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Abstract

Background and objective:

Limited information is available regarding the impact of prior outpatient use of systemic corticosteroids (SCS) in patients subsequently developing community-acquired pneumonia (CAP). We investigate the effects of prior SCS on severity of illness, microbiology and clinical outcomes for patients hospitalized with CAP.

Methods:

A retrospective cohort study of subjects with CAP (according to International Classification of Diseases, 9th edition codes) was conducted over a 3-year period at two tertiary teaching hospitals. Subjects were considered to be SCS users if they received oral corticosteroids prior to admission. Primary outcomes were severity of illness, microbiology and 30-day mortality.

Results:

Data were abstracted on 698 patients [prior SCS users, 75 (10.7%) versus prior non-SCS users 623 (89.3%)]. Prior SCS users were more likely to have chronic obstructive pulmonary disease. No differences were found in severity of disease at admission, microbiological etiology including opportunistic and drug-resistant pathogens and clinical outcomes, including 30-day mortality, intensive care unit admission, length of hospital stay, need for mechanical ventilation and need for vasopressors.

Conclusion:

Prior SCS use is not associated with increased 30-day mortality for patients hospitalized with CAP. In addition, no differences were found in either the severity of the disease at the time of presentation or in the presence of the resistant or opportunistic pathogens among groups.

Keywords

corticosteroids drug resistance microbial mortality pneumonia severity of illness index

Introduction

Corticosteroids are anti-inflammatory agents widely used to treat many autoimmune and respiratory conditions. Corticosteroids influence the function of macrophages and granulocytes, the two major cells in host defenses against opportunistic and bacterial infections [Rhen and Cidlowski, 2005; Schacke et al. 2002]. Numerous reports of opportunistic pulmonary infections [Stuck et al. 1989; Conesa et al. 1995; Wiest et al. 1989; Maskell et al. 2003] and potentially highly resistant bacterial infections [Falguera et al. 2009; Sousa et al. 2012] have been described in patients receiving systemic corticosteroids.

Excessive inflammatory response has been linked as the main cause of death by infection in patients with community-acquired pneumonia (CAP) [Menendez et al. 2008, 2009; Jemal et al. 2005]. It has been postulated that the acute administration of systemic corticosteroids may act as immunomodulators of this excessive inflammatory response by attenuating inflammatory cytokines in patients with pneumonia and sepsis [Monton et al. 1999; Sibila et al. 2008a]. However, the use of systemic corticosteroids remains a matter of controversy due to the variable results [Confalonieri et al. 2005; Garcia-Vidal et al. 2007; Snijders et al. 2010; Meijvis et al. 2011]. Some authors have shown a benefit of the acute administration of corticosteroids in patients with severe CAP [Confalonieri et al. 2005; Garcia-Vidal et al. 2007]. However, a lack of improved clinical outcomes has precluded the generalizability of the use of systemic corticosteroids for patients with pneumonia [Snijders et al. 2010; Meijvis et al. 2011]. In addition, limited data are available about the impact of prior outpatient corticosteroid administration in patients subsequently developing CAP.

Therefore, our aim was to investigate the effects of prior outpatient systemic corticosteroid use on etiology, severity of illness and clinical outcomes for patients hospitalized with CAP.

Methods

This is a retrospective cohort study of patients hospitalized with CAP at two academic teaching tertiary care hospitals in San Antonio, TX. The Institutional Review Board of the University Health Science Center at San Antonio approved the research protocol with exempt status.

Study sites/inclusion and exclusion criteria

We identified all patients admitted to the study hospitals between 1 January 1999 and 31 December 2002 with a primary discharge diagnosis of pneumonia (International Classification of Diseases, 9th edition codes 480.0-483.99 or 485-487.0) or secondary discharge diagnosis of pneumonia with a primary diagnosis of respiratory failure (518.81) or sepsis (038.xx). Subjects were included if they were over 18 years of age, had an admission diagnosis of CAP, and had a radiographically confirmed infiltrate or other finding consistent with CAP on chest X-ray or computed tomography scan obtained within 24 h of admission. Exclusion criteria included having been discharged from an acute care facility within 14 days of admission, transfer after being admitted to another acute care hospital, having comfort measures only on this admission, and using inhaled corticosteroids (to avoid possible interferences between both steroid treatments). If a subject was admitted more than once during the study period, only the first hospitalization was abstracted

Data abstraction

Chart review data included demographics, comorbid conditions, physical examination findings, laboratory data, guideline-concordant empirical antibiotic therapy and chest radiographic reports. Comorbid conditions were identified from either the admission or discharge notes or outpatient problem lists. Antimicrobial therapy was considered guideline concordant if it agreed with the American Thoracic Society (ATS) guidelines [Niederman et al. 2001]. Information on all corticosteroid outpatient medications that were either reported as currently being taken by the patient at presentation, or listed in the electronic medical record were recorded. Systemic corticosteroid (SCS) therapy was defined if the patient was receiving systemic prednisone, hydrocortisone, cortisone, dexamethasone, fludrocortisones, or methylprednisolone.

Diagnostic criteria

Microbiologic data results were reviewed, and a microbiologic cause was assigned independently by two of the investigators (M.I.R. and E.M.M.). The cause of pneumonia was considered if one of the following conditions was met: positive blood cultures for bacterial or fungal pathogens (in the absence of extra-pulmonary source of infection); pleural fluid cultures yielding a bacterial pathogen; endotracheal aspirates with moderate or heavy growth of bacterial pathogens; significant quantitative culture growth from bronchoscopic respiratory samples (protected specimen brush cultures of at least 10³ cfu/ml, and in bronchoalveolar lavage of at least 10⁴ cfu/ml). When two or more microbiologic causes were present, the patient was considered to have a polymicrobial infection. A patient was considered to have CAP of unknown cause if microbiologic studies were not performed or inconclusive.

Drug-resistant pathogens were defined as having one of the following microorganisms: drug-resistant Streptococcus pneumonia (DRSP – including resistance to penicillins, fluoroquinolones, macrolides, or cephalosporins), methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumanii, extended spectrum β lactamases (ESBL), or multidrug-resistant Pseudomonas aeruginosa (resistance to three or more antimicrobial categories).

Clinical outcomes

Primary outcomes selected were severity of illness at the time of presentation defined by the pneumonia severity index (PSI) [Fine et al. 1997], CURB-65 [Lim et al. 2003], the presence of modified severe CAP criteria according to the Infectious Diseases Society of America (IDSA)/ATS guidelines [Mandell et al. 2007], and severe sepsis and septic shock according to the ACCP consensus statement [Bone et al. 1992]; presence of resistant or opportunistic pathogens; and 30-day mortality. The secondary outcomes included length of hospital stay, need for intensive care unit (ICU) admission, need for vasopressors, and requiring mechanical ventilation. Length of hospital stay was calculated as the date of discharge minus the date of admission excluding those who died during hospitalization.

Mortality was assessed using information from the Texas Department of Health and Department of Veteran Affairs clinical database.

Statistical analyses

For the statistical analyses, patients were stratified into either having received prior SCS or not. Bivariate statistics were used to test the association of demographic and clinical characteristics with primary and secondary outcomes. Categorical variables were analyzed using the χ² test and continuous variables were analyzed using Student’s t test. We created survival curves using a Cox proportional hazard model for the dependent variable of 30-day mortality adjusting for severity of illness. We used logistic regression to examine P. aeruginosa as the dependent variable and adjusted for chronic obstructive pulmonary disease (COPD). Two-sided p-values < 0.05 were considered statistically significant. All analyses were performed using SPSS version 19.0 for Windows (SPSS Inc., Chicago, IL, USA)

Results

We identified 698 patients who met the inclusion criteria. Out of these, 75 (10.7%) patients had received outpatient SCS prior to admission and 623 (89.3%) had not received prior SCS.

Patient characteristics

Table 1 shows the patients’ demographic characteristics whether or not they received outpatient SCS therapy. No significant differences were found for the mean age, physical exam, laboratory, and radiological data. Prior SCS users were less likely to be men and more likely to have COPD. A trend to have less pleural effusion was observed in the prior SCS group (16% versus 25%, p = 0.08).

Table 1.

Subject demographic and clinical characteristics by the use of outpatient SCS.*

	Non-SCS users (n = 623)	SCS users n = 75)	p-value
Age, years (mean ± standard deviation)	59.1 ± 16.5	60.3 ± 16.6	0.6
Men	490 (78.8)	50 (66.7)	0.02
Preexisting comorbid conditions
Congestive heart failure	93 (14.9)	10 (13.3)	0.7
Chronic pulmonary disease	134 (21.5)	26 (34.7)	0.01
History of stroke	84 (13.5)	6 (8.0)	0.2
Chronic liver disease	79 (12.7)	9 (12.0)	0.9
History of malignancy	54 (8.7)	10 (13.3)	0.2
Renal insufficiency	69 (11.1)	8 (10.7)	0.9
History, physical, laboratory, and radiographic data
Altered mental status	76 (12.2)	4 (5.3)	0.08
Respiratory rate > 30 per min	61 (9.8)	13 (17.3)	0.05
Systolic blood pressure < 90 mmHg	16 (2.6)	2 (2.7)	1.0
Heart rate > 125 per min	85 (13.6)	12 (16.0)	0.6
Temperature < 95° or > 104°	18 (2.9)	2 (2.7)	0.9
Arterial pH < 7.35	39 (6.3)	7 (9.3)	0.3
Arterial oxygenation saturation < 90%	131 (21.0)	22 (29.3)	0.1
Hematocrit < 30%	58 (9.3)	5 (6.7)	0.5
Serum blood urea nitrogen > 30 mg/dl	131 (21.0)	17 (22.7)	0.7
Serum glucose > 250 mg/dl	61 (9.8)	9 (12.0)	0.5
Serum sodium < 130 meq/liter	98 (15.7)	7 (9.3)	0.1
Pleural effusion on chest radiograph	157 (25.2)	12 (16.0)	0.08
Processes of care
Initial antibiotics within 4 h	171 (27.4)	23 (30.7)	0.6
Blood cultures prior to antibiotics	473 (75.9)	57 (76.0)	1.0
Guideline-concordant antibiotics	498 (79.9)	62 (82.7)	0.6

Data are presented as number (%).

SCS, systemic corticosteroids.

Microbiological findings

An etiologic diagnosis was found in 158 (23%) patients hospitalized with CAP (Table 2). Prior SCS users had similar rates of isolated pathogens, including S. pneumonia and S. aureus compared with non-SCS users.

Table 2.

Etiologic diagnosis with an identifiable pathogen in patients with community-acquired pneumonia by the use of outpatient SCS.*

	Non-SCS users (n = 623)	SCS users (n = 75)	p-value
Streptococcus pneumonie	49 (7.9)	3 (4.0)	0.2
Macrolide-resistant S. pneumoniae	24 (3.8)	1 (1.3)	0.3
Penicillin-resistant S. pneumoniae	6 (0.9)	1 (1.3)	0.6
Other Streptococcus	3 (0.4)	0	0.7
Staphylococcus aureus	32(5.1)	4(5.3)	0.9
MRSA	7 (1.1)	1 (1.3)	0.6
Pseudomonas aeruginosa	11 (1.8)	6 (8.0)	0.01
MDR P. aeruginosa	1 (0.2)	0	1.0
Haemophilus influenza	13 (2.1)	3 (4.0)	0.2
Escherichia coli	7 (1.1)	1 (1.3)	0.6
Klebsiella pneumonia	7 (1.1)	0	0.6
Proteus mirabilis	3 (0.4)	0	0.7
Enterococcus	1 (0.1)	0	0.9
Aspergillus spp	4 (2.0)	0	0.6
Polymicrobial	9 (1.4)	1 (1.3)	0.9
Drug-resistant pathogens	35(5.6)	3 (4.0)	0.4
Total pathogens isolated	140 (22.5)	18 (24.0)	0.7

Data are presented as number (percentage) of patients.

MDR, Multidrug resistant; MRSA, methicillin-resistant S. aureus; SCS, systemic corticosteroids.

P. aeruginosa was most commonly found in the prior SCS treatment group (8.0% versus 1.8%, p = 0.01). However, after adjusting for COPD, prior SCS use was not significantly associated with higher risk of P. aeruginosa [odds ratio (OR) 2.2, 95% confidence interval (CI) 0.9–5.8, p = 0.09). Opportunistic pathogens were not found in outpatient SCS users. No differences in resistant pathogens were found among groups.

Clinical outcomes

We compared multiple severity and clinical outcome scores at the time of presentation, and there were no statistically significant differences between groups (Table 3).

Table 3.

Pneumonia severity at admission and clinical outcomes.*

	Non-SCS users (n = 623)	SCS users (n = 75)	p-value
Pneumonia Severity Index score	90.0 ± 35.6	91.0 ± 32.0	0.8
CURB-65	1.28 ± 1.11	1.31 ± 1.08	0.8
Severe ATS	100 (16.1)	11 (14.7)	0.8
Severe sepsis	196 (31.5)	22 (29.3)	0.9
Septic shock	18 (2.9)	2 (2.7)	0.9
ICU admission	125 (20.1)	12 (16.0)	0.4
Mechanical ventilation	59 (9.5)	5 (6.7)	0.4
Vasopressors	27 (4.3)	3 (4.0)	0.8

Data are presented as number (%) or mean ± standard deviation

ICU, intensive care unit; SCS, systemic corticosteroids.

There was no statistically significant difference in overall 30-day mortality among outpatient non-SCS users and SCS users (9.6% versus 6.7%; p = 0.6). The mean length of hospital stay (LOS) was also similar among groups, with 7.2 [standard deviation (SD) 8.5] days in non-SCS users versus 6.1 (SD 5.7) days in SCS users (p = 0.8). No differences were found among groups for ICU admission, need for mechanical ventilation and need for vasopressors (Table 3).

In the Cox proportional hazard model, after adjusting for severity of illness, there were no differences in 30-day mortality between the two groups (Figure 1).

Figure 1.

Mortality over the first 30 days by prior use of systemic corticosteroids (SCS) after adjusting for severity of illness at presentation.

Discussion

The main finding of our study was that prior outpatient use of SCS is not associated with increased 30-day mortality for patients hospitalized with CAP. In addition, no differences in either the severity of the disease at the time of clinical presentation or in the presence of resistant or opportunistic pathogens were found among groups.

The relationship between systemic corticosteroids and pneumonia is one of the more important questions that has yet to be resolved in the field of respiratory infections. More than 50 years after the first publication about the effect of corticosteroids in pneumococcal pneumonia there is still significant controversy about the impact of SCS in patients hospitalized with CAP [Wagner et al. 1956]. Corticosteroids inhibit cytokines and other inflammatory molecules stimulated by bacterial infections, which could be harmful for the host. Furthermore, the use of steroids also suppresses the immune function of macrophages and granulocytes, the main cell host defenses against bacteria [Rhen and Cidlowski, 2005]. Several studies have shown that patients with any degree of immunosuppression tend to have more severe pneumonia than immunocompetent patients [Sousa et al. 2012; Sanders et al. 2006]. By contrast, an excessive inflammatory response has been described as a marker of pneumonia severity at admission [Menendez et al. 2009], and corticosteroids have also been postulated as modulators of that response [Rano et al. 2006]. Our study did not find differences in the severity of illness at admission, defined by different scores such as PSI [Fine et al. 1997], CURB-65 [Lim et al. 2003], severe IDSA/ATS criteria [Mandell et al. 2007], and severe sepsis and septic shock [Bone et al. 1992], suggesting that prior SCS use may not play such an important role, either for or against, in the severity of CAP at admission. However, a trend to less pleural effusion was observed in the SCS group.

Different reports have identified an increase in the incidence of different opportunistic infections of the lung, such as Aspergillus spp (4), Pneumocystis jirovecci (6), and Nocardia spp [Martinez et al. 2007] in patients taking outpatient corticosteroids. Our study did not identify any of these opportunistic microorganisms as the cause of pneumonia in hospitalized patients with CAP treated as outpatients with SCS. The most common pathogen isolated in our cohort of hospitalized CAP patients treated with outpatients SCS was P. aeruginosa. Numerous previous reports associated P. aeruginosa to corticosteroid use [Falguera et al. 2009] and to COPD [Murphy et al. 2008]. In our study, after adjusting for SCS and COPD, presence of P aeruginosa was only associated with COPD (OR 3.3, 95% CI 1.3–8.4, p = 0.01) and not to the use of outpatient SCS (OR 2.2, 95% CI 0.9–5.8, p = 0.09). Furthermore, we did not identify more potentially multi-drug-resistant pathogens in the prior SCS group. These findings suggested that prior corticosteroid administration might not be responsible for variation of habitual flora in CAP.

In addition, there were no differences in 30-day mortality and other clinical outcomes such as LOS, ICU admission, need for mechanical ventilation or vasopressors between groups in our study. Agusti and colleagues previously reported that patients with long-term SCS therapy (>30 days) prior to admission for severe pneumonia who require mechanical ventilation had higher a mortality rate than patients with short-term SCS therapy or patients with severe pneumonia without SCS treatment [Agusti et al. 2003]. The small and heterogeneous sample size evaluated (only nine patients with long-term SCS and mechanical ventilation) precludes comparisons with our findings. The rest of the studies that have studied the impact of SCS treatment on CAP mortality have evaluated the acute administration of SCS after CAP diagnosis, instead of the impact of the chronic outpatient use of SCS. The acute administration of SCS has been shown to be beneficial in decreasing 30-day mortality in patients with severe CAP [Confalonieri et al. 2005; Garcia-Vidal et al. 2007]. In contrast, other studies did not find the benefit of acute administration of SCS in patients hospitalized with CAP, making the generalizability of a recommendation that may impact clinical practice very complex [Snijders et al. 2010; Meijvis et al. 2011]. Currently, there are two randomized controlled trials that are assessing the efficacy of acute administration of SCS. One of these trials has completed subject enrollment and may disclose its final results soon. The other is a large randomized controlled trial in patients with severe CAP admitted to the ICU, with an expected sample size (n = 1450) which is currently enrolling patients (Extended Steroid in CAP – ESCAPe [ClinicalTrials.gov identifier: NCT01283009]).

Our study has several limitations. First, this is a retrospective study involving only two centers with a relatively small simple size. Second, our sample was predominately men due to the higher population of veterans enrolled in this cohort. It is unknown if prior SCS use in women would have similar results. And third, our cohort did not have information regarding the indication, dose, duration, and stopping of SCS. These are important since there are studies reporting that if given for a short period of time, the right dose may be favorable and result in an attenuated inflammatory response [Garcia-Vidal et al. 2007; Agusti et al. 2003; Sibila et al. 2008b]. Further studies should consider measuring inflammatory biomarkers when assessing immunomodulatory agents such as SCS.

In conclusion, prior SCS use in patients hospitalized with CAP was not associated with higher severity of the disease at presentation, etiology or clinical outcomes, including 30-day mortality. Further prospective cohort and randomized controlled trials are needed to overcome the limitations of our current study and prior studies, and to finally lay to rest the controversy of SCS in pneumonia.

Footnotes

Funding

This research was supported by the Howard Hughes Medical Institute faculty startup grant 00378-001 and a Department of Veteran Affairs, Veterans Integrated Service Network 17 new faculty grant. Dr Laserna and Dr Sibila are supported by Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR), Societat Catalana de Pneumologia (SOCAP) and Fundacio Catalana de Pneumologia (FUCAP). Dr Sibila is supported by Instituto de Salud Carlos III (BAE11/00102). Dr Restrepo’s time is partially funded by award number K23HL096054 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

The funding agencies had no role in the preparation, review, or approval of the manuscript. The views expressed in this article are those of the author and do not necessarily represent the views of the Department of Veterans Affairs.

Conflict of interest statement

Marcos I. Restrepo participated in advisory boards for Theravance, Forest Laboratories, Johnson & Johnson, Trius and Novartis. Consultant for Theravance, Trius and Pfizer (Wyeth).

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Impact of prior systemic corticosteroid use in patients admitted with community-acquired pneumonia

Abstract

Background and objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Study sites/inclusion and exclusion criteria

Data abstraction

Diagnostic criteria

Clinical outcomes

Statistical analyses

Results

Patient characteristics

Microbiological findings

Clinical outcomes

Discussion

Footnotes

Funding

Conflict of interest statement

References