treatment
Medicines, the effectiveness of which in the treatment of patients with manifest CMVI has been proven by numerous studies, are the antiviral drugs ganciclovir, valganciclovir, foscarnet and sidofovir.
When active CMVI is detected in pregnant women or newborns, the drug of choice is a cytotect – a human immunoglobulin with a high content of antibodies to CMV. The use of cytotect as monotherapy in adult patients with clinically expressed CMVI is not shown.
Antiherpetic drugs (acyclovir, valaciclovir, famciclovir) are not very effective against CMV and should not be used for manifest forms of the disease.
CMV is hundreds of times less sensitive to acyclovir and its analogues than herpes simplex viruses. In many works of domestic authors, there are indications of the possible use of drugs of the interferon series (cycloferon, neovir, viferon, etc.) and / or immunocorrectors (Taktivin, thymalin, etc.) for the treatment of CMVI.
The mechanism of the effect of these drugs on the immune system has not been studied in detail. The optimal indications for the time of use of the drugs and the duration of their use in different phases of the infection process have not been determined. In this regard, interferon-type drugs and immunocorrectors should not be used to treat manifest CMV infection.
Ganciclovir is the drug of choice for the treatment and secondary prevention of manifest CMVI, in particular cytomegalovirus pneumonia. The antiviral effect of ganciclovir is due to the suppression of CMV DNA synthesis by competitively inhibiting viral DNA polymerase and impairing the extension of the DNA chain. The drug has dosage forms in the form of bottles for intravenous administration (one bottle contains 500 mg of ganciclovir) and capsules for oral administration (one capsule contains 250 mg of ganciclovir).
Treatment with CMV pneumonia with ganciclovir is carried out according to the scheme of 5 mg / kg intravenously 2 times a day with a 12-hour interval (daily dose of 10 mg / kg) for 21 days. If the patient maintains immunosuppression (reducing the number of CD4-lymphocytes, treatment with CMV pneumonia with ganciclovir is carried out according to the scheme of 5 mg / kg intravenously 2 times a day with a 12-hour interval (daily dose of 10 mg / kg) for 21 days. immunosuppression (reducing the number of CD4-lymphocytes <100 cells / mm3) and, accordingly, the likelihood of reactivation of the virus and the development of a relapse of the disease, maintenance therapy with the drug at a dose of 5 mg / kg / day is administered intravenously or 1000 mg 3 times a day orally. the course is determined individually, but its duration should not be less than one month.Patients with renal insufficiency should be adjusted depending on the creatinine clearance. Foreign works on the treatment of CMV pneumonia in patients undergoing kidney, liver, lung or heart transplantation show high efficacy of ganciclovir According to the generalized data of 15 studies, which included a total of 116 organ recipients with CMV lung disease, a significant improvement in the condition of patients or olnoe their cure after ganciclovir treatment had taken place, on average, 79% of the cases (17 to 100%). A virological response to treatment (disappearance of the virus from the blood) was observed, on average, in 80% of patients (from 33 to 100%). A number of authors recommend combination therapy with ganciclovir and a cytotect (2-4 ml / kg body weight every two days until the clinical symptoms disappear) for the treatment of CMV pneumonia after organ transplantation. If the patient has other infectious complications in addition to CMVI, it is possible to use pentaglobin instead of the cytotect (5 ml / kg daily for 3 days, repeating the course if necessary) or other immunoglobulins for intravenous administration.
As already mentioned, the appearance of CMV DNA in the blood is ahead of the development of clinical symptoms. At present, the strategy of “proactive” etiotropic therapy of patients with active CMVI to prevent the manifestation of the disease is gaining increasing recognition. Given the severe recurrent course of CMV pneumonia in patients with prolonged and severe immunodeficiency, the absence of a stable clinical response to etiotropic therapy in some patients, the possibility of determining laboratory markers that reliably indicate active virus replication is necessary if the patient has deep immunosuppression (with HIV infections – reducing the number of CD4 lymphocytes in the blood <100 cells / mm3) and detecting CMV DNA in the blood, conduct appropriate “proactive” therapy without waiting for clinical development severe forms of the disease.
Cytomegalovirus Pneumonia Prevention
In order to prevent the manifestation of CMVI, ganciclovir (at a dose of 5 mg / kg / day iv or 3 g / day per os), valganciclovir (900 mg / day) are used, in children and pregnant women – a cytotect (1 – 2 ml / kg / day for at least 6 injections with an interval of 1 to 2 weeks). The published results of studies on the prevention of manifest CMVI using ganciclovir or valganciclovir show a significant decrease in the incidence of clinically expressed forms of CMVI, in particular pneumonia, in patients after allogeneic transplantation of bone marrow, lungs, heart, kidney, liver, and also in HIV-infected patients. The first results of our work on the prophylactic use of ganciclovir in HIV patients with a CD4-lymphocyte count of <100 cells / mm3 and the presence of CMV DNA in the blood showed a significant decrease in the incidence of manifest CMV infection in this group of patients over two years of observation. In conclusion, we note that the diagnostic methods developed to date and the antiviral drugs created make it possible to timely detect lung cytomegalovirus infection and its effective treatment.