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Published ahead of print on April 29, 2004, doi:10.1164/rccm.200401-094OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 408-413, (2004)
© 2004 American Thoracic Society

Original Article

Association of Chronic Obstructive Pulmonary Disease Severity and Pneumocystis Colonization

Alison Morris, Frank C. Sciurba, Irina P. Lebedeva, Andrew Githaiga, W. Mark Elliott, James C. Hogg, Laurence Huang and Karen A. Norris

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, Los Angeles; Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; and University of British Columbia, McDonald Research Laboratories, St. Paul's Hospital, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Alison Morris, M.D., M.S., Division of Pulmonary and Critical Care Medicine, 2011 Zonal Avenue, HMR 911, Los Angeles, CA 90033. E-mail: alison.morris{at}usc.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Factors modulating the variable progression of chronic obstructive pulmonary disease (COPD) are largely unknown, but infectious agents may play a role. Because Pneumocystis has previously been shown to induce a CD8+ lymphocyte- and neutrophil-predominant response similar to that in COPD, we explored the association of the organism with accelerated disease progression. We examined Pneumocystis colonization rates in lung tissue obtained during lung resection or transplantation in smokers with a range of airway obstruction severity and in a control group with lung diseases other than COPD. Using nested polymerase chain reaction, Pneumocystis colonization was detected in 36.7% of patients with very severe COPD (Global Health Initiative on Obstructive Lung Disease [GOLD] Stage IV) compared with 5.3% of smokers with normal lung function or less severe COPD (Stages 0, I, II, and III) (p = 0.004) and with 9.1% of control subjects (p = 0.007). Colonized subjects exhibited more severe airway obstruction (median FEV1 = 21% predicted versus 62% in noncolonized subjects, p = 0.006). GOLD IV was the strongest predictor of Pneumocystis colonization (odds ratio = 7.3, 95% confidence interval = 2.4–22.4, p < 0.001) and was independent of smoking history. We conclude that there is a strong association between Pneumocystis colonization and severity of airflow obstruction in smokers, suggesting a possible pathogenic link with COPD progression.

Key Words: chronic obstructive pulmonary disease • epidemiology • Pneumocystis jiroveci

Smoking has long been recognized as the primary risk factor for the development of chronic obstructive pulmonary disease (COPD), but factors that determine which smokers will develop significant disease are largely unknown. Interest has focused on the potential role of infectious agents such as adenovirus, Chlamydia pneumoniae, and other bacteria as cofactors in accelerating the progression of airway obstruction (1–5). Pneumocystis jiroveci (formerly Pneumocystis carinii f. sp. hominis) (6) is a eukaryotic opportunistic pathogen that causes pneumonia in immunocompromised individuals and may be another pathogen involved in the progression of COPD.

Although nonimmunosuppressed hosts rarely develop Pneumocystis pneumonia (PCP), use of the polymerase chain reaction (PCR) has demonstrated that some groups of subjects have low levels of Pneumocystis DNA present in their lungs (7–11). Pneumocystis in these cases, which likely represents colonization or asymptomatic carriage, may lead to an exaggerated lung inflammatory response consisting primarily of CD8+ lymphocytes and neutrophils (12–16). These same cell types are thought to be important in the pathogenesis of COPD, and their numbers in the lung correlate with severity of airflow obstruction (2, 17–21).

Previous data are inconclusive in linking Pneumocystis colonization with COPD. One study found equivalent colonization rates in subjects with COPD compared with subjects with other lung diseases (22). Other data suggest that Pneumocystis colonization may be increased among those with COPD, but these studies were based on small numbers of subjects, did not document COPD by pulmonary function testing or pathology, and did not control for factors that might influence colonization or severity of COPD such as smoking (9, 11). We conducted a cross-sectional analysis to determine whether Pneumocystis colonization is associated with severity of COPD independent of smoking history. Some of the results of this study have been previously reported in the form of abstracts (23, 24).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The smokers group included current or former smokers categorized according to the Global Health Initiative on Obstructive Lung Diseases (GOLD) classification (25). GOLD 0 (normal spirometry, at risk), I (mild COPD), II (moderate COPD), and III (severe COPD) subjects were undergoing lung resection. GOLD IV (very severe COPD) subjects were undergoing lung transplantation. Control subjects were undergoing lung transplantation for primary pulmonary parenchymal disorders other than COPD. Lung tissue was obtained during surgery and snap-frozen. The University of Pittsburgh and University of British Columbia Institutional Review Boards approved the protocols.

DNA Preparation and PCR Amplification
DNA was extracted from a 1-cm3 sample of lung tissue, and nested PCR was performed at the Pneumocystis mitochondrial large subunit ribosomal RNA gene as previously described (26). Negative and positive samples (DNA from lung tissue known to contain human Pneumocystis) from control subjects were included. All PCRs were performed by personnel blinded to subject identities, and all reactions were performed in an identical manner.

DNA Sequencing
PCR products were purified and sequenced as previously described and determined to be Pneumocystis jiroveci (27).

Data Collection
Clinical data for GOLD IV and control patients were obtained from a prospective database. Demographic information included age, sex, and race. Primary diagnoses resulting in transplantation were determined. Subjects were defined as undergoing transplantation for COPD if they carried a diagnosis of emphysema/COPD or {alpha}-1 antitrypsin deficiency based on transplant pulmonologist evaluations. We included those with {alpha}-1 antitrypsin deficiency because factors mediating the variability of airway obstruction in these patients are poorly understood, even in individuals homozygous for the condition. Results were not significantly changed when excluding those with {alpha}-1 antitrypsin deficiency. All other diagnoses were considered non-COPD related. Other information recorded included spirometry, supplemental oxygen use, and diabetes mellitus. Smoking history included having ever smoked and number of pack-years smoked; subjects were required to have discontinued smoking for at least 6 months before transplantation. Although respiratory cultures from native lungs were not routinely tested, subjects were free of overt clinical infections at transplantation. Type and dose of pretransplant immunosuppression were recorded, as was use of trimethoprim–sulfamethoxazole. Clinical data for smokers in GOLD Stages 0–III were obtained from medical records review and included age, sex, and smoking history.

Statistical Analysis
Stata 7 (Stata, College Park, TX) was used for analysis, and significance was determined for a p value <= 0.05. Colonization status was determined for the smokers as a group and by GOLD stage. Rates of colonization were compared among GOLD stages, using test of trend and the Fisher's exact test. Odds ratios for colonization were computed by comparing Stage IV with other stages combined and with control subjects. Severity of obstruction based on FEV1/FVC and FEV1 and colonization was assessed by Mann–Whitney rank sum. Clinical characteristics of GOLD IV subjects were compared with those of control subjects. Univariate analyses were performed to determine clinical predictors of colonization in the entire cohort. For continuous variables, either the Mann–Whitney rank sum test or a t test was used. The {chi}2 test or Fisher's exact test was used for categorical variables. Spirometric measurements were expressed as a percentage of predicted normal values (28). Dichotomous variables using values above and below the median were created for analysis of spirometry values.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Smokers
Sixty-eight smokers were studied (10 in GOLD 0, 10 in GOLD I, 10 in GOLD II, 8 in GOLD III, and 30 in GOLD IV). Most were male (73.1%) and the median age was 60 years (range, 41–84 years). Median pack-years of smoking were 60 pack-years (range, 9–172 pack-years) and median FEV1 as a percentage of the predicted value was 46% (range, 12–120%). Subject characteristics for each GOLD stage are shown in Table 1 . Thirteen smokers (19.1%) were colonized with Pneumocystis as determined by a positive nested PCR result and confirmed by DNA sequencing.


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  		TABLE 1. Clinical characteristics of smokers according to gold stage

 
Pneumocystis Colonization and Severity of COPD
Among smokers, Pneumocystis colonization was associated with a higher GOLD stage (Table 2) . Colonized subjects appeared similar to noncolonized subjects in terms of age, sex, and pack-year smoking history. Colonized subjects had a higher median GOLD stage than did noncolonized subjects (four versus two, p = 0.001). No subjects in GOLD Stage 0 or I were colonized. Furthermore, the rate of colonization increased with increasing GOLD stage (p = 0.002 for test of trend) (Figure 1) , and the odds ratio (OR) for colonization of Stage IV patients compared with patients in the other stages was 10.4 (95% confidence interval [CI] = 2.1–51.9, p = 0.004). To determine whether Pneumocystis colonization increased COPD risk independent of smoking history, we adjusted the odds ratio for pack-year history and found that the association with COPD severity as determined by GOLD stage actually became stronger (adjusted odds ratio = 21, 95% CI = 2.3–191.6, p = 0.007). Average pack-year history by stage did not differ significantly (p = 0.39) (Table 1).


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  		TABLE 2. Clinical characteristics of gold stage 0–IV subjects according to pneumocystis colonization status

 


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  		Figure 1. Percentage of subjects colonized with Pneumocystis according to GOLD stage. GOLD = Global Health Initiative on Obstructive Lung Disease. Number of subjects per group: 0 = 10, I = 10, II = 10, III = 8, IV = 30.

 
Colonized subjects had significantly worse airway obstruction than did noncolonized subjects (Table 2). The median percent predicted FEV1 for colonized subjects was 21% compared with 62% for noncolonized subjects (p = 0.006), and the FEV1/FVC ratio was similarly decreased (32% in colonized subjects versus 54% in noncolonized subjects, p = 0.001). Colonized subjects were significantly more likely to have FEV1 and FEV1/FVC values below the cohort median, even when adjusted for pack-year smoking history (adjusted OR = 16.7, 95% CI = 1.78–157.2, p = 0.014 for FEV1; adjusted OR = 14.4, 95% CI = 1.6–127.7, p = 0.016 for FEV1/FVC).

Comparison with Control Subjects
Because colonization in the patients with severe COPD might have resulted from factors associated with end-stage lung disease rather than COPD itself, we compared clinical characteristics of the GOLD IV subjects and control subjects (Table 3) . As control subjects were all undergoing lung transplantation, they had severe lung diseases and were similar in overall health status to the GOLD IV subjects.


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  		TABLE 3. Clinical characteristics of gold stage IV subjects and control subjects*

 
There were 44 control subjects who underwent lung transplantation for diagnoses other than COPD. Reasons for transplantation included cystic fibrosis (n = 15) and idiopathic pulmonary fibrosis (n = 12). No subject had a history of immunodeficiency or PCP. Spirometry was performed an average of 194 days before transplantation. GOLD IV subjects were significantly older than control subjects (median age of 58 versus 42 years, p < 0.001). They were similar in terms of sex, race, oxygen dependence, and use of trimethoprim–sulfamethoxazole at time of transplantation. More control subjects tended to be receiving prednisone and at a higher dose, although the difference was not statistically significant. Only control patients carried a diagnosis of diabetes mellitus (15.9 versus 0%, p = 0.04); however, diabetes was not related to colonization (p = 0.73). As would be expected, GOLD IV subjects were more likely to have smoked and had a greater pack-year history of smoking. They also had a significantly lower FEV1 percent predicted value (21 versus 31%, p = 0.004) and FEV1/FVC (32 versus 69%, p < 0.001).

Four control subjects (9.1%) were colonized with Pneumocystis in the explanted lung at the time of transplantation. When compared with control subjects, GOLD IV subjects had a significantly higher rate of colonization (36.7%, OR = 5.8, 95% CI = 1.6–20.6, p = 0.007). The rate of colonization was similar in control subjects and other GOLD stages (5.4% for GOLD Stage 0–III, OR = 0.55, 95% CI = 0.1–3.2, p = 0.56).

Two subjects developed PCP after transplantation. Both were GOLD IV subjects who had Pneumocystis colonization of their native lungs before transplantation. These cases occurred between 104 and 154 days after transplantation and were diagnosed by bronchoscopic alveolar lavage. The subjects both had single-lung transplantation and were receiving prophylaxis with trimethoprim–sulfamethoxazole at the time of diagnosis.

Predictors of Pneumocystis Colonization
Univariate analyses were performed to determine clinical predictors of colonization in the entire cohort of smokers and control subjects (Table 4) . Data for some variables were not available for the GOLD Stage 0–III subjects; however, none of these variables (prednisone use, diabetes mellitus, trimethoprim–sulfamethoxazole use, and oxygen use) was found to be relevant to colonization when comparing GOLD IV with control subjects. Univariate analyses demonstrated that age, sex, history of smoking, and number of pack-years were not related to colonization risk in the cohort as a whole. The most significant clinical predictor of Pneumocystis colonization was a diagnosis of very severe (GOLD IV) COPD (OR = 7.3, 95% CI = 2.4–22.4, p < 0.001). In addition to COPD, both a low FEV1 and a low FEV1/FVC were predictive of colonization. FEV1 and FEV1/FVC were clinically and statistically correlated with a diagnosis of severe COPD (p < 0.001), and once Pneumocystis colonization risk was adjusted for a severe COPD diagnosis, neither were independently predictive of risk.


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  		TABLE 4. Univariate risk factors for pneumocystis colonization

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we demonstrated that Pneumocystis colonization was associated with severity of airway obstruction in a cohort of patients at risk for COPD. Colonization was not increased in subjects with severe lung disease from causes other than COPD. In addition, the association of colonization with severe COPD was not explained by clinical factors such as age, use of immunosuppressive medication, or the presence of comorbid conditions.

Use of PCR for detection of Pneumocystis has led to discovery of Pneumocystis DNA in subjects without clinical PCP. The presence of Pneumocystis in respiratory specimens from subjects without signs or symptoms of clinical infection and without progression to PCP has been defined as colonization. Colonization has not generally been detected in healthy subjects (29–31), but rates of colonization in human immunodeficiency virus (HIV)–infected subjects may be as high as 69% (32). Rates of colonization in patients with chronic lung diseases range from 7 to 41% (7–10), and colonization in the non–HIV-infected host has been shown to be more common in subjects with a CD4+ T cell count below 400 cells/µl and a CD4+ T cell/CD8+ T cell ratio of less than one (33).

This study examined clinical variables that might affect Pneumocystis colonization in a well characterized subject group. By comparing colonization in subjects with equivalent smoking histories, we were able to assess Pneumocystis as a factor that may affect differential progression of COPD in smokers. By comparing colonization status in transplant patients with equivalent severity of lung disease, we were able to examine the specific association of Pneumocystis and COPD. We have thus shown an association between Pneumocystis colonization and severity of COPD and demonstrated that colonization is not a result of other clinical factors or comorbid conditions.

Previous work has been contradictory regarding detection of Pneumocystis in those with COPD. One study found that there was no increase in the risk of colonization in subjects with COPD (22). These results may differ from ours because the authors studied a population with less severe obstruction. Average FEV1 in their study was 2.1 L/min, a value much higher than the average of our colonized patients with COPD (mean FEV1 = 0.8 L/min). Another series that studied patients with chronic sputum production during a time of exacerbation found that 10% had Pneumocystis detectable by standard staining methods of sputum (7). This rate might be lower than in our population because Pneumocystis colonization was determined by microscopic examination and not by PCR. Probst and colleagues reported a colonization rate of 41% in 37 subjects with COPD on the basis of nested PCR of various respiratory samples (9). Helweg-Larsen and coworkers found that 43% of 23 subjects with COPD were colonized (11). However, these subjects were hospitalized with respiratory symptoms and therefore might have a different colonization rate than at baseline. Pulmonary function data and smoking history were not reported for subjects in either study, and results were not controlled for other clinical variables that might influence colonization. An additional difficulty with all studies of Pneumocystis colonization is the inability of PCR to determine viability of the organism.

Other microbiologic agents have also been implicated in the pathogenesis of COPD progression in smokers. Retamales and colleagues, using a study design similar to ours, have reported a higher rate of detection of adenovirus E1A protein in lung tissue of smokers with emphysema compared with age- and smoking-matched control subjects without evidence of airway obstruction (2). On the basis of elevated levels of CD8+ lymphocytes and interferon-{gamma} in lung samples, the authors speculated that the presence of latent adenovirus in the lungs provokes a heightened inflammatory response that leads to worsening of airway obstruction. Data from animals support this hypothesis, as guinea pigs with adenoviral infections have a more pronounced inflammatory response and accelerated emphysema development compared with noninfected control subjects (34).

Occult bacterial infections with organisms such as Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis have also been implicated in COPD progression. The vicious circle hypothesis proposed by Sethi and Murphy postulates that bacterial colonization of the lower respiratory tract leads to amplification of chronic inflammation and worsening airway obstruction (3, 35). Previous work has shown high levels of bacterial colonization in subjects with COPD and also demonstrated that bacterial colonization is associated with increased numbers of inflammatory cells and cytokines (5, 36). One study found that subjects with increases in sputum bacterial load had higher sputum interleukin (IL)-8 levels and more rapid declines in FEV1 than those with lower levels of bacterial colonization (5). Other investigators have demonstrated elevated IL-8, tumor necrosis factor-{alpha}, and neutrophil elastase in subjects with bacterial colonization during acute exacerbations (17, 36, 37).

Pneumocystis may accelerate progression to COPD through a similar inflammatory mechanism. One study of simian immunodeficiency virus–infected macaques reported that animals colonized with Pneumocystis had a T lymphocyte influx in lung lavage fluid composed of more than 90% CD8+ T cells (16). This influx was greater than that seen in simian immunodeficiency virus-infected animals without Pneumocystis and was not reflected by peripheral blood lymphocyte levels. Lung neutrophil levels, IL-8, and interferon-{gamma} were also significantly increased in Pneumocystis-colonized macaques (26). This inflammatory response developed well before the onset of PCP in the animals. Studies of HIV- and non–HIV-infected human subjects with PCP have also shown a sharp increase in the number of CD8+ cells and neutrophils in the lung (12–15).

The clinical significance of inflammation resulting from Pneumocystis is unknown, but the host response to Pneumocystis resembles that of COPD. COPD is characterized by inflammation of peripheral airways and destruction of lung parenchyma resulting in airflow limitation. The exact nature of the inflammatory changes that occur in COPD and how these differ from those seen in smokers without lung disease are not completely understood, but high levels of neutrophils and lymphocytes, particularly CD8+ lymphocytes, appear to play a critical role. The number of CD8+ lymphocytes in the lung correlates directly with the degree of airflow limitation (2, 18–20). Numbers of neutrophils and IL-8 levels are also correlated with severity of disease (17, 19, 21).

There is some previous evidence linking Pneumocystis to COPD-like changes. The Pulmonary Complications of HIV Infection Study, a prospective cohort of more than 1,100 HIV-infected subjects monitored for a median of 4 years, included serial pulmonary function studies of subjects at predefined intervals and after an episode of pneumonia. HIV-infected subjects with PCP had accelerated declines in FEV1, FEV1/FVC, and diffusing capacity beyond that expected from age and smoking history. These changes in pulmonary function were indistinguishable from those seen clinically with COPD and persisted for years after the acute infection resolved (38). Furthermore, the accelerated progression of emphysema in HIV-infected subjects described by Diaz and coworkers may be present in the absence of an overt history of PCP infection and may be related to occult infection with microorganisms such as Pneumocystis (39–42).

Specific factors that render the lung susceptible to Pneumocystis colonization are not known. Previous work has found that smoking is an independent risk factor for colonization in HIV-infected subjects (43), but the mechanism through which this occurs has not been elucidated. It is possible that structural remodeling associated with COPD renders smokers more likely to become colonized and/or less able to clear subclinical infection. Once colonization with Pneumocystis is established, the organism might stimulate chronic inflammation that facilitates accelerated decline with or without the persistence of tobacco exposure. Possible factors that may increase the likelihood of colonization or decrease the lung's ability to clear the organism include defects in mucociliary clearance and surfactant abnormalities produced by smoking (44–48).

Although the association of Pneumocystis with a diagnosis of COPD is intriguing, the current study cannot provide definitive conclusions regarding cause and effect. Because subjects were tested at a single time point, we do not have information about the time course of colonization relative to disease progression. We also cannot determine whether Pneumocystis colonization results in acceleration of COPD or if some factor unique to COPD results in Pneumocystis colonization. The design of the study, by using a control group with similarly severe lung disease and overall health status, minimizes the possibility that colonization is merely associated with end-stage lung disease. Because we tested only for Pneumocystis, other occult infections may also have been present in these subjects. It is interesting, however, that subjects with cystic fibrosis and bronchiectasis, diseases in which airway colonization is prominent, did not have an increased detection of Pneumocystis colonization. Pneumocystis may act alone or in concert with other organisms to provoke inflammation and lung damage, and the relationship of Pneumocystis and colonization with various organisms should be explored in future studies. In addition to direct studies of colonization, studies of serologic responses to Pneumocystis and other organisms might also help in understanding the role of these infections in airway obstruction.

In summary, we have shown that there is a strong association of Pneumocystis colonization and severity of airflow obstruction in subjects at risk for COPD. Colonization is disproportionately increased among those with severe COPD compared with other smokers and compared with subjects with end-stage lung diseases not related to COPD. These findings suggest that Pneumocystis is an infectious agent that may play a role in the accelerated progression of airway obstruction. The pronounced pulmonary inflammatory response that occurs in response to Pneumocystis may contribute to the pathogenesis of airway and parenchymal damage in smokers or individuals with structural airway obstruction. Because infectious agents such as Pneumocystis are potentially treatable, future studies are needed to further define the nature of Pneumocystis colonization in COPD and its role in disease pathogenesis.


   Acknowledgments
 
The authors thank Joseph Pilewski, M.D., Joseph LaToche, Kenneth McCurry, M.D., Judi Vensak, Jan Manzetti, Lisa Kyper, and the University of Pittsburgh Transplantation Service for graciously providing tissue samples. They also thank Edward D. Crandall, Ph.D., M.D., for review of the manuscript.


   FOOTNOTES
 
Supported by NIH HL072837 (A.M.), HL072117 (L.H.), and Canadian Institute for Health Research 7246 (W.M.E. and J.C.H.).

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; F.C.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.P.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.A.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 21, 2004; accepted in final form April 27, 2004


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 METHODS
 RESULTS
 DISCUSSION
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