Infection (2011) 39:379383 DOI 10.

1007/s15010-011-0122-8

CORRESPONDENCE

Anemia and community-acquired pneumococcal pneumonia

S. M. Doshi A. M. Rueda V. F. Corrales-Medina D. M. Musher

Received: 27 January 2011 / Accepted: 14 April 2011 / Published online: 10 May 2011 Springer-Verlag 2011

Community-acquired pneumonia (CAP) is a leading cause for hospitalization in the elderly, and pneumonia is the leading infectious cause of mortality in the United States [1]. The most common cause of CAP is Streptococcus pneumoniae [2]. Risk factors most commonly implicated in the development of pneumococcal pneumonia include chronic lung disease and previous hospitalization for pneumonia [3]. Other risk factors include age, male sex, chronic heart disease, smoking, alcohol consumption, cancer, and corticosteroid therapy. Low hemoglobin has been noted in up to 30% of patients with proven pneumococcal pneumonia or CAP [47]. In vitro studies have suggested that anemia is associated with impaired phagocytic capacity and decreased cellmediated immunity [8]. Low hemoglobin levels have been associated with poor prognosis and increased mortality in patients admitted with CAP [9]. An undetermined attribute of anemia could predispose to infection, or anemia could be a manifestation of an underlying comorbidity. A low hematocrit has also been implicated as an adverse prognostic indicator for CAP in a scoring system derived from the Pneumonia Patient Outcomes Research Team
S. M. Doshi University of Texas School of Public Health, Houston, TX, USA A. M. Rueda D. M. Musher Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA V. F. Corrales-Medina University of Ottawa, Ottawa, ON, Canada S. M. Doshi (&) Infectious Diseases, Veterans Affairs Medical Center, Houston, TX 77030, USA e-mail: simit.doshi@uth.tmc.edu

(PORT) cohort study or the Pneumonia Severity Index (PSI). The severity score assigned to a hematocrit \30% is equivalent to that of comorbid illnesses, such as congestive heart failure, renal disease, or cerebrovascular disease [10, 11]. Other studies investigating pneumonia prognosis have shown that low hematocrit and hemoglobin values are common in hospitalized CAP patients and are associated with prolonged length of stay [12] and higher mortality [9, 1316]. However, most of the studies were small and none of them focused specically on anemia in CAP and its role as a predisposing factor. The larger studies [10, 11, 15] have been multicenter studies with results based upon multivariable analyses. No study has focused on the early/ immediate effect on survival or used a comparison group to evaluate the association. The purpose of the present case-controlled study was to investigate whether the prevalence or severity of anemia is associated with an increased risk for pneumococcal pneumonia or with increased severity of disease in a large group of patients admitted to a single medical center. To our knowledge, this is the rst examination of this subject using a casecontrol design. This study also examines early mortality at various intervals after admission in patients with pneumococcal pneumonia The Institutional Review Board at the Baylor College of Medicine and the Research and Development Committee at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) approved this study. Cases were consecutive patients hospitalized at MEDVAMC from January 1, 2000 to June 30, 2010 with a diagnosis of pneumococcal pneumonia. These cases were identied from a database of all patients from whom S. pneumoniae is isolated from any source by the Microbiology Laboratory at MEDVAMC. Diagnostic criteria for pneumonia were those which we have previously published

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[1719]. In brief, patients had clinical and radiologic evidence of pneumonia within 48 h of admission and either (1) C1 blood culture(s) positive for S. pneumoniae or (2) a good-quality sputum specimen ([10 inammatory cells per epithelial cell) showing predominantly gram-positive cocci in pairs and a sputum culture positive for S. pneumoniae without the isolation of other likely bacterial pathogens. Two controls were selected for each case from patients hospitalized at MEDVAMC for any reason other than pneumonia during the same period. Each control was matched to a given case by date of admission, age, and race, in that order of priority. A list of all patients admitted on days 1, 7, 13, 19, and 25 of each month from January 2000 to June 2010 was requested from the medical records department. All patients in this list admitted within 1 week from the date of admission of the case were selected. Subjects with the same age as the case were shortlisted. If there were no patients of the same age, we moved 1 years and so on until at least two patients were found. If more than two patients of the same age met the criteria, they were matched by race. If multiple patients fullled all criteria, the two patients admitted earliest in the 2-week window were selected. We excluded patients with acute bleeding episodes, since it would indicate transient and potentially rapidly reversible cause of anemia. We wanted to evaluate the potential association of chronic anemic state with impaired immunity, which was unlikely with acute change in hemoglobin level and short period of anemic state. Although most of the patients excluded for this reason had an episode of bleeding within the 2 weeks prior to admission, we excluded patients for acute blood loss any time during the 6 months prior to admission. Complete electronic medical records were reviewed for evidence of pre-existing chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), congestive heart failure (CHF), chronic kidney disease, liver disease, and alcohol abuse. Medical progress notes and discharge summaries were reviewed in order to determine the nal diagnoses. Laboratory data were reviewed so as to record hemoglobin and hematocrit levels at the time of admission or immediately prior to it. Anemia was dened as hemoglobin \10 g/dL. The results are reported as mean values standard deviation (SD). Regarding mortality in the pneumococcal pneumonia group, we noted deaths due to any cause within 30 days of admission. The time to event was calculated considering the day of admission as day 0 (zero). We compared mortality in pneumococcal pneumonia patients who were or who were not anemic at 4, 7, 14, 20, and 30 days after admission. The data were analyzed using the Stata version 10.0. The Chi-square test was used to test for statistical

difference among categorical variables, while continuous variables were compared using the t-test for differences among means. Differences in the severity of anemia between the two groups were assessed using conditional logistic regression. Model t was assessed using the HosmerLemeshow test. Variables with a two-tailed p-value of \0.05 were considered to be statistically signicant. KaplanMeier analysis was used to compare mortality. Log-rank test p-values are reported. A total of 347 cases of pneumococcal pneumonia were identied at our medical center from January 1, 2000 to June 30, 2010. Positive blood cultures were obtained in 134 (38.6%) of these patients. The mean age of the patients was 64.0 11.9 years. We selected 694 matched controls with a mean age of 63.9 12.0 years. Sixty-three percent of the patients and 65% of the controls were self-identied as white. Table 1 shows the demographic characteristics and comorbidity proles of the study population. Patients with pneumonia were more likely to have pre-existing COPD as compared to matched controls (p \ 0.001). There were, otherwise, no signicant differences between the groups, although there was a tendency for controls to have a higher rate of DM and chronic renal insufciency (p = 0.07 for both comparisons). Pneumonia cases and controls were evaluated for differences in the rate and severity of anemia, using hemoglobin and hematocrit as both continuous and categorical variables, and no differences were detected. The mean hemoglobin levels were 12.8 2.2 gm/dL for cases and 13.0 2.2 gm/dL for controls (p = 0.15), and the mean
Table 1 Patient cohort characteristics (% or mean standard deviation [SD]) Cases, n = 347 Age (years) Race (%) White Black Hispanic Othersa Comorbidity Chronic obstructive pulmonary 36.0 disease Diabetes mellitus Congestive heart failure Chronic kidney disease Liver disease Alcohol abuse 21.9 10.6 7.2 4.0 18.2 16.3 27.1 13.9 10.6 4.9 21.8 \0.001 0.07 0.13 0.07 0.53 0.18 63.1 31.9 4.3 0.7 65.3 30.8 2.9 1.0 0.49 0.72 0.27 0.73 Controls, n = 694 p-value 0.86

64.0 11.9 63.9 12.0

The p-value is based on the t-test in the case of continuous variables and the Chi-square test in the case of categorical variables a Includes Asian, Filipino, Pacic Islander, and American Indian

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hematocrit levels for these two groups were 37.8 6.3 and 38.4 6.8, respectively (p = 0.2). Anemia (hemoglobin \10 g/dL) was noted in 10.1% of cases and 9.8% of controls (p = 0.91) (Fig. 1). A total of 125 cases and 113 controls had COPD. The mean hemoglobin levels after excluding patients with COPD was 12.6 2.3 gm/dl in pneumococcal pneumonia patients and 12.9 2.2 gm/dl in controls (p = 0.09). The percentage of anemic patients in these two groups was essentially identical (10.8 vs. 10.9%, p = 0.98) (Fig. 1). Hemoglobin levels were used as a continuous variable in a conditional logistic regression model in order to assess the effect of severity of anemia on the development of pneumonia. Higher hemoglobin levels did not decrease the odds for developing pneumococcal pneumonia (odds ratio [OR] 0.84, 95% condence interval [CI] 0.591.19, p = 0.33). A similar result was obtained with higher versus lower hematocrit levels (OR 1.04, 95% CI 0.931.18, p = 0.46). Of the 347 patients admitted with pneumococcal pneumonia, a total of 45 (13.3%) died during the 30-day period following admission. In the control group, 5 (7.2%) of the anemic patients died within 30 days. Thirty-nine (12.5%) deaths occurred in 312 pneumococcal pneumonia patients with normal hemoglobin levels on admission; 6 (17.1%) deaths were noted in 35 patients who were anemic on admission. The difference in the rate of death in anemic

patients versus those with normal hemoglobin at admission was signicant at 4 days (11.4 vs. 3.5%, p = 0.03) and 10 days (17.1 vs. 7.1%, p = 0.03), and marginally significant at 7 days (14.3 vs. 5.8%, p = 0.051). There was no difference in mortality at 20 (p = 0.21) or 30 days (p = 0.38) (Table 2). KaplanMeier survival curves are displayed in Fig. 2. To our knowledge, this is the rst case-controlled study designed to evaluate an association between anemia and the development of pneumococcal pneumonia. We found that neither the frequency nor the severity of anemia had any signicant association with the likelihood of developing pneumococcal pneumonia. To minimize variability between the groups and to account for unknown confounders, we applied strict criteria during the matching process. Each case was matched to two controls in order to increase the power of the study. Since data were collected for all cases admitted over a period of 10 years, we had a large sample size for analysis. The fact that the entire study
Table 2 Mortality at various intervals following admission in the pneumococcal pneumonia group Number of days after admission Total deaths in pneumococcal pneumonia cases, n(%) Hb \10 g/dL, n = 35 4 7 10 20 30 4 (11.4) 5 (14.3) 6 (17.1) 6 (17.1) 6 (17.1) Hb C10 g/dL, n = 312 11 (3.5) 18 (5.8) 22 (7.1) 33 (10.6) 39 (12.5) 0.03 0.05 0.03 0.21 0.38 p-value*

* p-value calculated from the log-rank test

Fig. 1 Mean hemoglobin levels among pneumococcal pneumonia cases and matched controls

Fig. 2 KaplanMeier survival analysis for pneumococcal pneumonia patients with and without anemia

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population receives medical care at the same center positively inuences the validity of the results. We initially examined the frequency and severity of anemia in cases and matched controls and its possible predisposition to the development of pneumococcal pneumonia by considering various factors. We found that about 9% of patients had anemia at the time of admission, a number similar to that recently reported by Reade et al. [9] in patients with CAP. There was no signicant difference between cases and controls with regard to the frequency or severity of anemia. There was no increased risk of the development of pneumonia with lower hemoglobin levels. We noted no signicant association between low hemoglobin and the development of pneumococcal pneumonia. We noted signicantly higher 4- and 10-day mortality in pneumococcal pneumonia patients who were anemic at admission. The PSI or PORT score is used as a prognostic prediction rule for patients with CAP [1]. The scoring system adds 10 points to the total severity score if the patient has a hematocrit\30% [10, 11], suggesting that low hemoglobin or hematocrit concentration have a signicant effect on morbidity and mortality in pneumonia patients. Brancati et al. [14] showed that a hematocrit less than 35% at presentation carried a 2.9 times higher risk of death at 2 years in CAP patients. Waterer et al. [16] showed the same association at 4 years. None of the studies investigated the early or in-hospital mortality in the patients. We studied mortality rates in the pneumonia group at different time points after admission and compared patients with and without anemia. Mortality was higher in those who were anemic at admission at 4 and 10 days, although by 30 days, the mortality was similar in those with or without anemia. The rst 10 days in hospital could be a potentially critical period in the management of patients with pneumococcal pneumonia. Our study, thus, provides data supporting the inclusion of anemia as an indicator of a poor prognosis in CAP. Interestingly, Reade et al. [9] recently reported a 1.59-fold increase in death at 90 days in CAP patients with hemoglobin B10 g/dL. We do not know why anemia appeared to be less prevalent in our patients than we have previously reported patients with pneumococcal pneumonia at our medical center [4]. One reason for a lower prevalence noted in our study could be because we looked at hemoglobin on or immediately prior to admission in order to avoid falsepositive results due to the dilutional effect of uids received on admission. A decline in hemoglobin of[0.5 g/dL/day by several mechanisms has been noted in the intensive care unit (ICU) setting [20] and also in non-ICU settings [9] during hospitalization. Since COPD was noted with a higher frequency in patients with pneumonia, we reanalyzed the data excluding COPD patients (Fig. 1), but this process did not alter the results.

A limitation of this study is the use of a retrospective design which precludes a determination of the incidence of pneumonia. We, thus, cannot estimate a relative risk or establish temporality. However, the design was chosen taking into consideration that it could serve as an initial step in testing the hypothesis. Other limitations could be the inclusion of predominantly males, the study being at the Veterans Affairs Medical Center, and the inability to match for all of the possible risk factors for pneumococcal pneumonia. This study shows the importance of establishing a control or comparison group when evaluating associations between risk factors and disease. As noted in Table 1, alcohol consumption, diabetes, and other comorbidities that are commonly regarded as risk factors for pneumococcal pneumonia were not signicantly different between the groups and were, in some instances, even more prevalent in the control group.
Conict of interest None.

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