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Original Research: Chest Infections |

Thrombocytosis Is a Marker of Poor Outcome in Community-Acquired PneumoniaThrombocytosis in Pneumonia FREE TO VIEW

Elena Prina, MD; Miquel Ferrer, MD, PhD; Otavio T. Ranzani, MD; Eva Polverino, MD, PhD; Catia Cillóniz, PhD; Encarnación Moreno, RN; Josep Mensa, MD; Beatriz Montull, MD; Rosario Menéndez, MD, PhD; Roberto Cosentini, MD; Antoni Torres, MD, PhD
Author and Funding Information

From the Servei de Pneumologia (Drs Prina, Ferrer, Ranzani, Polverino, Cillóniz, and Torres, and Ms Moreno), Institut del Torax, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Emergency Medicine Department (Drs Prina and Cosentini), Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CibeRes, CB06/06/0028) (Drs Ferrer, Polverino, Cillóniz, Menéndez, and Torres, and Ms Moreno), Barcelona, Spain; Respiratory Intensive Care Unit (Dr Ranzani), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Brazil; Servicio de Enfermedades Infecciosas (Dr Mensa), Hospital Clínic, IDIBAPS, Barcelona, Spain; and Servicio de Neumologia (Drs Montull and Menéndez), Hospital Universitario La Fe, Valencia, Spain.

Correspondence to: Miquel Ferrer, MD, PhD, Unitat de Vigilancia Intensiva Respiratoria, Servei de Pneumologia, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: miferrer@clinic.ub.es


Funding/Support: This work was supported by the Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CibeRes CB06/06/0028)-Instituto de Salud Carlos III [Grant 2009 SGR 911], PII de infecciones respiratorias of SEPAR, and IDIBAPS.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(3):767-775. doi:10.1378/chest.12-1235
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Background:  Thrombocytosis, often considered a marker of normal inflammatory reaction of infections, has been recently associated with increased mortality in hospitalized patients with community-acquired pneumonia (CAP). We assessed the characteristics and outcomes of patients with CAP and thrombocytosis (platelet count ≥ 4 × 105/mm3) compared with thrombocytopenia (platelet count < 105/mm3) and normal platelet count.

Methods:  We prospectively analyzed 2,423 consecutive, hospitalized patients with CAP. We excluded patients with immunosuppression, neoplasm, active TB, or hematologic disease.

Results:  Fifty-three patients (2%) presented with thrombocytopenia, 204 (8%) with thrombocytosis, and 2,166 (90%) had normal platelet counts. Patients with thrombocytosis were younger (P < .001); those with thrombocytopenia more frequently had chronic heart and liver disease (P < .001 for both). Patients with thrombocytosis presented more frequently with respiratory complications, such as complicated pleural effusion and empyema (P < .001), whereas those with thrombocytopenia presented more often with severe sepsis (P < .001), septic shock (P = .009), need for invasive mechanical ventilation (P < .001), and ICU admission (P = .011). Patients with thrombocytosis and patients with thrombocytopenia had longer hospital stays (P = .004), and higher 30-day mortality (P = .001) and readmission rates (P = .011) than those with normal platelet counts. Multivariate analysis confirmed a significant association between thrombocytosis and 30-day mortality (OR, 2.720; 95% CI, 1.589-4.657; P < .001). Adding thrombocytosis to the confusion, respiratory rate, and BP plus age ≥65 years score slightly improved the accuracy to predict mortality (area under the receiver operating characteristic curve increased from 0.634 to 0.654, P = .049).

Conclusions:  Thrombocytosis in patients with CAP is associated with poor outcome, complicated pleural effusion, and empyema. The presence of thrombocytosis in CAP should encourage ruling out respiratory complication and could be considered for severity evaluation.

Figures in this Article

In addition to being part of the hemostatic process, platelets have been increasingly recognized as an important component of the immune response to infection.13 Thrombocytopenia is a recognized severity criterion and a predictor of mortality in hospitalized patients with community-acquired pneumonia (CAP)4,5 and is included in the minor severity criteria defined by the current Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) guidelines to predict ICU admission.6 Conversely, thrombocytosis has often been considered a sign of normal inflammatory reaction, but not as a marker of poor outcome.

Mirsaeidi et al7 showed recently in a retrospective single-center study an association between thrombocytopenia and thrombocytosis and increased mortality in patients hospitalized with CAP. Their article, however, did not evaluate the reason for the higher mortality rate of patients with thrombocytosis and did not assess or compare the clinical and etiologic characteristics of the three groups of patients with thrombocytopenia, thrombocytosis, and normal platelet count. Furthermore, this study generated doubts on this issue8,9 that required further research.

We hypothesized that the clinical profile, inflammatory biomarkers, and mortality in patients with CAP may be different in those presenting with thrombocytosis and thrombocytopenia than in patients with a normal platelet count. Therefore, the objective of our study was to define these three groups of patients to confirm the association between abnormal platelet count and patients’ outcome.

Study Population

We prospectively assessed consecutive patients aged ≥ 14 years hospitalized with a diagnosis of CAP at Hospital Clinic, Barcelona, Spain, and Hospital Universitario La Fe, Valencia, Spain, from January 2000 to October 2006. Pneumonia was defined as a new pulmonary infiltrate on chest radiograph at admission and symptoms and signs of lower respiratory tract infection. We excluded patients with previous use of oral corticosteroids (≥ 10 mg prednisone-equivalent per day for at least 2 weeks); other immunosuppressive therapy; active solid or hematologic neoplasms; HIV infection; active TB; hematologic disease involving platelets and/or leukocytes, such as essential thrombocytosis or myelodysplastic syndrome; and hospitalization within the preceding 21 days.

This study was approved by the ethics committees of both centers (Register: 2009/5251). Patients’ identification remained anonymous and informed consent was waived due to the observational nature of the study.

Data Collection and Microbiologic Evaluation

The data collected, the severity scores, and the criteria for the microbiologic diagnosis have been described elsewhere.10 The laboratory findings reported were obtained within 6 h after admission to the ED.

Definitions

Thrombocytopenia and thrombocytosis were defined as platelet counts < 105/mm3 and ≥ 4 × 105/mm3, respectively. We defined sepsis, severe sepsis, and septic shock according to the sepsis guidelines.11 We calculated the Pneumonia Severity Index12 and the confusion, respiratory rate, and BP plus age ≥ 65 years (CRB-65) score13 at admission. The definition of severe CAP followed the IDSA/ATS guidelines.6 We defined complications as organ diseases besides the pneumonia presented at admission or appearing during hospitalization. We defined complicated pleural effusion and empyema according to the literature definition.14 We defined pneumonia as the cause of death when patients died of acute respiratory failure and/or septic shock due to the respiratory infection. We assessed the adherence of the empirical antibiotic treatment to the guidelines15,16 and its appropriateness to the isolated pathogens.17

Determination of Cytokines, C-Reactive Protein, and Procalcitonin

We determined serum levels of cytokines and procalcitonin in a subgroup of 550 patients. The laboratory techniques used were described elsewhere.18

Statistical Analysis

Categorical variables were described as frequencies and percentages and compared with the χ2 test or Fisher exact test when appropriate. Continuous variables were expressed as mean ± SD and compared between groups using one-way analysis of variance; for data not normally distributed, these variables were expressed as median (interquartile range) and compared using the nonparametric Kruskal-Wallis test. All post hoc comparisons were made with the Bonferroni correction. Correlations between two continuous variables were made with the Pearson correlation.

Two different models of logistic regression were developed as follows: First, the association between platelet count and 30-day mortality was assessed as categorical variables, with the predefined values, normal range being the reference category. Second, we performed the same analysis with platelet count and leukocyte cells as continuous variables. Continuous variables were checked for the assumption of linearity in the logit. Single collinearity was evaluated with the Pearson correlation among the independent variables and multicollinearity was evaluated with the variance inflation factor. The ORs and corresponding 95% CIs for each variable were computed. The discriminative ability of the model to predict the outcome of patients was assessed by the area under the receiver operating characteristic curve (AUC). Estimated AUC values were compared using the nonparametric method described by Hanley and NcNeil.19 The calibration ability for the model was evaluated with the Hosmer-Lemeshow goodness-of-fit statistics. To explore the role of the platelet count in patient outcome, we retrieved the predicted 30-day mortality for each patient from the final model and plotted it against the respective absolute platelet count. Data were processed with the SPSS version 18.0 (IBM). The level of significance was set at 0.05 (two-tailed).

Patient Characteristics

During the study period, we evaluated 3,010 patients with CAP (Fig 1), and it was possible to analyze 2,423 subjects who met inclusion criteria and in whom the platelet count at admission was available: 53 patients (2%) with thrombocytopenia, 204 patients (8%) with thrombocytosis, and 2,166 (90%) with a normal platelet count. The general characteristics of the patients are shown in Tables 1 and 2.

Figure Jump LinkFigure 1. Flow diagram of the selected population. CAP = community-acquired pneumonia.Grahic Jump Location
Table Graphic Jump Location
Table 1 —General Characteristics of the Study Population at Admission

Data given as No. (%) unless otherwise indicated.

a 

Differences between thrombocytopenia and thrombocytosis.

b 

Differences between thrombocytosis and the other groups.

c 

Differences between thrombocytopenia and the other groups.

Table Graphic Jump Location
Table 2 —Characteristics of Pneumonia at Admission

Data given as mean (± SD) unless otherwise indicated. APTT = activated partial thromboplastin time; CRB-65 = confusion, respiratory rate, and BP plus age ≥ 65 y score; MAP = mean arterial pressure.

a 

Differences between thrombocytopenia and normal platelet count.

b 

Differences between thrombocytopenia and the other groups.

c 

Differences between thrombocytopenia and thrombocytosis.

d 

Differences between thrombocytosis and normal platelet count.

Patients with thrombocytosis were younger, had more frequently received previous antibiotics, and had a lower CRB-65 score at admission. Patients with thrombocytopenia more frequently had chronic heart and liver disease, and heart rate, leukocyte counts, fibrinogen level, and prothrombin time were all lower at admission. Moreover, there was a weak but significant positive correlation between platelet count and leukocyte count (r = 0.21, P < .001) and fibrinogen level (r = 0.18, P < .001).

In the overall population, 2,072 patients (86%) received antibiotic treatment adherent to ATS guidelines. Among 1,060 patients with a known etiology, 947 (89%) were treated with an appropriate antimicrobial therapy. Adherence to the guidelines and appropriateness of the empirical antibiotic treatment were not significantly different among the three groups.

Microbial Etiology

An etiologic diagnosis was established in 1,060 patients (44%). Streptococcus pneumoniae was the most frequent pathogen in all groups. Atypical agents were less frequently identified in thrombocytopenic patients, and there was no significant difference in the remaining pathogens (Table 3).

Table Graphic Jump Location
Table 3 —Etiologic Diagnosisa

Data given as No. (%).

a 

The percentages of pathogens are related to the number of patients with etiologic diagnosis in each group.

Complications, Length of Stay, and Readmission Rate

Patients with thrombocytosis more frequently had respiratory complications due to higher rate of empyema and complicated pleural effusion. By contrast, patients with thrombocytopenia presented more often with severe CAP, severe sepsis, and septic shock, and need for invasive mechanical ventilation and ICU admission, with a trend toward a higher rate of cardiovascular complications.

The length of hospital stay was significantly longer in patients with thrombocytosis and those with thrombocytopenia compared with those with normal platelet count; no statistical difference in length of stay was found between the two former groups. Among the survivors of the first hospitalization, the 30-day hospital readmission rate was higher in patients with thrombocytopenia and those with thrombocytosis, with no significant difference between them (Table 4).

Table Graphic Jump Location
Table 4 —Complications and Outcome Variables

Data given as No. (%) unless otherwise indicated. CAP = community-acquired pneumonia.

a 

Differences between thrombocytopenia and the other groups.

b 

Readmission rates are calculated from the survivors from the initial episode that required hospital admission.

c 

Differences between normal platelet count and the other two groups.

d 

One hundred eight patients (4.5%) presented with more than one respiratory complication as follows: four (7.5%) in the thrombocytopenia group, 91 (4%) in the group. with normal platelet counts, and 13 (6%) in the thrombocytosis group (P = .194).

Thrombocytosis and Severity Scores

Adding thrombocytosis to the CRB-65 score slightly improved the accuracy of this score to predict mortality (the AUC increased from 0.634 to 0.654, P = .049). Adding thrombocytosis to the pneumonia severity index score and the IDSA/ATS minor criteria of severe CAP did not improve the prediction of mortality and ICU admission, respectively.

Mortality and Causes of Death

Overall, 127 patients (5%) died within 30 days of hospital admission. The mortality rate was higher in patients with thrombocytopenia and patients with thrombocytosis, with no significant difference between them (Table 4). Patients with pulmonary complications had a higher mortality rate with respect to patients without pulmonary complications (65.4% vs 62.7%, P = .003). The multivariate analysis, using platelet count as a categorical variable, confirmed the association between higher platelet count and 30-day mortality (Table 5). By contrast, the association of a low platelet count with 30-day mortality did not reach statistical significance.

Table Graphic Jump Location
Table 5 —Multivariate Logistic Regression Model for 30-d Mortality

To evaluate the role of continuous platelet count, the multivariate analysis showed that the increased risk of death was significantly associated with increasing platelet count (Fig 2). The same analysis was run for leukocyte count, without significant association within mortality.

Figure Jump LinkFigure 2. Multivariate logistic regression model to evaluate the association between platelet count as a continuous variable and mortality.Grahic Jump Location

In all groups, the main cause of death was pneumonia, but through different mechanisms: Patients with thrombocytosis died more frequently of acute respiratory failure, whereas patients with thrombocytopenia died more frequently of septic shock. The thrombocytosis group did not show higher frequency of thrombotic events as cause of death compared with the other groups (Table 6).

Table Graphic Jump Location
Table 6 —Cause of Death

Data given as No. (%).

a 

Differences between thrombocytosis and the other groups.

b 

Differences between thrombocytopenia and the other groups.

Inflammatory Biomarkers

IL-1 at admission was lower in patients with normal platelet count (P = .048). We also observed a nonsignificant trend for higher procalcitonin and tumor necrosis factor (TNF)-α levels in patients with thrombocytopenia (Table 7).

Table Graphic Jump Location
Table 7 —Inflammatory Biomarkers

Data given as median (interquartile range). TNF = tumor necrosis factor.

a 

Differences between thrombocytosis and normal platelet count.

The main findings of our study were as follows: (1) Thrombocytosis was observed in 8% and thrombocytopenia in 2% cases of a large series of consecutively hospitalized patients with CAP; (2) thrombocytosis but not thrombocytopenia is an independent marker of poor outcome; and (3) thrombocytosis was more frequently associated with empyema and complicated pleural effusion, whereas patients with thrombocytopenia presented more often severe sepsis, septic shock, and the need for mechanical ventilation.

We have shown that according to platelet count, it is possible to identify populations with different characteristics. Patients with thrombocytopenia were older, often had cardiac and liver diseases, and presented more frequently with higher acuity and severity of disease (ie, higher rate of severe CAP, need for ICU admission, need for mechanical ventilation, and septic shock). Patients with thrombocytosis were younger, had a lower CRB-65 score at admission, and presented more often with respiratory complications (especially related to a local inflammatory reaction such as empyema and complicated pleural effusion).

Compared with patients with normal platelet counts, both the thrombocytopenia and thrombocytosis groups presented with a worse prognosis but apparently for different reasons: Infection in patients with thrombocytopenia patients tended to spread with the development of systemic complications (ie, septic shock), whereas in patients with thrombocytosis, infection tended to compartmentalize with the development of local respiratory complications with a subacute course (ie, empyema/complicated pleural effusion).

In the literature, thrombocytopenia in severe CAP has already been studied and its role as a marker of severity is well established.4,5 On the other hand, few studies have investigated thrombocytosis in CAP. Recently, however, it has been proposed that thrombocytosis could be a marker of poor outcome and specific complications.

Mirsaeidi et al7 analyzed 500 patients with CAP, of whom 65 (13%) presented thrombocytosis and 27 (5%) presented thrombocytopenia. These authors reported that both patients with thrombocytopenia and those with thrombocytosis had significantly higher mortality and that platelet count was a better predictor of outcome than an abnormal leukocyte count. However, the cause of mortality, complications, etiology, and systemic inflammatory response were not analyzed and the population studied included elderly patients with cancer.

In pediatric patients with CAP, two studies showed that thrombocytosis was associated with a poor outcome and more severe and protracted disease, with a higher probability of developing empyema.20,21 In another study in adults with CAP, thrombocytosis (platelet count > 400,000/mm3) was an independent risk factor for the development of complicated parapneumonic effusion or empyema.22

In our study, multivariate logistic regression confirmed the association between thrombocytosis and 30-day mortality. The adjusted risk of death was 2.7-fold greater in patients presenting with an elevated platelet count at hospital admission relative to patients with a normal platelet count. Surprisingly, in contrast to other studies,4,2325 we could not confirm the independent association between thrombocytopenia and mortality. Several reasons may explain this result: the presence of a low number of patients with thrombocytopenia, the higher weight of septic shock and hypoxemia in determining mortality in these patients, and the different characteristics of our population, with the inclusion of patients with less severe CAP (patients not in the ICU), compared with previous studies. However, our results do not discard the idea that thrombocytopenia remains a marker of serious underlying diseases and complications that are ultimately associated with death. In accordance with the results of Mirsaeidi et al,7 we did not find an association in our population between leukocyte count and mortality, so an increase of platelet count appeared to better identify patients with higher mortality risk.

A possible explanation of why patients with thrombocytosis had a poor outcome would be the higher rate of empyema and complicated pleural effusion. In the literature, these types of complications have been associated with a longer length of hospital stay, treatment failure, and higher mortality.2630 Moreover, as explained in the sepsis guidelines,11 besides the implementation of rapid, adequate antibiotic treatment, control of the source of infection is fundamental for the resolution of infections. We can, therefore, hypothesize that the higher mortality of patients with thrombocytosis could be related to inadequate management of these complications for different reasons, for example, delayed diagnosis and drainage, antibiotic treatment that is too brief, or a lack of adequate follow-up.

In our population, we did not observe a higher rate of thrombotic/cardiovascular events in patients with thrombocytosis, as hypothesized by Mirsaeidi et al.7 These results were in line with other studies that showed that reactive thrombocytosis, in contrast to primary thrombocytosis, was not associated with higher risk of cardiovascular or thrombotic events.3134

According to our results, we suggest that platelet count should be monitored in patients with CAP: Thrombocytopenia requires awareness of septic complications and hemodynamic alterations, whereas in patients with thrombocytosis, clinicians should pay attention to local respiratory complications, such as pleural effusion that may need specific treatment (eg, drainage or a different follow-up). Adding thrombocytosis to the CRB-65 score slightly but significantly improved the capacity of this score to recognize patients with higher mortality risk.

This large, two-center, cohort study has some limitations that should be addressed. First, we only evaluated data regarding platelet counts on admission, since the main purpose of assessing platelet count at admission was to help decide patients’ allocation based on the prediction of outcome. Serial measurements of platelet counts during hospitalization could differentiate between a transient event and sustained derangements in the platelet count. Second, we did not evaluate possible differences in the functional activity of platelets among the different groups. Third, biomarkers and cytokines were not analyzed in all the patients, thereby limiting our analyses.

In conclusion, thrombocytosis has been proved to be a marker of poor outcome in CAP. Consequently, it should be considered in the severity evaluation of patients with CAP and can help promptly identify patients at higher risk for respiratory complications.

Author contributions: Dr Ferrer takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Prina: contributed to study design, analysis of data, and writing the manuscript and served as principal author.

Dr Ferrer: contributed to the study design, analysis of data, and writing of the manuscript.

Dr Ranzani: contributed to the study design, analysis of data, and approved the manuscript.

Dr Polverino: contributed to the recruitment of patients, data collection, and approved the manuscript.

Dr Cillóniz: contributed to the recruitment of patients, data collection, and approved the manuscript.

Ms Moreno: contributed to the recruitment of patients, data collection, and approved the manuscript.

Dr Mensa: contributed to the revision of the manuscript with important intellectual content.

Dr Montull: contributed to the recruitment of patients, data collection, and approved the manuscript.

Dr Menéndez: contributed to the recruitment of patients, data collection, and approved the manuscript.

Dr Cosentini: contributed to the revision of the manuscript with important intellectual content.

Dr Torres: contributed to the study design and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank all the clinicians who took part in the preparation of this paper.

ATS

American Thoracic Society

AUC

area under the curve

CAP

community-acquired pneumonia

CRB-65

confusion, respiratory rate, and BP plus age ≥ 65 years

IDSA

Infectious Disease Society of America

TNF

tumor necrosis factor

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Meade TW, Cooper JA, Miller GJ Platelet counts and aggregation measures in the incidence of ischaemic heart disease (IHD). Thromb Haemost. 1997;78(2):926–-929. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Flow diagram of the selected population. CAP = community-acquired pneumonia.Grahic Jump Location
Figure Jump LinkFigure 2. Multivariate logistic regression model to evaluate the association between platelet count as a continuous variable and mortality.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —General Characteristics of the Study Population at Admission

Data given as No. (%) unless otherwise indicated.

a 

Differences between thrombocytopenia and thrombocytosis.

b 

Differences between thrombocytosis and the other groups.

c 

Differences between thrombocytopenia and the other groups.

Table Graphic Jump Location
Table 2 —Characteristics of Pneumonia at Admission

Data given as mean (± SD) unless otherwise indicated. APTT = activated partial thromboplastin time; CRB-65 = confusion, respiratory rate, and BP plus age ≥ 65 y score; MAP = mean arterial pressure.

a 

Differences between thrombocytopenia and normal platelet count.

b 

Differences between thrombocytopenia and the other groups.

c 

Differences between thrombocytopenia and thrombocytosis.

d 

Differences between thrombocytosis and normal platelet count.

Table Graphic Jump Location
Table 3 —Etiologic Diagnosisa

Data given as No. (%).

a 

The percentages of pathogens are related to the number of patients with etiologic diagnosis in each group.

Table Graphic Jump Location
Table 4 —Complications and Outcome Variables

Data given as No. (%) unless otherwise indicated. CAP = community-acquired pneumonia.

a 

Differences between thrombocytopenia and the other groups.

b 

Readmission rates are calculated from the survivors from the initial episode that required hospital admission.

c 

Differences between normal platelet count and the other two groups.

d 

One hundred eight patients (4.5%) presented with more than one respiratory complication as follows: four (7.5%) in the thrombocytopenia group, 91 (4%) in the group. with normal platelet counts, and 13 (6%) in the thrombocytosis group (P = .194).

Table Graphic Jump Location
Table 5 —Multivariate Logistic Regression Model for 30-d Mortality
Table Graphic Jump Location
Table 6 —Cause of Death

Data given as No. (%).

a 

Differences between thrombocytosis and the other groups.

b 

Differences between thrombocytopenia and the other groups.

Table Graphic Jump Location
Table 7 —Inflammatory Biomarkers

Data given as median (interquartile range). TNF = tumor necrosis factor.

a 

Differences between thrombocytosis and normal platelet count.

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