CMV pneumonitis
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Overview
Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunocompromised hosts, and pneumonitis is a common manifestation of CMV infection. When immunocompromised patients present with fever and dyspnea, CMV pneumonitis should be a consideration.
Epidemiology and Demographics
- CMV inclusions were first described in 1881 by Ribbert in the kidney of a stillborn, and the virus was later isolated by Smith, Rowe and Weller in 1956. The term cytomegalovirus was coined by Weller.
- Except in newborns, CMV infection is only characteristically clinically relevant in immunocompromised individuals, particularly AIDS (Acquired Immunodeficiency Syndrome) patients (CD4 <50-100) and transplant patients.
- Approximately 40% of the U.S. have been infected.
- Transmission is through secretions, either via sexual contact, mother-infant transmission, or prolonged close personal contact.
- CMV is a member of the herpes family, and once a patient is infected, the virus persists and can become reactivated under immunocompromising circumstances. Sites of latency include monocytes and PMNs (polymorphonuclear leukocytes).
- CMV is usually asymptomatic in immunocompetent hosts.
- Infected cells characteristically show large intranuclear inclusions with surrounding clearing, smaller cytoplasmic inclusions, and increased cell size.
- CMV causes significant morbidity and mortality in transplant patients, and is the most common infection in lung transplant patients after bacterial pneumonia. CMV negative transplant patients who receive transplants from CMV negative donors usually are unaffected, but CMV positive or negative transplant patients who receive CMV positive or negative kidneys are at significant risk for CMV disease, and prophylaxis is now commonly given with CMV immune globulin or antivirals. Peak onset is 1-4 months post transplant.
- Involvement of most organ systems have been described, but the most common include pneumonitis, colitis, retinitis, hepatitis, pancreatitis, and meningoencephalitis.
- Patients will often present with a mononucleosis-like syndrome with fever/cough, myalgias, fatigue, headache, splenomegaly, and atypical lymphocytosis. Pharyngitis and cervical lymphadenopathy are less common.
Diagnosis
- The detection of CMV in bronchoalveolar lavage (BAL) specimens in BMT (bone marrow transplantation) patients is highly predictive of CMV pneumonitis. In HIV infected patients the presence of CMV in BAL specimens is less predictive of CMV pneumonitis, and definitive diagnosis requires lung tissue specimens.
- CMV may be detected by culture, characteristic viral inclusions, or CMV antigens.
- Infected cells characteristically show large intranuclear inclusions with surrounding clearing, smaller cytoplasmic inclusions, and increased cell size
- Culture is not sensitive, at ~50%. A shell-vial technique is now commonly used and improves the speed (24-48 hours instead of weeks) and sensitivity of the test. It uses a fluorescence tagged monoclonal antibody to detect growth sooner than cytopathic changes develop.
- PCR (polymerase chain reaction) testing is not standardized but may become the best test; it’s sensitivity tends to be higher than other tests.
- Blood and urine should also be tested for viremia, but these are less sensitive than BAL.
- As suggested above, CMV may be seen in patients without evidence of active disease or inflammation, so CMV infection may not always be clinically significant.
- This is a particularly difficult scenario when evidence of CMV is found in BAL specimens performed for PCP. Studies have not shown that these patients overall were clinically any different or recovered any differently when treated for PCP than those patients treated with the same who did not have evidence of CMV.
- Cytopathic changes are probably more specific for significant disease than culture.
- CMV infection may be defined as seroconversion with the presence of IgM antibodies, a four-fold increase in anti-CMV IgG titers, or viral isolation by culture. In contrast CMV disease is defined as clinical evidence of CMV infection, including fever, leukopenia and/or end-organ involvement.
History and Symptoms
- Symptoms may be present for 1-4 weeks before presentation; usually <2 weeks.
- The clinical presentation is variable depending on the severity of the illness, and ranges from a self-limited upper respiratory infection to progressive fatal pneumonia. CMV inclusions may be found at autopsy in up to half of patients who die of HIV, of which half were probably not clinically significant.
- Fever (89-100%)
- Cough (76-94%) – often nonproductive
- Dyspnea (71-94%)
- Patients with CMV pneumonitis are likely to suffer from extrapulmonary CMV.
- Infected individuals are also at risk for coinfection with other pulmonary pathogens, such as PCP.
- Advanced AIDS is major risk factor for disease and mortality.
- CMV pneumonia may be seen following immunosuppression, such as with chemotherapy.
Laboratory Findings
Electrolyte and Biomarker Studies
- LDH elevation in 94% – mean 450 IU/l
- pO2 reduced in most – severity is predictive of mortality
- Microangiopathic hemolytic anemia develops in some patients
Chest X Ray
- Chest x-ray (CXR) – findings present in most patients. Usually bilateral.
- Interstitial changes are most common
- Alveolar consolidation in ~25%
- Ground glass appearance may be present in some
- Nodular opacities in ~10%
- Pleural effusion in ~30%
- Adenopathy in ~10%
- Most patients with normal CXR will have findings on CT scan and gallium scan.
Differential Diagnosis
- Pneumonia due to bacteria
- Fungal infection
- Mycobacteria
- PCP (Pneumocystis carinii)
Risk Stratification and Prognosis
- Prognosis is poor. Particularly in significantly immunocompromised hosts, mortality from significant CMV pneumonitis may be greater than 50%.
Treatment
Pharmacotherapy
- Treatment is most commonly with ganciclovir 5 mg/kg q12h, though results are disappointing. BMT patients characteristically respond, but clinical response is quite variable in AIDS patients, inconsistently showing a significant benefit in different studies.
Transplantation
- Prophylaxis is now being used at some transplant centers. Options include CMV hyperimmune globulin or antiviral treatment such as ganciclovir.
Future or Investigational Therapies
- Trials of ganciclovir with CMV IgG have not shown a consistent benefit in all studies.
- Foscarnet is an alternative agent but data on its efficacy is lacking