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Dr. Masur is Chief, Critical Care Medicine, and Dr. Shelhamer is Deputy Chief, Critical Care Medicine, National Institutes of Health, Clinical Center.
Correspondence to: Henry Masur, MD, National Institutes of Health, Clinical Center, Critical Care Medicine Department, 10 Center Dr, Room 7D43, Bethesda, MD 20892-1662; e-mail: hmasur{at}cc.nih.gov
When Pneumocystis carinii pneumonia (PCP) appeared in previously healthy patients in the late 1970s, clinicians quickly recognized that a new form of immunosuppression had occurred, and, thus, PCP was the most prominent feature in the initial reports of the syndrome now designated as AIDS. Clinicians promptly recognized that the PCP they were seeing in patients with AIDS differed in important ways from the PCP that was seen in other patient populations. In fact, most opportunistic pathogens such as Candida, cytomegalovirus, and herpes simplex caused somewhat different manifestations in AIDS patients compared to patients who had cancer or had undergone organ transplantation.
In the early 1980s, Kovacs et al1 compared the clinical features of 49 cases of AIDS-associated PCP with 39 episodes of PCP occurring in patients with other immunosuppressive disorders. They described AIDS-related PCP as a more indolent disease process. The median time to diagnosis was longer for AIDS-related PCP (28 days) than for PCP related to other disorders (5 days), yet despite this longer symptomatic period, AIDS-related PCP patients presented with a higher median room air PaO2 (69 mm Hg) than the non-AIDS patients (52 mm Hg). Despite these differences, the survival rate of patients with PCP was similarly dismal in both groups (about 50%).
In this issue of CHEST (see page 704), Mansharamani and colleagues assess the management and outcome patterns for adults with AIDS-related and non-AIDS-related PCP during the period 1985 to 1995, the decade following the report by Kovacs et al.1 They reviewed 605 confirmed cases of HIV-associated PCP and 33 cases of non-HIV-associated PCP. They emphasize two interesting observations about management. First, over the period of their study, a declining fraction of patients with HIV-related PCP required hospitalization, while, in contrast, non-HIV-infected patients with PCP almost always required hospitalization. Second, the mortality rate for patients with HIV-related PCP fell during the study period from 11.7 to 6.6%, while the mortality rate for non-HIV-infected PCP patients was much higher (39%; there were too few patients in this group to assess a chronologic trend). Mansharamani et al conclude that, despite major advances in the tools for managing PCP, not nearly as much progress has been made in improving the prognosis of PCP in non-HIV-infected patients compared to those with HIV infection.
Is HIV-related PCP truly a less severe disease than PCP that is associated with cancer, organ transplantation, or high-dose corticosteroid use? Data from many sources support the concept that, while HIV-related PCP can progress rapidly and can be severe and lethal, it is, in fact, much more often a slowly progressive disease than the PCP that occurs in other immunosuppressed patients. A recent review of the experience at a Swiss hospital from 1983 to 1998 supports this concept.3 Thus, the biology of the host-pathogen interaction seems to differ between HIV-infected patients and other immunosuppressed individuals, and there is more opportunity to intervene before hypoxemia becomes severe.
Do patients with HIV-related PCP truly fare better than patients with PCP and other immunosuppressive illnesses, as Mansharamani et al report? The number of non-HIV-infected patients in the study by Mansharamani et al is small (n = 33 over 10 years), so it is possible that real improvements were not recognized. The recent study from Switzerland2 found that the PCP-related mortality rate in the two groups was actually similar (HIV-infected group, 11%; non-HIV-infected group, 19%). In the Swiss study, however, the authors document that, while the number of non-HIV-infected patients was also small (n = 32), during the period of their study the non-HIV-infected patients with PCP had, in fact, benefited from advances since their mean length of hospital stay declined during the study period along with their mortality rate.
There are several additional reasons, as Mansharamani et al comment, why HIV-infected patients might have better outcomes when they develop PCP: (1) their period of susceptibility can be predicted by an objective laboratory test, the CD4 T-lymphocyte count; (2) PCP is by far the most likely cause of diffuse pulmonary disease in those with CD4 T-lymphocyte counts < 200/µL, while in patients with other immunosuppressive disorders the differential diagnosis is much broader, making a focused diagnostic approach and an appropriate empiric therapeutic regimen much more difficult to construct; (3) many HIV-infected patients are well-educated about the initial manifestations of PCP and the need for prompt medical interventions; and (4) many HIV-infected patients are free of other confounding systemic insults from underlying disease, cytotoxic drug treatment, and concurrent infections. Thus, recognizing the onset of PCP, establishing the specific diagnosis, and completing a course of therapy are often much more straightforward in patients with HIV than in patients who have cancer or have undergone organ transplantation.
Over the past 20 years, much has been learned about the diagnosis and treatment of PCP. It is possible to identify patients at high risk for HIV-related PCP based on peripheral blood CD4 T-lymphocyte counts, and the period of risk for other patients is recognizable in relation to the immunosuppressive therapies. Effective regimens for prophylaxis have been developed. Sensitive and specific methods for diagnosis have allowed for earlier diagnosis in many cases. Adjuvant corticosteroid therapy has decreased the number of patients with HIV-related PCP who develop respiratory failure. Finally, the armamentarium of therapeutic agents has increased to include atovaquone, clindamycin-primaquine, and trimetrexate.
There is, however, much work yet to be done, especially in patients who have cancer and have undergone organ transplantation. First, cancer and organ transplant patients would benefit from the development of an objective test of their susceptibility to PCP; unfortunately, in these populations the circulating CD4 T-lymphocyte count is not nearly as sensitive a marker as it is for patients with HIV infection. Second, less invasive diagnostic tests would facilitate early diagnosis: the use of oral washes tested with sensitive and specific nucleic acid amplification techniques hold considerable promise.3 Third, as sulfonamide-resistant PCP appears to be a clinically important occurrence,4 tests for clinical laboratories to identify resistant organisms and new drugs with novel mechanisms of action need to be developed. There is woefully little activity in the area of drug development, although echinocandins5 and primaquine analogs hold some promise.6
The dual message of Mansharamani et al is both that progress has been made and that there is much yet to be done. Clearly, with this problem, as with so many others, there are "miles to go" before the morbidity and mortality produced by PCP are effectively eliminated.
References
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