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ORIGINAL RESEARCH ARTICLE

Prognostic value of C-reactive protein in HIV-infected patients with Pneumocystis jirovecii pneumonia
E K Sage MRCP*, M Noursadeghi MRCP*, H E Evans S G Edwards FRCP* and R F Miller FRCP*
BSc,

S J Parker

MBBS*,

A J Copas

PhD,

*T8, University College London Hospitals NHS Trust; Division of Infection and Immunity, University College London; Research Department of Infection and Population Health, University College London; Camden Provider Services NHS Trust, London, UK

Summary: C-reactive protein (CRP) is a sensitive marker of inammation and tissue damage. We aimed to describe CRP responses in HIV-infected patients presenting with Pneumocystis pneumonia (PCP), bacterial pneumonia (BP) and pulmonary tuberculosis (TB) and, in patients with PCP, to identify if elevated CRP has prognostic signicance. Data obtained by case-note review of consecutive HIV-infected adults with acute respiratory episodes included admission CRP (elevated .5 mg/L), haemoglobin, white blood count, CD4 count and partial pressure of oxygen in the blood (PaO2), presence of pulmonary copathology/intercurrent infection and outcome (survival). Median (range) CRP in patients with BP 120 mg/L (,5 620 mg/L), TB 44 mg/L (,5 256.3 mg/L) and PCP 35 mg/L (,5 254 mg/L). CRP was elevated in 93/103 (90.3%) patients with PCP; six patients died; and all had an elevated CRP. PaO2 and CRP values were associated as follows: average CRP levels declined by 10% (95% condence interval [CI] 0.20%) per kPa increase in PaO2 0.002. Factors associated with death were higher CRP, odds ratio (OR) (95% CI) 5.30 (1.61 to 17.51) per 100 mg/L increase, P 0.006 and haemoglobin, OR (95% CI) 0.52 (0.29 to 0.93) per g/dL, P 0.033. CRP is elevated in the majority of HIV-infected patients with PCP, BP and TB. Admission CRP measurement lacks specicity, but in PCP elevations of CRP are associated with disease severity ( PaO2) and poor outcome and might be used prognostically, together with other mortality risk factors; further prospective evaluation is needed. Keywords: C-reactive protein, acute phase protein, pneumonia, Pneumocystis, prognosis

INTRODUCTION
The acute-phase protein C-reactive protein (CRP) is a sensitive marker of inammation and tissue damage caused by many infectious and non-infectious stimuli.1,2 Histologically Pneumocystis pneumonia (PCP) is characterized by an eosinophilic alveolar exudate together with an interstitial mononuclear inammatory inltrate. In more severe PCP, hyaline membrane formation, interstitial oedema and brosis, variable alveolar damage and proliferation of type II pneumocytes (in response to tissue damage) may occur.2 4 Several reports describe elevations of CRP among patients with PCP who have underlying immunosuppression caused by HIV infection,2,5 10 haematological malignancy,11 transplantation9 and rheumatoid arthritis.12 One multicentre study of patients with haematological malignancy and PCP reported that CRP levels were higher among patients who died than those who survived,11 and a small study of HIV-infected patients with PCP suggested that an elevated CRP may have prognostic signicance.6 Elevations of CRP have also been described in
Correspondence to: Professor R F Miller, Research Department of Infection and Population Health, University College London, Mortimer Market Centre, off Capper Street, London WC1E 6JB, UK Email: rmiller@gum.ucl.ac.uk

HIV-infected patients with bacterial pneumonia and tuberculosis.5,13,14 The aims of the present study were rst to describe CRP responses in HIV-infected patients with PCP and those with bacterial pneumonia and pulmonary tuberculosis and second, among those with PCP, to identify if an elevated CRP had prognostic signicance.

METHODS
By means of case-notes review consecutive HIV-infected adults admitted to University College London Hospitals (London, UK) between October 1999 and October 2008 with acute respiratory episodes were identied. Patients had: (a) PCP, conrmed by demonstration of the cystic form of Pneumocystis jirovecii in bronchoscopic alveolar lavage (BAL) uid using Grocott Gomori methenamine silver stain, as described previously;15 (b) bacterial pneumonia, dened by acute onset of fever and or pleuritic pain (with or without purulent sputum), focal or diffuse chest radiographic abnormalities, with either positive culture of a pathogen from blood, spontaneously expectorated sputum or BAL uid, or no pathogen was identied in blood, sputum or BAL uid, but there was a clinical and radiological response to conventional dose antibiotics that were not effective against P. jirovecii, as described previously16; or (c) pulmonary

International Journal of STD & AIDS 2010; 21: 288 292. DOI: 10.1258/ijsa.2010.009551

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tuberculosis, diagnosed by identication of Mycobacterium tuberculosis by culture of sputum or BAL uid and response to specic antituberculosis therapy. Cytomegalovirus (CMV) infection was dened by identication on BAL uid of typical intranuclear and intracytoplasmic inclusions and by a positive result of testing for CMV (detection of early antigen by uorescent foci), as described previously.17 For all patients, CRP level (normal ,5 mg/L) at presentation and outcome (alive or dead one month after presentation) was recorded. If CRP level was !5 mg/L then the exact value was recorded, otherwise CRP levels recorded as ,5 mg/L were ascribed a value of 4.9 mg/L. In patients with PCP additional data were obtained: HIV risk factor, haemoglobin, white blood count (WBC), CD4 count, partial pressure of oxygen in the blood (PaO2) breathing room air (all prior to starting treatment), presence of pulmonary co-pathology and intercurrent morbidity and CRP values obtained 57 days after commencing specic anti-Pneumocystis therapy. The PaO2 was used as a marker of disease severity. No patient was receiving combination antiretroviral therapy at the time of diagnosis of PCP. CD4 counts were normalized by a log10 transformation. The Mann Whitney and Kruskal Wallis test were used to test for an association between diagnosis and CRP level. A log-normal interval regression model was used to quantify the association of CRP with CD4 count and PaO2. Missing CRP data were imputed by multiple imputation.18 Co-variables showing evidence of an association with CRP in univariable analysis were used to impute missing CRP values (through a log-normal imputation model) and results were compared with analyses where patients with missing CRP values were excluded. Imputation was stratied by disease category as different factors were associated with CRP level. Among those with PCP, Fishers exact test was used to assess the association between mortality and multiple variables. Logistic regression was used to assess differences in mortality rates and clinical variables, but adjusted odds ratios (OR) are considered approximate because there were only a small number of deaths. Stata software, version 9.0 (Stata, Cary, NC, USA) was used for statistical analysis. A P value of ,0.05 was taken to be signicant.

CRP values
CRP values were available in 244 of 263 episodes (93%); 103 of 105 patients with PCP, 116 of 130 with bacterial pneumonia and all 28 patients with pulmonary tuberculosis. Median CRP levels were higher among patients with bacterial pneumonia and pulmonary tuberculosis 120 mg/L (range ,5 620 mg/L) and 44 mg/L (,5256.3 mg/L), respectively, compared with patients with PCP, 35 mg/L (range ,5 254 mg/L). CRP levels in patients with bacterial pneumonia were higher than in those with PCP and pulmonary tuberculosis, P , 0.001 and P 0.022, respectively (Figure 1). When analysis was repeated using multiple imputation techniques, to account for missing CRP values, results were similar, P , 0.001 and P 0.018, respectively. Elevations of CRP among those with S. pneumoniae and those with no identiable pathogen were similar, median 250.5 mg/L (range ,5620 mg/L) and 103.2 mg/L (,5559.3 mg/L); in those with other pathogens CRP values were lower, median (range) 73.3 mg/L (7.5 123 mg/L).

Patients with PCP


There was strong evidence of an association between PaO2 (kPa, breathing room air) measured at admission, a marker for disease severity, and CRP levels, 10% (95% condence interval [CI] 0.20%) decline in average CRP per kPa increase in PaO2, P 0.002 (Figure 2), but there was no association between CRP and CD4 count, 20% (95% CI 0.30%) decline per 10-fold increase in CD4 count (P 0.125). Table 2 shows univariable analysis of factors associated with death in PCP patients. There was evidence that high levels of CRP (P 0.006), low levels of haemoglobin (P 0.033), acquisition of HIV infection via heterosexual sex (P 0.001) and borderline evidence low levels of PaO2 (P 0.092) were associated with death. For every 100 mg/L increase in CRP, the odds of death are increased by ve times (OR 5.30 [95% CI 1.61 to 17.51]). For every 1 g/dL increase in haemoglobin the odds of death are reduced (OR 0.52 [95% CI 0.29 to 0.93]). Patients whose HIV risk factor was heterosexual sex and those who were men who have sex with other men (MSM) were similar in age (median 34 versus 37 years), CD4 count (median 40 versus 40 cells/mL), WBC (median 5.5 versus 6.2 109/L) and PaO2 (median 8.3 versus 8.7 kPa), all P NS; however, heterosexual patients had a lower haemoglobin than those with MSM as their HIV risk factor (median 10.8 versus 12.1 g/dL), P 0.002. When a multivariable model was tted to include both haemoglobin and CRP levels as factors, the ORs changed very little, adjusted OR (AOR) 4.72 (95% CI 1.34 to 16.65) and AOR 0.55 (95% CI 0.29 to 1.03), but the strength of evidence for association with death was reduced, as indicated by an increase in P value for CRP levels to be 0.016 and for haemoglobin to be 0.064. There was no association between CRP and pulmonary co-pathology/intercurrent infection (data not shown). Follow-up CRP values, obtained 5 7 days after starting anti-Pneumocystis therapy, were recorded in 89 (86.5%) patients. Twenty-four patients (22 receiving co-trimoxazole and two receiving clindamycin-primaquine) developed a drug rash and two (receiving co-trimoxazole) had a drug fever. Among these 26 patients, follow-up CRP levels having initially fallen in response to therapy had risen again by days 57.

RESULTS Patients
In total 263 patients were studied; 105 patients had PCP, their characteristics are shown in Table 1. Ninety-eight patients were treated with co-trimoxazole, ve with clindamycinprimaquine and two with intravenous pentamidine; 62 patients with admission PaO2 ,9.3 kPa (breathing room air) received adjunctive corticosteroids. Nine patients had pulmonary co-pathology (CMV infection six, bacterial infection three [Streptococcus pneumoniae two, Klebsiella pneumoniae one]) and three had intercurrent infection (tuberculosis two, shigellosis one); six (5.8%) patients with PCP died. A total of 130 patients had bacterial pneumonia. The aetiology was S. pneumoniae (41 patients), other pathogens (four patients; Staphylococcus aureus and Haemophilus inuenzae (two patients), H. inuenzae and K. pneumoniae (one patient each); no pathogen was identied in 85 patients; no patient with bacterial pneumonia died. Twenty-eight patients had pulmonary tuberculosis; all patients survived.

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Table 1

Characteristics of 105 patients with PCP 37 (18 72) 93 (88.5) 98 5 2 62 11.9 6.2 40 35 8.9 9 6 3 2 6 (93) (5) (2) (59) (8.8 16.8) (1.5 22.4) (0 480) (,5 254) (2.1) (4%) (5.8) (3.9) (1.9) (5.8)

Age (years), median (range) Gender (male), n (%) Treatment Co-trimoxazole, n (%) Clindamycin-primaquine, n (%) Intravenous pentamidine, n (%) Adjunctive corticosteroids, n (%) Admission haemoglobin (g/dL), median (range) Admission WBC (cells 109/L), median (range) Admission CD4 count (cells/mL), median (range) Admission CRP (mg/L), median (range) Admission PaO2 (kPa) (breathing room air), mean (SD) Pulmonary co-pathology, n (%) CMV in BAL uid, n (%) Bacterial infection in BAL uid, n (%) Pulmonary Kaposi sarcoma, n (%) Died, n (%)

Figure 2 Association between PaO2 and CRP in 103 patients with Pneumocystis pneumonia

WBC peripheral blood white blood count; CMV cytomegalovirus; BAL bronchoscopic alveolar lavage; CRP C-reactive protein; PaO2 partial pressure of oxygen in the blood; SD standard deviation

Follow-up CRP values were available in four of the six patients who died. In three patients CRP levels fell by days 57 in response to treatment, and the fourth patient developed a rash due to co-trimoxazole, associated with a rise in CRP level.

DISCUSSION
In this study CRP values were elevated at presentation in the majority of HIV-infected patients presenting with respiratory infection due to PCP, bacterial pneumonia and pulmonary tuberculosis and additionally, among patients with PCP, an elevated CRP at the time of presentation had prognostic signicance.

Figure 1 C-reactive protein (CRP) values in HIV-infected patients with respiratory disease. Scatter-plot based on 244 patients in whom CRP levels were measured; 103 patients with Pneumocystis pneumonia (PCP), 28 with pulmonary tuberculosis (Pulm TB) and 116 with bacterial pneumonia (Bact Pneum). Bars indicate median values

The nding of an elevated CRP among adult HIV-infected individuals at presentation with an acute respiratory illness is consistent with observations from previous studies.2,5 8,10,13 In the present study, higher CRP values were observed in those with bacterial pneumonia when compared with patients with PCP and pulmonary tuberculosis, as reported previously.5,7,13 Intriguingly, in all three groups a dimorphic frequency distribution of CRP values was evident, suggesting that factors other than the individual microbial pathogens had a signicant effect. Additionally, not all patients with PCP, bacterial pneumonia or pulmonary tuberculosis at presentation had an elevated CRP, which suggests that an active respiratory infection cannot be excluded among HIV-infected patients with respiratory symptoms on the basis of a normal CRP value. Given this lack of diagnostic certainty clinicians will need to use additional investigations in order to secure a specic pathogen-related diagnosis. Our study showed that among HIV-infected patients with PCP, there was a signicant association between elevated CRP values at presentation and disease severity (PaO2 measured breathing room air, before starting therapy) and with death. From our data we suggest that CRP measurement at the time of presentation may be of prognostic use along with other mortality risk factors in patients with PCP, but further prospective evaluation is needed. The observation that patients who had heterosexual sex as their HIV risk factor were more likely to die from PCP than MSM is of note. This nding has no immediate explanation, but may be confounded by the former group having lower haemoglobin levels, a previously described prognostic factor in PCP.19,20 Follow-up measurements of CRP among those with PCP after 57 days of therapy, performed in order to assess the reduction in pulmonary inammatory burden, lacked utility as CRP levels in 25% of patients having fallen initially in response to treatment rose again in the context of drug-associated toxicity. These observations contrast with reports describing general medical immunocompetent patients with community-acquired bacterial pneumonia, among whom measurement of CRP values after four days of treatment has been used to assess response to therapy. In those with CRP values that remain elevated after !4 days of treatment, there was a greater risk of treatment failure and increased mortality.21 Additionally, among HIV-infected patients with PCP, an ongoing pulmonary inammatory burden, as measured by persistently elevated serum

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Table 2

Associations with death in 105 patients with PCP Mortality rate (n deaths/ n episodes) (%) 4/69 (5.8) 1/26 (3.9) 1/10 (10) 5/93 (5.4) 1/12 (8.3) 3/24 (12.5) 3/31 (9.7) 0/50 (0) 0/16 1/23 2/32 3/34 (0) (4.4) (6.3) (8.8) Odds ratio for death (95% CI)

Variable Age (years) ,40 40 49 .50 Gender Male Female Haemoglobin (g/dL) ,10.6 10.6 11.99 !12.0 WBC (cells 3109/L) ,3.9 3.9 5.39 5.4 7.29 !7.3 CD4 (cells/mL) ,50 !50 PaO2 (kPa) ,8.0 8.0 9.29 !9.3 CRP (mg/L) ,5 5 50 .50 CMV in BAL uid Yes No Kaposi sarcoma Yes No Risk group Men who have sex with other men Heterosexual Intravenous drug user

P value

0.88 (0.335, 2.24) 1 0.63 (0.07, 5.85)

0.526

0.680

In summary the majority of patients with HIV infection at presentation with an acute pulmonary infection had an elevated CRP. Higher CRP values were more suggestive of bacterial infection, but the nding lacked specicity and was not useful in distinguishing between PCP and other causes of respiratory infection. In patients with PCP higher CRP values were associated with more severe disease and a poor outcome, suggesting CRP measurement might be used prognostically, together with other mortality risk factors; further prospective evaluation is needed. Among patients with PCP follow-up measurement of CRP after 57 days of therapy did not provide an indication of treatment response.

0.53 (0.29, 0.95)

0.033 ACKNOWLEDGEMENTS

1.004 (0.79, 1.27) 1 0.55 (0.15, 2.28)

0.977

3/55 (5.5) 3/50 (6.0) 5/38 (13.2) 0/24 (0) 1/43 (2.3) 0/10 (0) 2/62 (3.2) 4/31 (12.9) 1/6 (16.7) 5/99 (5.1) 0/2 (0.0) 6/103 (5.94) 0/73 (0.0) 6/31 (19.3) 0/1 (0.0)

0.162

Source of funding: The National Institutes of Health, USA (Grant RO1 HL-090335) and The Dr Hadwen Trust for Humane Research (RFM) and The Wellcome Trust (Grant WT077161) and NIHR UCLH/UCL Comprehensive Biomedical Research Centre (MN).

0.69 (0.43, 1.11)

0.092 REFERENCES

5.30 (1.61, 17.51)

0.006 0.312

0.888

0.001

WBC peripheral blood white blood count; CMV cytomegalovirus; BAL bronchoscopic alveolar lavage; CRP C-reactive protein; PaO2 partial pressure of oxygen in the blood Odds ratio is based on a 10-year increase in age Odds ratio is based on a one unit increase. Odds ratios were not calculated for risk group categories or pulmonary Kaposi sarcoma because of small numbers; no deaths in two of the risk groups and there were no deaths among patients with pulmonary Kaposi sarcoma Analysis based on 103 patients. Odds ratios for laboratory measurements are treated as continuous Odds ratio is based on a 100 mg/L increase

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23 Miller RF, Allen E, Copas A, Singer M, Edwards SG. Improved survival for HIV infected patients with severe Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy. Thorax 2006;61:716 21 24 Forrest DM, Zala C, Djurdjev O, et al. Determinants of short- and long-term outcome in patients with respiratory failure caused by AIDS related Pneumocystis carinii pneumonia. Arch Intern Med 1999;159:741 7 25 Fei MW, Kim EJ, Sant CA, et al. Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study. Thorax 2009;64:1070 6 (Accepted 1 March 2010)

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