Obstructive Lung Disease in HIV—Phenotypes and Pathogenesis
Purpose of Review
In the antiretroviral therapy era, people living with HIV (PLWH) are surviving to older ages. Chronic illnesses such as chronic obstructive pulmonary disease (COPD) occur more frequently. COPD is often described as a single entity, yet multiple manifestations may be considered phenotypes. HIV is an independent risk factor for certain COPD phenotypes, and mechanisms underlying pathogenesis of these phenotypes may differ and impact response to therapy.
Impaired diffusing capacity, airflow obstruction, and radiographic emphysema occur in PLWH and are associated with increased mortality. Age, sex, tobacco, and HIV-specific factors likely modulate the severity of disease. An altered lung microbiome and residual HIV in the lung may also influence phenotypes.
COPD is prevalent in PLWH with multiple phenotypes contributing to the burden of disease. HIV-specific factors and the respiratory microbiome influence disease pathogenesis. As tobacco use remains a significant risk factor for COPD, smoking cessation must be emphasized for all PLWH.
KeywordsChronic obstructive HIV Pulmonary Emphysema Phenotypes Pathogenesis
Compliance with Ethical Standards
Conflict of Interest
Deepti Singhvi declares that she has no conflict of interest.
Jessica Bon declares that she has received grants from the NIH and the VA.
Alison Morris has received grants from the NIH and Gilead.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Global HIV & AIDS statistics — 2018 fact sheet | UNAIDS. http://www.unaids.org/en/resources/fact-sheet. Accessed 23 Feb 2019.
- 2.Maitre T, Cottenet J, Beltramo G, Georges M, Blot M, Piroth L, et al. Increasing burden of noninfectious lung disease in persons living with HIV: a 7-year study using the French nationwide hospital administrative database. Eur Respir J. 2018;52:1800359. https://doi.org/10.1183/13993003.00359-2018.CrossRefPubMedGoogle Scholar
- 3.• Bigna JJ, Kenne AM, Asangbeh SL, Sibetcheu AT. Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis. Lancet Glob Health. 2018;6:e193–202. This study established the global prevalence of COPD in PLWH to be 10.6%, with a persistent association between COPD and HIV even when controlling for tobacco use. A higher prevalence was seen in those with higher income, more tobacco use, detectable viral load, and from European countries. CrossRefPubMedGoogle Scholar
- 9.Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2019 report. http://www.goldcopd.org. Accessed 22 Feb 2019.
- 15.• Risso K, Guillouet-de-Salvador F, Valerio L, Puglièse P, Naqvi A, Durant J, et al. COPD in HIV-infected patients: CD4 cell count highly correlated. PLoS One. 2017;12:e0169359. This study, a single center cross-sectional analysis of HIV-infected patients in France, found that low CD4 cell count and a low nadir CD4 cell count are independently associated with a diagnosis of COPD. CrossRefPubMedPubMedCentralGoogle Scholar
- 17.•• Li Y, Nouraie SM, Kessinger C, Weinman R, Huang L, Greenblatt RM, et al. Factors associated with progression of lung function abnormalities in HIV-infected individuals. J Acquir Immune Defic Syndr. 2018;79:501–9. This study demonstrated decreased DLCO in 79% of PLWH with faster rates of FEV1 decline in patients who were male with higher GOLD stage and older age. There was no difference in baseline FEV1 based on CD4 + count, viral load, or ART use. CrossRefPubMedGoogle Scholar
- 21.• MacDonald DM, Melzer AC, Collins G, et al. Smoking and accelerated lung function decline in HIV-positive individuals: a secondary analysis of the START pulmonary substudy. J Acquir Immune Defic Syndr. 2018;79:e85–92. In this secondary analysis of the START pulmonary substudy, the authors found a faster rate of annual decline in FEV1 in HIV-infected smokers compared to nonsmokers. CrossRefGoogle Scholar
- 22.•• Kunisaki KM, Niewoehner DE, Collins G, Aagaard B, Atako NB, Bakowska E, et al. Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial. Lancet Respir Med. 2016;4:980–9. This was a pulmonary substudy of a randomized controlled trial in which participants with HIV infection were randomized to immediate initiation of ART versus deferred until CD4 + cell count < 350 cells/μl. No difference was found between these groups in the rate of annual FEV1 decline, suggesting that the use of ART does not impact lung function decline. CrossRefPubMedPubMedCentralGoogle Scholar
- 31.•• Triplette M, Attia EF, Akgün KM, Soo Hoo GW, Freiberg MS, Butt AA, et al. A low peripheral blood CD4/CD8 ratio is associated with pulmonary emphysema in HIV. PLoS One. 2017;12:e0170857. In this study, the authors found that a low peripheral CD4:CD8 ratio is associated with radiographic emphysema and low DLCO in PLWH, suggesting that this blood test may be able to be used as a marker of emphysema in PLWH. CrossRefPubMedPubMedCentralGoogle Scholar
- 32.•• Leung JM, Malagoli A, Santoro A, Besutti G, Ligabue G, Scaglioni R, et al. Emphysema distribution and diffusion capacity predict emphysema progression in human immunodeficiency virus infection. PLoS One. 2016;11:e0167247. This study demonstrated that emphysema progression can be predicted based on radiographic emphysema distribution and DLCO values. PLWH who were more likely to have emphysema progression had higher baseline emphysema score and greater smoking exposure history. CrossRefPubMedPubMedCentralGoogle Scholar
- 39.• Akgün KM, Tate JP, Oursler KK, Crystal S, Leaf DA, Womack JA, et al. Association of chronic obstructive pulmonary disease with frailty measurements in HIV-infected and uninfected veterans. AIDS. 2016;30:2185–93. This study identified that while COPD is strongly associated with frailty in both HIV-infected and HIV-uninfected individuals, there is a stronger association in HIV-infected individuals. COPD is an independent risk factor for frailty in PLWH. CrossRefPubMedGoogle Scholar
- 43.• Petraglia A, Leader JK, Gingo M, Fitzpatrick M, Ries J, Kessinger C, et al. Emphysema is associated with thoracic vertebral bone attenuation on chest CT scan in HIV-infected individuals. PLoS One. 2017;12:e0176719. The authors in this study measured thoracic vertebral bone attenuation as a surrogate for bone mineral density on CT chest imaging in PLWH. They found that greater emphysema is independently associated with lower bone mineral density in PLWH and the use of ART further reduces this bone mineral density. CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Alwan A. (2011). Burden: mortality, morbidity, and risk factors. Global status report on noncommunicable diseases (pp. 9-31). Geneva, Switzerland: World Health Organization.Google Scholar
- 47.• Besutti G, Raggi P, Zona S, Scaglioni R, Santoro A, Orlando G, et al. Independent association of subclinical coronary artery disease and emphysema in HIV-infected patients. HIV Med. 2016;17:178–87. This study scored emphysema and coronary artery calcium on CT chest radiographs from PLWH and found the presence of emphysema is independently associated with a positive coronary artery calcium score. Radiographic emphysema was also associated with a CD4 + count nadir < 200 cells/μl. CrossRefPubMedGoogle Scholar
- 50.•• Triplette M, Justice A, Attia EF, Tate J, Brown ST, Goetz MB, et al. Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV. AIDS. 2018;32:487–93. This study demonstrated that airflow obstruction, DLCO, and emphysema are associated with increased mortality, independent of smoking exposure, in PLWH. PubMedPubMedCentralGoogle Scholar
- 51.•• Gingo MR, Nouraie M, Kessinger CJ, Greenblatt RM, Huang L, Kleerup EC, et al. Decreased lung function and all-cause mortality in HIV-infected individuals. Ann Am Thorac Soc. 2018;15:192–9. This study reported that both obstruction (FEV1/FVC < 0.7) and diffusion impairment (DLCO<60%) are associated with increased mortality in PLWH. The decrease in the Kaplan-Meier curve occurs earlier in time for diffusion impairment, suggesting that this may be an earlier marker of mortality. CrossRefPubMedPubMedCentralGoogle Scholar
- 63.Lai S, Starke CE, Flynn JK, Vinton CL, Ortiz AM, Mudd JC, et al. SIV infects functionally polarized memory CD4 T cells equivalently in vivo. J Virol. 2019;93. https://doi.org/10.1128/JVI.02163-18.
- 69.• Morris A, Paulson JN, Talukder H, Tipton L, Kling H, Cui L, et al. Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infection. Microbiome. 2016;4:38. In a study of microbiome analysis from serial bronchoalveolar lavage samples in nonhuman primates before and after infection with SHIV, half of the monkeys developed COPD over longitudinal follow-up and tended to have more oral bacteria in their BAL microbiota. There was no relationship between the presence of Tropheryma whipplei in BAL and the development of COPD. CrossRefPubMedPubMedCentralGoogle Scholar
- 80.Kling HM, Shipley TW, Guyach S, Tarantelli R, Morris A, Norris KA. Trimethoprim-sulfamethoxazole treatment does not reverse obstructive pulmonary changes in Pneumocystis-colonized nonhuman primates with SHIV infection. J Acquir Immune Defic Syndr. 2014;65:381–9.CrossRefPubMedPubMedCentralGoogle Scholar