Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization.
ABSTRACT 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 FEV(1) = 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.
- Nippon rinsho. Japanese journal of clinical medicine 08/1992; 50 Suppl:443-7.
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. The precise role of bacterial infection in the course and pathogenesis of COPD has been a source of controversy for decades. Chronic bacterial colonization of the lower airways contributes to airway inflammation; more research is needed to test the hypothesis that this bacterial colonization accelerates the progressive decline in lung function seen in COPD (the vicious circle hypothesis). The course of COPD is characterized by intermittent exacerbations of the disease. Studies of samples obtained by bronchoscopy with the protected specimen brush, analysis of the human immune response with appropriate immunoassays, and antibiotic trials reveal that approximately half of exacerbations are caused by bacteria. Nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common causes of exacerbations, while Chlamydia pneumoniae causes a small proportion. The role of Haemophilus parainfluenzae and gram-negative bacilli remains to be established. Recent progress in studies of the molecular mechanisms of pathogenesis of infection in the human respiratory tract and in vaccine development guided by such studies promises to lead to novel ways to treat and prevent bacterial infections in COPD.Clinical Microbiology Reviews 05/2001; 14(2):336-63. · 17.31 Impact Factor
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ABSTRACT: Previous studies have shown an increased number of inflammatory cells and, in particular, CD8+ve cells in the airways of smokers with chronic obstructive pulmonary disease (COPD). In this study we investigated whether a similar inflammatory process is also present in the lungs, and particularly in lung parenchyma and pulmonary arteries. We examined surgical specimens from three groups of subjects undergoing lung resection for localized pulmonary lesions: nonsmokers (n = 8), asymptomatic smokers with normal lung function (n = 6), and smokers with COPD (n = 10). Alveolar walls and pulmonary arteries were examined with immunohistochemical methods to identify neutrophils, eosinophils, mast cells, macrophages, and CD4+ve and CD8+ve cells. Smokers with COPD had an increased number of CD8+ve cells in both lung parenchyma (p < 0.05) and pulmonary arteries (p < 0.001) as compared with nonsmokers. CD8+ve cells were also increased in pulmonary arteries of smokers with COPD as compared with smokers with normal lung function (p < 0.01). Other inflammatory cells were no different among the three groups. The number of CD8+ve cells in both lung parenchyma and pulmonary arteries was significantly correlated with the degree of airflow limitation in smokers. These results show that an inflammatory process similar to that present in the conducting airways is also present in lung parenchyma and pulmonary arteries of smokers with COPD.American Journal of Respiratory and Critical Care Medicine 09/1999; 160(2):711-7. · 11.04 Impact Factor
Association of Chronic Obstructive Pulmonary Disease Severity and Pneumocystis
Alison Morris MD, MS1,2*, Frank C. Sciurba MD2, Irina P. Lebedeva3, Andrew Githaiga
MD2, W. Mark Elliott PhD4, James C. Hogg MD4, Laurence Huang MD5, Karen A.
1Department of Medicine, Division of Pulmonary and Critical Care Medicine, University
of Southern California, Los Angeles, CA
2Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine,
University of Pittsburgh, Pittsburgh, PA
3Department of Immunology, University of Pittsburgh, Pittsburgh, PA
4Universityof British Columbia, McDonald Research Laboratories, St. Paul’s Hospital,
Vancouver, BC, Canada
5Department of Medicine, San Francisco General Hospital, University of California, San
*Corresponding author: Alison Morris, MD, MS
Division of Pulmonary and Critical Care Medicine
2011 Zonal Avenue, HMR 911
Los Angeles, CA 90033
Supported by NIH HL072837 (AM), HL072117 (LH), and Canadian Institute for Health
Research #7246 (WME, JCH).
This manuscript has an Online Data Supplement which is accessible through this issue's
table of contents online at www.atsjournals.org.
Running head: COPD severity and Pneumocystis
Subject category: 50
Word count: 3221
AJRCCM Articles in Press. Published on April 29, 2004 as doi:10.1164/rccm.200401-094OC
Copyright (C) 2004 by the American Thoracic Society.
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 to 5.3% of smokers with normal lung
function or less severe COPD (stages 0, I, II, and III)(p=0.004) and to 9.1% of controls
(p=0.007). Colonized subjects exhibited more severe airway obstruction (median
FEV1=21% predicted vs. 62% in non-colonized, 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.
Abstract word count: 199
Key words: Pneumocystis jiroveci, chronic obstructive pulmonary disease, epidemiology
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. Recent interest has
focused on the potential role of infectious agents such as adenovirus, Chlamydia
pneumoniae, and other bacteria as co-factors in accelerating the progression of airway
obstruction (1-5). Pneumocystis jiroveci (formerly Pneumocystis carinii f. sp. hominis)
(6) is an eukaryotic opportunistic pathogen that causes pneumonia in
immunocompromised individuals and may be another pathogen involved in the
progression of COPD.
Although non-immunosuppressed 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 to
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 if
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 an
abstract (23, 24).
Word count: 521
Subjects: The smokers group were 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 performed at the Pneumocystis mitochondrial large sub-unit
(mtLSU) ribosomal RNA gene as previously described (26). Negative and positive
(DNA from lung tissue known to contain human Pneumocystis) controls were included.
All PCR was performed by personnel blinded to the subject identities, and all
reactions were carried out 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, gender, 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-one antitrypsin deficiency based on transplant pulmonologists’ evaluations. We
included those with alpha-one 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-one 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 six months prior to transplantation. Although respiratory cultures
from native lungs were not routinely tested, subjects were free of overt clinical infections
at transplantation. Type and dose of pre-transplant immunosuppression were recorded, as
was use of trimethoprim-sulfamethoxazole. Clinical data for smokers in GOLD 0-III
were obtained from medical records review and included age, gender, and smoking
Statistical analysis: Stata 7 (Stata Corporation, College Park, TX) was used for analysis,
and significance 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 Fisher’s exact. Odds ratios for colonization
were computed by comparing stage IV to other stages combined and to controls.