This is, to our knowledge, the largest single-center study to date that has examined PCP-associated mortality risk factors; it describes patients presenting over a 21-year period and includes detailed data on several clinical risk factors. Mortality from HIV-associated PCP at this center over the 21-year study period was 13.5%. Analysis of mortality risk factors specifically excluded events occurring subsequent to patient hospitalization, including treatment failure, need for ICU admission, need for mechanical ventilation, and development of pneumothorax. These latter events may be regarded as being “on the road to death” and, as such, might bias interpretation of mortality risk factors. The difference in mortality rate in July 1996 and after (in the era of HAART), compared with before July 1996, was small and was not statistically significant; no patient in this study received HAART before presenting with PCP or during treatment of this infection.
The epidemiology of patients with PCP at our center evolved during the study period. In later years, heterosexual sex was the major HIV risk factor, and an increasing number of patients were female. After June 1996, patients were more likely to be unaware of their HIV infection status, were less likely to be receiving PCP prophylaxis before presenting with PCP, and had lower CD4+
cell counts, compared with patients presenting in or before June 1996. These observations reflect the overall evolving epidemiology of HIV infection in the United Kingdom [28
This study found some evidence that survival among patients with PCP improved in the post-HAART era. These data contrast with previous reports from the early HAART era that suggest more clearly an improved survival among patients with PCP [29
]. One multicenter study described the outcomes of 1660 episodes of PCP in 78 hospitals (overall mortality, 11.3%). In patients who had received HAART, mortality was 9.9%; in those who had not received HAART, mortality was 12.0% [29
]. By contrast, another multicenter study conducted during the same study period described 1231 episodes of PCP from 34 hospitals. Mortality rates of 8.2%–13.5% were identified [30
]; improved survival, when compared with survival a decade earlier, was ascribed to general improvements in medical care, rather than to a direct effect of HAART.
Improved survival has been described in the era of HAART among the subgroup of patients with severe PCP admitted to the ICU [22
]. Whether improved outcome is attributable to the direct effects of HAART [32
] or to general improvements in ICU care (in particular, protective ventilator strategies) remains unclear [22
]. In the present study, no patient received HAART before or during hospitalization with PCP. This observation might in part account for the lack of apparent improvement in mortality in the era after June 1996, when HAART became available.
The present study identified that mortality from second- or third-episode PCP was greater than that from first-episode PCP. This finding confirms results from the Adult and Adolescent Spectrum of HIV Disease Project, which identified recurrent PCP as a risk factor for mortality from PCP [8
], and results from a study by Mansharamani et al. [33
], which showed higher mortality associated with second- or third-episode PCP (17% and 21%, respectively) than with first-episode PCP (11%). Details of patient disease severity are not provided in either study, limiting comparison with the present study. By contrast, a study from the pre-HAART era by Dohn et al. [34
] showed that patients with second- or third-episode PCP had milder disease, as indicated by PaO2
at admission to the hospital, and better outcome than patients with first-episode PCP. In the present study, patients with subsequent-episode PCP had milder disease (as indicated by PaO2
at admission to the hospital) but worse outcome. There are 2 possible explanations for this discrepant observation. First, persistent abnormalities of lung function following PCP [35
], together with the demonstration of post-PCP fibrosis on CT [36
], suggest reduced pulmonary compliance and increased susceptibility to pneumothorax. In the present study, almost twice as many patients with second - or third-episode PCP had a pneumothorax (14.1%), compared with patients with first-episode PCP (7.1%). Second, there might be greater impairment of immune function among persons with recurrent PCP than among those with first-episode PCP. This explanation is supported by findings from this study, because patients with recurrent PCP had lower CD4+
cell counts and lower systemic inflammatory responses (as measured by peripheral blood neutrophil counts). This hypothesis is supported by demonstration of impaired antibody responses in HIV-infected patients recovering from recurrent PCP, compared with responses in those recovering from first-episode PCP [37
In the present study, pulmonary KS was an independent risk factor for mortality. An explanation for this observation is not immediately apparent. Reports of reduced gas transfer factor and coefficient in HIV-infected patients with pulmonary KS and without intercurrent opportunistic infection suggest that pulmonary KS may contribute to impaired gas exchange during PCP [23
]. Medical comorbidity, when present, adversely impacted outcome from PCP. Likely explanations are multifactorial and include an additional inflammatory burden from intercurrent infective processes, underlying chronic respiratory compromise, and intercurrent cardiovascular disease.
Although season was not a significant risk factor for mortality, the present study reports possible seasonal changes in PCP-associated mortality. Additional details regarding overall hospital admissions and deaths and changes in staffing and in policies and procedures over the study period are needed to make further inferences. However, reports of seasonal variation in concentration of Ascomycetous
species and other fungi in air [26
] suggest that patients might have been exposed to a greater burden of Pneumocystis
species in the autumn or been exposed to a more virulent genotype [26
]. Recent reports describing an association between Pneumocystis
species colonization and worsening of chronic lung disease [39
] raise the possibility that medical problems caused by Pneumocystis
species extend beyond HIV-infected patients and emphasize the need for further studies examining environmental aspects of this infection.
This study has several limitations. First, it was retrospective and included only patients with laboratory-proven PCP, precluding analysis of patients with presumptive PCP, who may have had different clinical manifestations or severity of the disease [41
]. Second, it only examined mortality risk factors present at or soon after hospital admission. Other factors that are regarded as being on the “road to death” were excluded from analysis. Lack of patient demographic and clinical data, including race and/or ethnicity, smoking history, and laboratory test results (e.g., serum albumin and lactate dehydrogenase levels) further limits comparison with other studies.
In summary, at this center, overall mortality from PCP over the 21-year period of the study was 13.5%. The difference between the mortality rate in the era of HAART (after June 1996) and the mortality rate in or before June 1996 was small and was not statistically significant. Factors identified early in the course of patient hospitalization were associated with risk of death. The continuing presentation of patients with PCP and their attendant mortality rate underscores the need for earlier diagnosis of HIV infection to identify patients before they develop PCP.