Pneumocystis in Pathogenesis of HIV-associated Emphysema (PACT)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2011 by University of Pittsburgh.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Cathy Kessinger, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT00869544
First received: March 25, 2009
Last updated: June 17, 2013
Last verified: February 2011
  Purpose

A. Statement of Hypotheses:

HIV-infected patients have an increased incidence of emphysema compared to non-HIV-infected smokers, and it has been hypothesized that this accelerated disease progression is the result of one or more latent infections that amplifies the pulmonary inflammatory response to cigarette smoke. Pneumocystis is one infectious agent that likely plays a key role in the development of HIV-associated emphysema. Colonization with Pneumocystis has been demonstrated in HIV-infected subjects, and HIV-infected smokers are particularly susceptible to Pc colonization regardless of CD4 cell count or use of prophylaxis. Pneumocystis colonization is also increased in non-HIV-infected patients with chronic obstructive pulmonary disease (COPD) and is directly related to the severity of the disease. The presence of Pneumocystis in the lungs, even at low levels as seen in colonization, produces inflammatory changes similar to those seen in COPD, with increases in the numbers of neutrophils and cytotoxic CD8+ lymphocytes. We propose that Pneumocystis accelerates emphysema in HIV-infected smokers by stimulating inflammation and tissue destruction. We will examine the role of co-infection with Pneumocystis in the pathogenesis of HIV-associated emphysema and the mechanism by which it causes emphysema progression. These studies will lead to information that will provide a rational basis for prevention and therapy of HIV-associated emphysema and provide a model for emphysema in the general population


Condition
HIV Infections
Pneumocystis Pneumonia
Emphysema
Chronic Obstructive Pulmonary Disease
Asthma

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pneumocystis in Pathogenesis of HIV-associated Emphysema

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Biospecimen Retention:   Samples With DNA

oral wash blood sputum BAL


Enrollment: 250
Study Start Date: August 2007
Estimated Study Completion Date: July 2013
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts
HIV
Those positive for HIV and those negative but at high risk for HIV. Both positive and negative for HIV who smoke and those who do not smoke. Both HIV positive and negative with and without asthma and/or COPD

  Hide Detailed Description

Detailed Description:

We propose that Pneumocystis accelerates emphysema in HIV-infected smokers by stimulating inflammation and tissue destruction. This grant will examine the role of co-infection with Pneumocystis in the pathogenesis of HIV-associated emphysema and the mechanism by which it causes emphysema progression. These studies will lead to information that will provide a rational basis for prevention and therapy of HIV-associated emphysema and provide a model for emphysema in the general population

antiretroviral therapy (HAART), impressive declines in morbidity and mortality from HIV have been seen [18]. These improvements do not constitute a cure, however; and over 400,000 people are currently living with HIV in the United States and there are 40 million people infected worldwide. With improved treatment and increases in life expectancy, incidence of other types of lung diseases such as HIV-associated emphysema and pulmonary hypertension may become more common. Respiratory symptoms are extremely common in the HIV-infected population, even among those without a history of pulmonary infections. HIV-infected subjects have been noted to have an accelerated form of chronic obstructive pulmonary disease (COPD)/emphysema [4, 5]. This disease is seen in those with untreated HIV disease and may become more common in the treated HIV population as it has frequently been reported in those without a history of AIDS-related pulmonary complications.

Smoking-related diseases such as emphysema are of particular concern in the HIV+ population. Smoking rates are high in this population and long term exposure to cigarette smoke in the setting of HIV infection may increase the number of complications seen. Smoking in the HIV+ population is associated with worse general health, physical functioning, quality of life, and cognitive functioning Before the HAART era, HIV+ subjects were noted to have an accelerated form of emphysema. Unlike many of the AIDS-defining opportunistic infections, HIV-associated emphysema may actually be more common in the current era of HIV as it is frequently reported in those without a history of AIDS-related pulmonary complications and because the aging HIV+ population has a longer exposure to smoking and HIV. HIV-associated emphysema was identified as a critical area for future research by a recent NIH workshop on pulmonary complications of HIV.

Whether emphysema continues to be increased in the HIV+ population in the HAART era is unknown. We hypothesize that emphysema may actually have increased as subjects live longer with chronic pulmonary exposure to the virus, to smoking, and to the inflammation that occurs in even treated HIV+ patients. We believe that prevalence will be increased compared to HIV- controls and that progression will be accelerated. Assessment of degree of emphysema and its distribution can be accomplished using quantitative CT morphometry density analysis. This technique measures lung density by pixel analysis expressed in Hounsfield units (HU) or its inverse (ml of gas/gram of tissue) which increases proportionately with the magnitude of emphysema. These measurements have been histologically-verified and give quantitative, reproducible measurements of percentage and distribution of lung considered normal, mildly emphysematous, and severely emphysematous. By adding the lung images to this protocol, we will be maximizing the information gained from this study with minimal increases in risk or subject inconvenience.

Pneumocystis jirovecii Based on our preliminary data in humans and primates, we believe that Pneumocystis (Pc) is one infectious agent that is critical in the pathogenesis of HIV-associated emphysema. Pneumocystis jirovecii (formerly known as Pneumocystis carinii f. sp. hominis)[19] is a eukaryotic pathogen that causes pneumonia in immunocompromised hosts. Despite the fact that PCP is responsible for a large degree of morbidity and mortality in immunosuppressed populations, little is understood about the organism's epidemiology. The recent development of molecular techniques to identify and genotype Pc has provided an important tool with which to explore the epidemiology of the organism. Polymerase chain reaction (PCR) detects low numbers of organisms, particularly in cases where routine histochemical staining methods are negative [21, 22]. Use of PCR, particularly nested PCR, for detection of Pc has led to discovery of the organism among asymptomatic subjects. The rate of colonization in asymptomatic HIV-infected subjects appears to be higher than that seen in the general population with estimates ranging from 12 to 46% depending on the subject population and respiratory samples studied [11, 12, 14, 16, 22].

Evidence linking HIV-associated emphysema and Pc colonization Pathogenesis of HIV-associated emphysema is not understood. The disease is likely multifactorial with contributions from smoking, HIV infection, and subclinical infections. Based on several lines of preliminary data, we believe that Pc plays a key role in development of HIV-associated emphysema. The evidence linking Pc and emphysema includes the high rates of both emphysema and Pc colonization in HIV-infected smokers, COPD-like changes that occur after PCP, an increase in Pc colonization in COPD that corresponds to disease severity and is independent of smoking history, and similarity between the inflammatory response in Pc colonization and COPD. The role of Pc colonization in HIV-associated emphysema has not been tested directly.

With the completion of the human genome project and advances in human genetic research, it is now possible for us to conduct comprehensive population genetic studies aimed at the identification of genetic factors associated with development of, and outcomes from, different diseases. Separately, newer technologies such as Luminex, microarray, SAGE, and proteomic analyses have made it possible to study expression profiles of thousands of genes. Simultaneous development of statistical methods to detect patterns of gene expression and link these patterns with clinical outcomes, have facilitated the identification of prognostic markers of disease (e.g. breast cancer and BRCA-1, and markers of tumor metastasis in melanoma). In particular, these studies both elucidate the mechanisms of disease pathogenesis, as well as identify targets for potential therapeutic intervention. It is crucial to the success of these scientific endeavors to link the cellular, protein, and gene expression and genetic data to clinical and demographic data on a large substrate of subjects, or the interpretation and results of these statistical analyses will be flawed.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

patients who have been determined to attend the UPMC HIV/AIDS program and/or participants in the Pitt Mens study.

Criteria

Inclusion Criteria:

  • Subject is Male / Female 18years of age or older.
  • Subject has been previously determined to be HIV-infected or has been participating in the Pitt Men's study or is seen at the UPMC HIV/AIDS program

Exclusion Criteria:

  • Subject is experiencing acute onset of shortness of breath, cough, fevers or heart conditions problems such as tachycardia, angina or arrhythmias
  • Female subject has told us she is pregnant (this might affect pulmonary function values,we will not require pregnancy testing.)
  • Subject has had an MI, CVA, or cardiovascular event within the past 3 months.
  • Subject has had eye or abdominal surgery within past 3 months.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00869544

Locations
United States, Pennsylvania
UPMC Montefiore Hospital, CTRC MUH, Keystone Bldg.
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Alison Morris-Gimbel, MD University of Pittsburgh
  More Information

No publications provided

Responsible Party: Cathy Kessinger, clinical research coordinator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00869544     History of Changes
Other Study ID Numbers: IRB0606151, 5RO1 HL083461 05
Study First Received: March 25, 2009
Last Updated: June 17, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
HIV
smoker
emphysema
antiretrovirals
COPD

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Asthma
Emphysema
Pulmonary Emphysema
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Pneumonia
Pneumonia, Pneumocystis
Lung Diseases, Obstructive
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Bronchial Diseases
Respiratory Tract Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Pathologic Processes
Respiratory Tract Infections
Lung Diseases, Fungal
Mycoses
Pneumocystis Infections

ClinicalTrials.gov processed this record on July 23, 2014