In this single-center study of 524 HIV-infected patients with laboratory-diagnosed PCP during the CART era, we found an overall mortality of 10.3% and identified five independent and objective predictors of mortality that are readily available at illness presentation. Using these predictors, we then developed two prediction rules that stratify patients by mortality risk upon presentation to medical care.
The overall mortality of 10.3% in our study cohort is within the range of mortality rates, 7 to 13%, reported in large cohorts (> 500 subjects) of HIV-infected patients with PCP from the pre- and early CART eras,[9
] suggesting that mortality from PCP has not changed in the current era. Other studies, however, have documented a trend toward decreased PCP mortality in the CART era even in patients who were not receiving CART,[18
] a finding that has been attributed to improvements in ICU care.[26
] While the number of PCP cases per year has declined at our institution, those persons still presenting with PCP are rarely receiving antiretroviral therapy or PCP prophylaxis and still have an appreciable, and possibly unchanged, mortality.
We identified five significant and objective predictors of mortality that are readily available at illness presentation. Except for the A-a O2
gradient, none of the significant predictors of mortality identified in multivariate analysis were strictly associated with the severity of underlying HIV disease or respiratory compromise from PCP. Instead, our results suggest that non-HIV associated factors that reflect the presence of underlying medical comorbidities and general severity of illness, namely age, injection drug use, serum total bilirubin, and serum albumin, may be more accurate predictors of mortality from PCP than HIV-associated factors, such as CD4 cell count or history of opportunistic infection. Age is a predictor that is widely used in risk-stratification rules for community-acquired pneumonia, and correlates with the number of medical comorbidities in HIV-infected patients.[29
] In addition, many studies have reported age and serum albumin as predictors of mortality for not only PCP but also HIV-infected patients requiring intensive care.[12
] To our knowledge, the associations between recent injection drug use and serum total bilirubin with increased PCP mortality have not been reported. Recent injection drug use increases the presence of concurrent medical co-morbidities and reflects the absence of appropriate, preventive medical care. Prior studies have either had a low prevalence of injection drug users or evaluated the association between any history of injection drug use and PCP mortality, which would include persons who had quit years previously.[18
] The serum bilirubin has been used in validated scoring systems (e.g., Simplified Acute Physiology Score II, Pneumonia Severity Index) to assess severity of illness and predict mortality in patients with critical illness and pneumonia.[30
] As a reflection of end-organ dysfunction, bilirubin may also be a marker of sepsis or septic shock, and has recently been reported to predict development of acute respiratory distress syndrome and mortality in patients with sepsis.[33
Both mortality prediction rules we present have distinct advantages. The three predictor rule is easier to use and requires less clinical data, but classified fewer patients into groups with extremely high or low mortality compared to the five predictor rule. Although the sensitivities and specificities of the two prediction rules were comparable, model testing using QIC scores showed that the five predictor rule had a better fit. Two prior studies from the pre- and early CART eras have described strategies to predict mortality from PCP. One prediction model incorporated the A-a O2
gradient, total lymphocyte count, and body mass index,[9
] while the other used HIV wasting, A-a O2
gradient, and serum albumin.[20
] However, both studies included patients who had presumptive PCP without microbiologic confirmation. In addition, HIV wasting is subject to variability in provider categorization and varying clinical manifestations, as noted by the study’s authors.[20
] By contrast, our mortality prediction rules are based on objective clinical and laboratory characteristics which are widely available and easily assessed in most HIV-infected patients presenting with PCP in high income countries. Because our goal was to provide a simple, clinically useful prediction rule to identify patients at presentation with the highest and lowest risk for mortality, the algorithm has limited ability to further stratify patients with an intermediate mortality risk (Group 2, and ). At institutions where the risk of loss to follow-up is low, it is possible that persons who are predicted to have a low risk for mortality may not require admission for diagnosis and treatment. Similarly, persons who are predicted to have a high risk for mortality may warrant closer observation, such as on a “step-down” unit or in the ICU. Further research is needed to validate the predictive accuracy of our algorithm in patient cohorts from other institutions.
In addition to the limitations discussed above, our study’s main drawback is that it reflects the experience and patient population at a single public hospital in the United States and may not be more broadly applicable to all HIV-infected patients with PCP. Earlier studies have documented variations in patient demographics and processes of care among HIV-infected patients with PCP based on hospital type (i.e. Veterans Affairs, public, or private),[35
] and the high prevalence of injection drug use and sensitivity of sputum induction for PCP diagnosis in our study may make our findings less generalizable to other institutions. Our center’s reliance on sputum induction rather than bronchoscopy for PCP diagnosis may explain why we did not identify pulmonary KS as a predictor of mortality, in contrast to findings reported by Walzer and colleagues at a center that predominantly performs bronchoscopy for PCP diagnosis.[18
] We hope that our prediction rules will be validated using large cohorts of HIV-infected patients with PCP at other institutions, as have been recently described.[17
] Nevertheless, while sociodemographic characteristics, severity of illness, and clinical practices may differ across patient cohorts and institutions, we believe that there is a biologic basis and clinical rationale for the variables we identified to stratify patients by mortality. These are predictors which reflect presence of medical comorbidity, severity of pulmonary disease, and overall health status, and should be broadly applicable to most HIV-infected patients with PCP.
In conclusion, we found that mortality from HIV-associated PCP in the CART era remains unchanged from studies performed earlier in the HIV/AIDS epidemic. Using clinical and laboratory data routinely obtained at the time of presentation, we developed two mortality prediction rules that stratify patients by risk for in-hospital mortality. While our prediction rules require further validation in cohorts from different institutions, they are potentially a practical method of identifying patients who are at high and low risk for death early in the hospital course, and therefore may assist clinicians in assessing severity of illness and more accurately deciding on management strategies.