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(Chest. 2001;119:844-851.)
© 2001 American College of Chest Physicians

Prognostic Markers of Short-term Mortality in AIDS-Associated Pneumocystis carinii Pneumonia*

Thomas L. Benfield, MD; Jannik Helweg-Larsen, MD; Didi Bang, MD; Jette Junge, MD and Jens D. Lundgren, MD, DMsc

* From the Departments of Infectious Diseases (Drs. Benfield, Helweg-Larsen, Bang, and Lundgren) and Pathology (Dr. Junge), University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark.

Correspondence to: Thomas L. Benfield, MD, Department of Infectious Diseases 144, University of Copenhagen, Hvidovre Hospital, DK-2650 Hvidovre, Denmark; e-mail: tbenfield{at}inet.uni2.dk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Since 1990, corticosteroids have been recommended as adjunctive therapy for patients with AIDS-associated Pneumocystis carinii pneumonia (PCP) and respiratory failure. We hypothesized that the natural course of AIDS-associated PCP has changed in the era of adjunctive corticosteroid therapy.

Objective: To study variables obtained on hospital admission for possible prognostic value of short-term (3-month) outcome of PCP.

Design and patients: Prospective observational study of 176 consecutive HIV-1–infected individuals with PCP between 1990 and 1999.

Method: Cox proportional-hazards regression models.

Results: Univariate analysis showed that age, one or more prior episodes of PCP, use of antimicrobial therapy other than trimethoprim-sulfamethoxazole (TMP-SMZ), use of PCP prophylaxis at diagnosis, and culture of cytomegalovirus (CMV) in BAL predicted progression to death within 3 months. After adjustment, age (relative risk [RR], 4.1; 95% confidence interval [CI], 1.8 to 9.3), initial antimicrobial therapy other than TMP-SMZ (RR, 3.1; 95% CI, 1.2 to 8.5), use of PCP prophylaxis (RR, 5.6; 95% CI, 2.2 to 14.4), and culture of CMV in BAL fluid (RR, 2.7; 95% CI, 1.3 to 5.6) remained independent predictors of a poor outcome. In contrast, neither PO2 nor serum lactate dehydrogenase, which in earlier studies were identified as prognostic markers, were predictors of mortality.

Conclusion: Age, initial anti-PCP therapy, use of PCP prophylaxis, and BAL CMV status may be useful predictors of outcome of PCP in patients treated in the era of adjunctive corticosteroid therapy.

Key Words: Pneumocystis carinii pneumonia • prognosis • survival


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In the first decades of the AIDS epidemic, Pneumocystis carinii pneumonia (PCP) has been the most common serious opportunistic infection among individuals infected with the HIV type 1. Milestones in the prevention and treatment of AIDS-associated PCP have included the recommendation of prophylaxis to individuals at risk,1 the use of adjunctive corticosteroid therapy,2 and the introduction of highly active antiretroviral treatment.3 4 However, PCP continues to be the most frequent index diagnosis of AIDS.5 6

Mortality from PCP has decreased considerably over the past 15 years,7 8 9 10 but short-term mortality remains high, at 15 to 20%.10 11 Several studies have identified factors that reflect disease severity and have prognostic value, including decreased alveolar oxygenation,7 9 11 12 13 14 decreased serum albumin levels,9 12 15 increased serum lactate dehydrogenase (LDH) levels,9 12 16 17 and BAL fluid neutrophilia.11 18 19 20 The majority of these studies were performed before the routine use of corticosteroids in 1990. Adjunctive corticosteroids rapidly improve oxygenation21 and reduce acute mortality by up to 40%.22 23 24 It is likely that the impact of corticosteroids on the pathophysiology may also have changed the natural course of AIDS-associated PCP. Therefore, we assessed the prognostic significance of routinely measured baseline variables in multivariate analyses in a cohort of consecutive patients diagnosed with and treated for PCP after May 1990, ie, from the time that corticosteroids were used routinely in our department.24


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Between June 1, 1990, and January 31, 1999, all episodes of HIV-1–related PCP diagnosed at the Department of Infectious Diseases at Hvidovre Hospital, Copenhagen, were included in the study. Clinical and laboratory data were collected prospectively. Outcome was recorded from the medical files.

A diagnosis of PCP was established by bronchoscopy with BAL as previously described.25 BAL fluid was divided into aliquots for microbiological and cytologic examination, including a Gram’s stain and cultures for bacteria, mycobacteria, and fungi. Cytomegalovirus (CMV) culture was performed at Statens Serum Institute, Copenhagen, using standard techniques; samples were inoculated in shell vial cultures of human fetal lung fibroblasts, and growth was examined at day 1 and day 7 using direct immunofluorescent staining.

P carinii infection was diagnosed if a honeycombed, foamy material (ie, trophozoites) or cysts could be demonstrated by May-Grünwald-Giemsa or Grocott methenamine-silver stain and confirmed by immunoperoxidase staining (DAKO-Pneumocystis M 778; DAKO; Glostrup, Denmark).

A differential count of the inflammatory cells was performed in a representative area of the May-Grünwald-Giemsa-stained slide containing a monolayer of cells. Cell counts were performed in a hemocytometer (since May 1993).

Variables and Treatment Policy
In all patients, the following variables were recorded: age, sex, HIV-1 status, transmission category, AIDS index diagnosis, prior AIDS diagnosis, previous episodes of PCP, and therapy. Laboratory variables included arterial blood gas levels on hospital admission, CD4 cell count, and serum LDH.

For treatment, IV or oral trimethoprim-sulfamethoxazole (TMP-SMZ) is the drug of choice at our institution, with IV pentamidine as the second choice. Some patients were treated with clindamycin/primaquine or trimetrexate. Since May 1990, all patients with an arterial PO2 < 67.5 mm Hg have received adjunctive corticosteroids. All patients at our department are treated as inpatients.

Primary and secondary prophylaxis against PCP was offered throughout the study period. Until December 1991, some patients participated in controlled trials1 26 27 28 studying the efficacy of various regimens. After this time, TMP-SMZ has been the primary choice of prophylaxis, followed by dapsone/pyrimethamine and aerosolized pentamidine.

Antiretroviral therapy was available throughout the study period. Until 1995, therapy was generally offered as monotherapy, between 1995 and 1996 as combination therapy with two nucleoside analogs, and since August 1996 has included a protease inhibitor.

Statistics
All values are expressed as median and range. Differences between groups were estimated by the Mann-Whitney test and {chi}2 statistics, as appropriate. Patients were left-truncated with regard to episode of PCP (ie, only the last episode was included in analyses), and survival was dated from the date of the last diagnosis of PCP to the date of death (if death had not occurred, to the last follow-up on February 13, 2000). Relative risk (RR) with the 95% confidence interval (CI) for progression to death from the time of diagnosis was estimated using univariate and multivariate Cox proportional-hazards regression models after stratification for adjunctive corticosteroid therapy. Survival curves were constructed by the method of Kaplan-Meier and compared with the log-rank test. Statistical analyses were done using the Statistical Package for Social Sciences (version 9.0; SPSS; Chicago, IL).


   Results
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 Abstract
 Introduction
 Materials and Methods
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Discussion
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Patient Characteristics
During the study period, there were 189 episodes of confirmed PCP in 176 individuals. As shown in Table 1 , the majority of patients were male (94%), had had sex with men (70%), and presented with PCP as a first diagnosis of AIDS (88%). Forty-five percent had HIV-1 diagnosed at the same time as their diagnosis of PCP. Sixteen patients had a previous diagnosis of PCP. Few patients were treated with antiretroviral therapy at the time of PCP (20%).


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  		Table 1.. Demographic and Laboratory Characteristics of 176 Patients With PCP*

 
Laboratory Characteristics at Admission
Measures of PO2 and PCO2, on room air, were 65 mm Hg (range, 32 to 104 mm Hg) and 34 mm Hg (range, 23 to 45 mm Hg), respectively. Serum LDH was 754 U/L (range, 186 to 2,830 U/L), and the CD4 cell count was 16/µL (range, 0 to 259/µL). BAL fluid cell analysis showed an increased proportion of lymphocytes (20%; range, 0 to 76%) and neutrophils (11%; range, 0 to 92%). CMV was cultured in 68 of 163 specimens (42%). Bacteria were cultured in 32 of 163 samples.

PO2 was significantly lower in the corticosteroid-treated group compared to the noncorticosteroid-treated group (59 mm Hg; range, 32 to 98 mm Hg vs 76 mm Hg; range, 38 to 104 mm Hg; p = 0.0001).

Treatment of PCP
As shown in Table 1 , the majority of patients were treated with TMP-SMZ (89%) and 111 patients were treated with adjunctive corticosteroids (63%). Thirty-six patients (21%) had their initial antimicrobial therapy changed, mainly because of side effects. Mechanical ventilation was necessary in 20 cases (11%); mortality associated with mechanical ventilation was 70%.

Survival
There were 28 fatal episodes and 40 fatal episodes within 1 month and 3 months, respectively, after the diagnosis of PCP, resulting in mortality rates of 16% and 23%. Thirty-six of these deaths (90%) occurred in the hospital.

The survivors were significantly younger; they were less likely to have received antiretroviral therapy, prophylaxis against P carinii, or adjunctive corticosteroids; and they were more often treated initially with TMP-SMZ, compared to nonsurvivors (Table 1) .

To explore the risk of progression to death associated with baseline variables, each variable was entered in a Cox regression model. In order to control for the use of adjunctive corticosteroids, data were stratified in the model according to use of corticosteroids at the time of diagnosis. Age > 32 years (median), use of PCP prophylaxis, initial antimicrobial therapy other than TMP-SMZ, more than one episode of PCP, and a positive finding on BAL CMV culture were each univariately associated with a decreased survival at 1 month and 3 months after the diagnosis of PCP (Table 2 ). The following variables were not associated with survival: sex, HIV-1 status at PCP, a prior AIDS diagnosis, use of antiretroviral therapy, transmission category, PO2, PCO2, CD4 count, serum LDH, BAL cell count and differential, BAL culture of bacteria, and year of diagnosis.


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  		Table 2.. Univariate Predictors of 1-Month and 3-Month Mortality Stratified for Use of Corticosteroids

 
In multivariate analysis, age, initial antimicrobial therapy other than TMP-SMZ, use of PCP prophylaxis, and a positive BAL CMV culture were independent predictors of survival (Table 3 ). Azoulay et al11 recently identified PaO2 < 60 mm Hg and BAL neutrophils > 10% as independent predictive factors of progression to death at 90 days in a logistic regression model. When our data were stratified by the method of Azoulay et al,11 neither PaO2 nor BAL neutrophils were statistically significantly associated with mortality at day 90 by logistic regression analysis or Cox proportional-hazards regression analysis: PaO2 < 60 mm Hg (RR, 1.0; 95% CI, 0.5 to 2.1) compared to PaO2 > 60 mm Hg; and BAL neutrophils > 10% (RR, 1.4; 95% CI, 0.7 to 3.0) compared to BAL neutrophils < 10%.


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  		Table 3.. Multivariate Predictors of 3-Month Mortality Stratified for Use of Corticosteroids

 
Kaplan-Meier survival curves for each of the independent predictors were constructed to further explore the cumulative frequency of death (Figs 1 2 3 4 ). Mortality appears equally distributed among patients treated and not treated with adjunctive corticosteroids for the independent predictors of age, initial antimicrobial therapy other than TMP-SMZ, and use of PCP prophylaxis. However, excess mortality associated with BAL CMV culture is overrepresented in the corticosteroid-treated group. Subgroup analyses showed RR of 2.5 (95% CI, 1.2 to 5.5) for corticosteroid-treated BAL CMV-positive patients, and RR of 1.4 (95% CI, 0.4 to 5.5) for noncorticosteroid-treated patients.



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  		Figure 1.. Survival curves for patients not treated (Non-CS) and treated with adjunctive corticosteroids (CS) according to age group (p = 0.004).

 


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  		Figure 2.. Survival curves for patients treated and not treated with adjunctive corticosteroids according to initial choice of antimicrobial therapy (p = 0.00001). See Figure 1 legend for expansion of abbreviations.

 


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  		Figure 3.. Survival curves for patients treated and not treated with adjunctive corticosteroids according to the use of PCP prophylaxis (p = 0.00001). See Figure 1 legend for expansion of abbreviations.

 


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  		Figure 4.. Survival curves for patients treated and not treated with adjunctive corticosteroids according to culture result of CMV in BAL fluid (p = 0.02). See Figure 1 legend for expansion of abbreviations.

 
Autopsy Findings
Autopsy was performed in 10 of 40 patients who died within 3 months. CMV lung infection, as demonstrated by the presence of CMV inclusions, was present in eight patients (80%). Their median CD4 count was 10/µL (range, 0 to 66/µL). Six of the eight patients were BAL CMV positive at the time of diagnosis, and four patients were treated with adjunctive corticosteroids. Two patients who received adjunctive corticosteroids but were BAL CMV negative had lung CMV inclusions at autopsy. Only one patient had established CMV disease (chorioretinitis) before the current episode of PCP. One patient had possible CMV inclusion bodies in a transbronchial biopsy specimen obtained at the time of the diagnosis of PCP. Two of eight patients with pulmonary CMV at autopsy had evidence of CMV infection elsewhere (kidney and adrenal gland).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we show that age, initial anti-PCP therapy, use of PCP prophylaxis, and BAL CMV status may be useful markers for identification of patients with a severe prognosis. Surprisingly, classic markers such as PO2 and serum LDH did not have independent prognostic value.

The choice of initial antimicrobial therapy (IV pentamidine) was associated with a threefold increased risk of death. Trimetrexate or clindamycin/primaquine was associated with an increased RR of progression to death as well, but because of a limited number of patients, sufficient power was lacking to determine if this was statistically significant. Our findings are in accordance with controlled trials29 that show that these drugs are associated with more treatment failures than TMP-SMZ. Drugs other than TMP-SMZ are usually used because the patient is intolerant to TMP-SMZ. Therefore, development of new drugs to provide an efficacious alternative to patients intolerant to TMP-SMZ seems warranted.

Patients failing to respond to prophylaxis therapy against PCP had a threefold increased risk of fatal progression from the pneumonia. A previous study30 has suggested that shorter overall survival from PCP after failing prophylaxis is associated with a higher degree of immunosuppression. In our study, failure of prophylaxis was, independently of CD4 counts, a marker of progression to death, suggesting that other mechanisms are at play. Widespread use of prophylaxis may have led to development of resistance among P carinii strains, so patients who have received prophylaxis may have acquired infection with a more virulent strain or strains. In support of this hypothesis is our finding from a recent study,31 showing that mutations in the target of sulfamethoxazole, the dihydropteroate-synthase gene product, are associated with an increased mortality rate, and that patients receiving sulfa-containing prophylactic regimens have a higher frequency of dihydropteroate-synthase mutations than prophylaxis-naïve patients. Therefore, the development of a reliable culture technique to test drug resistance or clinical validation of outcome measures related to genetic polymorphisms is needed.

Culture of CMV in BAL was independently associated with an increased (2.7-fold) risk of short-term mortality. The clinical significance of CMV in HIV-related lung disease is an issue of controversy. Several studies32 33 34 35 36 37 conducted before the introduction of adjunctive corticosteroid therapy concluded that CMV coinfection does not contribute directly to HIV-associated pulmonary disease. However, CMV does cause significant pulmonary disease in some individuals with HIV-1 infection, although the diagnosis frequently is missed antemortem.38 39 It is possible that CMV may be a significant pathogen in patients treated with immunosuppressants or who have other infections. In one study,40 the use of corticosteroids was related to the subsequent development of CMV retinitis and colitis in HIV-1–infected patients. In a previous study41 of PCP patients treated between 1989 and 1991, we showed a twofold increased mortality rate within 3 months of diagnosis in patients treated with adjunctive corticosteroids who were BAL CMV culture positive. However, the association did not reach statistical significance (p = 0.07). A previous study42 found increased short-term mortality in patients with CMV isolated from BAL but did not report on use of corticosteroids. In the present study, a positive BAL CMV culture finding in patients receiving adjunctive corticosteroid therapy was, independently of CD4 count, associated with a statistically significant increased risk of death within 3 months of diagnosis. Patients not receiving corticosteroids who were BAL CMV negative were not at an increased risk. Further, autopsy material showed a high frequency of lung CMV inclusion bodies in patients who died within 3 months, but the number of patients precluded statistical conclusions. The mechanisms through which CMV may shorten survival of patients treated with corticosteroids are unknown. In hypothesis, corticosteroids may impair host defense mechanisms against CMV, or CMV may be a marker of an unidentified factor associated with severe disease. In vitro data suggest that CMV replication is increased in corticosteroid-treated macrophages.43

In contrast to our study, Azoulay et al11 recently found in a retrospective study that a PO2 < 60 mm Hg and BAL neutrophilia > 10% predicted 90-day mortality among PCP patients managed from 1990 to 1995. In the present study, we applied the same statistical methodology but did not find these associations. There is no obvious explanation for this discrepancy because both study populations are comparable with regard to disease severity, and patients were treated according to generally accepted guidelines in both studies. Pooling of data from several centers could add statistical power to an analysis of prognostic markers of poor short-term outcome.

Mortality rates in our series are comparable to rates from the precorticosteroid era.7 9 12 13 44 This is somewhat surprising because the results of the controlled trials of adjunctive corticosteroid use would suggest a subsequent improvement in overall mortality rates. A possible explanation may be that our patients present with more advanced HIV-infection compared to earlier studies from the 1980s.

In summary, we have shown that the classic prognostic markers, PaO2 and serum LDH, may not have prognostic value in the era of adjunctive corticosteroid therapy. However, these markers continue to be useful to identify patients at risk of progression to respiratory failure, and to identify patients who should receive adjunctive corticosteroids (ie, level of alveolar oxygenation).2 In our multivariate analysis, age, choice of initial antimicrobial therapy, use of PCP prophylaxis, and BAL CMV culture were highly predictive of a severe prognosis. We suggest that one strategy to improve survival rates of patients with severe PCP is to study the efficacy of adjunctive anti-CMV therapy in a controlled trial.


   Footnotes
 
Abbreviations: CI = confidence interval; CMV = cytomegalovirus; LDH = lactate dehydrogenase; PCP = Pneumocystis carinii pneumonia; RR = relative risk; TMP-SMZ = trimethoprim-sulfamethoxazole

Supported by grants from the Danish Medical Research Council (Nos. 9400576 and 12–1451-1) and the Danish AIDS Foundation.

Received for publication May 23, 2000. Accepted for publication September 25, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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P M Jeena, L M McNally, M Stobie, H M Coovadia, M A Adhikari, and A J Petros
Challenges in the provision of ICU services to HIV infected children in resource poor settings: a South African case study
J. Med. Ethics, April 1, 2005; 31(4): 226 - 230.
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 ThoraxHome page
R J Boyton, D M Mitchell, and O M Kon
The pulmonary physician in critical care * Illustrative case 5: HIV associated pneumonia
Thorax, August 1, 2003; 58(8): 721 - 725.
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