Cytomegalovirus: The Monster in the Closet?

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Young children often go through a phase when, late at night, they are terrified by the "monster in the closet." The hapless parent has to enter the room, turn on the lights, and show there is nothing in the closet to prove there is no reason to be afraid. One of my nighttime fears is cytomegalovirus (CMV) in the lungs of patients with AIDS. This fear usually occurs while I'm sitting in the intensive care unit, watching an AIDS patient dying of respiratory failure. We have done all we can, including bronchoscopy and lavage. Despite treatment for Pneumocystis carinii and other infections that have been identified, the patient is still failing. The student asks, "Shouldn't we treat the CMV grown from the BAL?" I try to shed some light on the situation by discussing the studies performed by ourselves and others. In those studies, a high incidence of CMV in the BAL specimens of AIDS patients was found, but CMV pneumonia in these AIDS patients was rare (1, 2). When the patient dies and the autopsy demonstrates severe CMV pneumonia, the pathologist asks the same question, "Shouldn't you treat CMV grown from the BAL?" The answer to that question lies in another question, "What is the predictive value of CMV in the BAL for significant CMV pneumonitis?"

Exposure to cytomegalovirus is common. Most people become infected with it by the time they are 40. The primary infection in the healthy host is unremarkable, occasionally associated with a mononucleosis-like illness (3). When the host becomes immunosuppressed, the virus causes all sorts of problems, which depend on the cause of the immunosuppression and the route by which the host becomes infected.

Solid organ transplant patients manifest symptoms of CMV infection about 6 wk after transplant. Viremia and acute organ disease such as pneumonitis and gastritis are seen at this stage. The prognosis for the transplant patient who is reactivating latent virus will be better than for the unfortunate patient who becomes infected from a donor organ with CMV. The bone marrow transplant recipient is at highest risk from CMV infection. The mortality of untreated CMV pneumonitis in that group is more than 80% (4, 5).

In the transplant population, bronchoalveolar lavage (BAL) has proved a successful method for diagnosing CMV pneumonia (3). Various techniques have been employed, including routine viral culture, cytopathologic examination, and stains for CMV antigen, including shell vial techniques, which enhance the early detection of CMV antigen. These methods have proved useful in detecting low levels of infection in patients and appear to assist in identifying patients for early treatment. Even asymptomatic bone marrow transplant patients may have CMV recovered from the BAL fluid. These patients with CMV shedding are at risk for the subsequent development of pneumonitis (6). Thus, CMV in the BAL of the transplant patient is a serious problem, usually requiring therapy.

In HIV-infected patients, BAL also has been useful for detecting CMV. However, the significance of CMV identified in the bronchoscopy sample is unclear. Over half of BAL samples from HIV patients with pulmonary symptoms will contain CMV, but these patients do not have a more severe clinical presentation, hypoxemia, or 3-wk mortality than do those patients with other forms of pneumonia (1, 2). In the May 1997 issue there appeared a detailed report of BAL culture results of select patients studied at the National Institutes of Health (NIH) (7). In this study, the authors have analyzed three groups of patients: the asymptomatic HIV-infected patient, patients with CMV retinitis but no pulmonary symptoms, and patients with pulmonary symptoms undergoing diagnostic bronchoscopy. They detected CMV in over half of the BAL specimens from patients without pulmonary symptoms. However, they did not find any evidence of CMV pneumonitis either clinically or pathologically. Of the patients undergoing diagnostic bronchoscopy for pulmonary symptoms, 72% had CMV, with only two patients having any pathologic evidence of CMV pneumonitis and one patient with clinical symptoms consistent with pneumonitis. One of the two patients with cytopathic changes for CMV died within 3 mo of the procedure. An autopsy confirmed that the cause of death was CMV pneumonitis.

The importance of cytopathic changes in the lung tissue was previously reported for 36 AIDS patients with cytopathologic evidence of CMV pneumonitis who were compared to 38 AIDS patients with positive CMV culture only and 40 patients with no evidence of CMV (8). There were no differences among the three groups in terms of initial presentation or 3-wk mortality rate. However, over the next 6 mo, those with CMV-positive cytology had a significantly higher mortality rate than the CMV-negative group. Unfortunately, this increased risk of mortality was not restricted to patients with cytopathic changes. A similar increase in mortality rate for the CMV culture-positive, cytology-negative patients was also found. In the current study by Mann and colleagues (7), the authors report an overall low 3-mo mortality rate for their patients, including those patients in whom CMV was grown from the BAL fluid. By studying a group with an overall low mortality rate, the relatively small sample size studied by Mann and colleagues may not have detected an increased mortality rate due to CMV infection. Also, CMV may not affect mortality in patients with mild to moderate pneumonia. For the 46 patients with pulmonary symptoms and CMV isolated, only one died during 3-mo follow-up. This is strikingly better than the > 25% mortality rate found by others treating AIDS patients with pneumonia (8). Other major infections seen in these patients include P. carinii and deep fungal infections. Although coinfection with both P. carinii and CMV would seem to make the patient sicker, this was not the case when mortality from pneumonia in HIV-infected patients was studied (8, 10).

CMV is a marker of immunosuppression. Several groups have shown that the lower the CD4 count, the higher the prevalence of CMV (11). In other studies, the patients with CMV histopathologic changes had the lowest CD4 count (7, 8). Another pulmonary marker for immunosuppression has been Mycobacterium avium complex (MAC), which has been recovered from the lung only in patients with very low CD4 peripheral blood counts (11). In AIDS, MAC rarely causes significant pulmonary disease (12).

However, CMV is not just a passive traveler in the lung. CMV pneumonia has been found to be a major cause of death in AIDS patients. In an autopsy study performed at the NIH, CMV was identified in pulmonary tissue from 44 of 75 patients dying from AIDS, and in 21 cases CMV pneumonitis was considered a significant cause of death (12). In another study analyzing AIDS-related deaths, CMV pneumonitis was found in 44% of cases, and 4 of 25 patients studied had "florid" CMV pneumonitis with little antemortem suspicion for this infection (13). Given the finding that patients who die from AIDS often die with CMV pneumonia, clinicians often struggle to identify who should be treated for CMV pneumonitis. One approach is to reserve treatment for those patients with pathologic evidence of CMV infection in the lung. This can be either CMV inclusion bodies seen in parenchymal tissue or cytopathologic examination of lung cells. A more aggressive choice would be to treat the patient as soon as any evidence of CMV infection in the lung is identified, such as a positive BAL culture. Obviously, this approach would result in a large number of patients being treated unnecessarily. In the usual approach, all other identified infections are treated, and if the patient continues to worsen, CMV is treated.

Unfortunately, clearing the lung of the CMV infection is difficult. Mann and colleagues (7) report six patients on foscarnet for CMV retinitis at the time of bronchoscopy who still had positive BAL cultures. In bone marrow transplant patients, the treatment of CMV pneumonia with ganciclovir alone was associated with a < 20% survival rate (4, 5). The addition of immunoglobulin (4) or cytomegalovirus-specific immunoglobulin (5) did improve the survival rate to > 50%. A trial of anti-CMV therapy to treat CMV pneumonitis may require both antiviral therapy plus immunoglobulin. This is an expensive regimen and should be reserved for patients in whom a high suspicion for CMV pneumonitis is present.

The host's response to infection defines the symptoms. With CMV, the inflammatory response mounted by patients may be just as important as the infection itself. In an analysis of nine cases of CMV pneumonitis at one institution, the most severe cases had the highest CD4 peripheral blood counts (14). The clinical significance of this host-infection interaction has been noted in other AIDS-related infections, for example, P. carinii pneumonia.

How can we identify who should be treated for CMV pneumonia? On the basis of studies by Mann and others (1, 2, 7), it does appear that asymptomatic patients with CMV in their BAL do not require therapy. If we treat for CMV, most of the patients will be treated unnecessarily, and there is no evidence that treatment of CMV pneumonitis at this stage of HIV will be successful. In the patient who has respiratory disease, one should look for something other than CMV to treat because the CMV is seldom the cause of disease, and there is no way to definitely determine when CMV is the cause of respiratory disease. New techniques, such as quantitative polymerase chain reaction, may provide a better estimate of viral burden and have been proposed to determine who has pneumonitis (15). Perhaps cofactors such as peripheral blood CD4 count, coexisting pulmonary infections, and the lung's inflammatory response may be important. However, one question that remains is what to do about the patient with worsening respiratory distress after treatment of other infections who has CMV in their BAL sample. Should one treat it or not treat it? In resolving this "monster in the closet," the light of research will have to be directed toward both specific diagnosis and effective therapy.

Pulmonary and Critical Care Medicine University of Cincinnati Medical Center Cincinnati, Ohio

	Footnotes

   This editorial should have accompanied the article "Lack of clinical utility of bronchoalveolar lavage cultures for cytomegalovirus in HIV infection" by M. Mann, J. H. Shelhamer, H. Masur, et al., which appeared in the May 1997 issue (Am. J. Respir. Crit. Care Med. 155:1723-1728). Due to unavoidable circumstances, the editorial appears in the current issue, rather than in the May issue.

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