Pulmonary immunocompromise in HIV disease

INTRODUCTION

The Human Immunodeficiency Virus (HIV) is a paradigmatic immunocompromised state that has profound impacts on pulmonary health, resulting in an increased burden of acute and chronic pulmonary diseases among people with HIV (PWH). The spectrum of pulmonary disease in PWH across the lifespan has shifted from acute, infectious, and AIDS-defining illnesses to a greater burden of chronic, non-communicable processes, including chronic obstructive pulmonary disease (COPD), pulmonary hypertension, post-tuberculosis lung disease (PTLD), lung cancer, and possibly asthma. The immune compromise associated with HIV continues to contribute to greater risk of acute infectious, opportunistic and AIDS-defining pulmonary diseases including bacterial, mycobacterial, viral, and fungal pneumonias and lymphocytic interstitial pneumonia (LIP), especially among those with detectable viral load. With expanding global access to contemporary antiretroviral therapy (ART) and improved survival, PWH are also at increased risk of the aforementioned chronic pulmonary diseases. Risk factors for pulmonary disease include HIV and HIV-related immunosuppression, tobacco smoking, inhaled pollutants, prior pulmonary infections, sex differences and disparities in social determinants of health, and differ in prevalence across high-income countries and low- and middle-income countries (LMICs). The pathogenesis of pulmonary disease in PWH is complex and includes potentially concurrent mechanisms such as chronic inflammation, innate and adaptive immune dysfunction, direct HIV infection and viral protein effects, oxidative stress, pulmonary and gut microbiome alterations, epigenetic changes and individual ART medications. These were comprehensively reviewed by Konstantinidis, et al.¹ There are sparse data to specifically guide prevention, diagnosis and management of pulmonary diseases for PWH, and most recommendations are drawn from those for the general population. However, recent and ongoing clinical trials suggest there may be interventions that can be targeted to PWH to mitigate the burden of chronic pulmonary disease and improve lung health globally.

Here, we review the epidemiology and risk factors of pulmonary disease in PWH across the lifespan during the contemporary ART era. We focus on recommendations for clinical care of pulmonary disease relevant to PWH, including emerging data from recent and ongoing clinical trials. Finally, we highlight future considerations for advancing clinical research in this field.

EPIDEMIOLOGY AND RISK FACTORS

Globally, there are 39 million PWH, of whom 1.5 million are children. The vast majority of PWH live in the LMICs of sub-Saharan Africa (66%) followed by southeast Asia (10%) and the Americas (8%). An estimated 25% of the world’s population is infected with Mycobacterium tuberculosis (M.tb), and up to 10% will progress to active TB disease during their lifetime.² Among PWH, especially those living in TB endemic regions, these rates are up to 30 times higher.³ Lower respiratory infections, including pulmonary TB along with bacterial, viral and fungal pneumonia, are a leading cause of morbidity and mortality worldwide, accounting for >90 million disability-adjusted life-years (DALYs) and >2 million deaths annually.^4–7 Lower respiratory infections along with HIV represent two of the top four contributors to DALYs sub-Saharan Africa. Importantly, the epidemiology of lower respiratory infections varies geographically. While TB and bacterial pneumonia caused by pathogens including Staphylococcus aureus, Streptococcus pneumoniae and some Gram-negative bacilli are common in sub-Saharan Africa, in Asia, bacterial pneumonia caused by Burkholderia pseudomallei (i.e., melioidosis) and fungal pneumonia caused by Talaromyces marneffei (i.e., talaromycosis) are unique pathogens in addition to M.tb. In temperate regions of the world, fungal pneumonia caused by Histoplasmosis capsulatum is an important consideration. The Pneumonia Etiology Research for Child Health (PERCH) Study South African and Zambian sites found that bacterial pneumonia caused by S.aureus and S.pneumoniae along with PCP and M.tb were the most common causes of severe pneumonia among hospitalized children with HIV, carrying a substantially higher related case fatality rate compared to children without HIV.^8–10

Additionally, up to 80% of chronic pulmonary disease morbidity and mortality occurs in LMICs where people are more often subject to concurrent and overlapping risk factors.¹¹ Importantly, chronic pulmonary disease may be underdiagnosed in LMICs in the setting of limited access to respiratory medicine specialists and diagnostic modalities.^12,13 Epidemiologic studies estimate COPD prevalence among PWH to be up to 38% in high-income settings^14–17 but only up to 22% in LMICs.^18–20

HIV and HIV-related immunosuppression

HIV itself is an important risk factor for acute and chronic pulmonary conditions through direct virally-mediated effects, indirectly via pathways of HIV-associated immunosuppression and/or inflammation, immune activation, and endothelial and epithelial dysfunction. However, HIV may also increase risk of pulmonary disorders by synergistically interacting with other exposures and risk factors.

The risk of acute and chronic pulmonary conditions increases with greater HIV-related immunosuppression. Although risk of some acute pulmonary infections varies with the degree of current immunosuppression (Figure 1), pneumonia due to bacterial pathogens and respiratory viruses, such as influenza, SARS-CoV-2, parainfluenza, human metapneumovirus, adenovirus, and, in children, respiratory syncytial virus (RSV), may occur at any CD4+ T-cell count. Bacterial pneumonia is the most common pulmonary infection among PWH in high-income settings. While all-cause hospitalizations in PWH have declined, there may be an increase in hospitalizations for bacterial pneumonia.²¹ Although the risk of bacterial pneumonia decreases as CD4+ increases, PWH have a 25-fold higher risk of bacterial pneumonia compared to people without HIV.²² Associated invasive disease, including bacteremia, is more common among PWH, and streptococcal pneumonia is linked with a 60-fold increased risk of invasive disease. Although current evidence suggests a greater risk of severe COVID-19 and related mortality among PWH across the spectrum of HIV severity,^23,24 low CD4+ is an independent risk factor for COVID-19 severity.²⁵ As the prevalence of immune reconstitution and viral suppression has improved in high-income countries, Pneumocystis jirovecii pneumonia (PCP), TB and LIP have become less frequent AIDS-defining illnesses.²⁶ Yet, mortality remains 3-fold higher among PWH hospitalized with PCP compared to those hospitalized for other reasons.^{26 27} In LMICs, PCP prevalence is less certain due to lack of molecular diagnostic techniques, awareness, and challenges with sample collection by sputum induction or bronchoscopy, but data support that it is also downtrending.²⁸ Nonetheless, the PERCH study in sub-Saharan Africa isolated Pneumocystis in 25% of children with HIV, finding PCP to be a major cause of severe pneumonia. Tuberculosis is a key co-infection in LMICs where it is endemic, and remains a global contributor to morbidity and mortality. Advanced HIV increases the risk of developing active TB by at least 20-fold among people with LTBI, while PWH with well-controlled HIV infection have a 4-fold increased risk compared to the general population. Chronic pulmonary conditions, including emphysema²⁹, reduced lung function¹⁵, and lung cancer³⁰ may be more likely to occur at lower nadir CD4+ T-cell counts.

Figure 1. Risk of pulmonary infections varies by CD4+ T-cell count.

*These infections are more likely to occur in children compared to adults.

ǂCan occur in CD4+ T-cells of up to 100 cells/μL in children.

CMV, cytomegalovirus; GNR, gram-negative rods (bacilli); NTM, non-tuberculous mycobacteria; S.aureus, Staphylococcus aureus; TB, tuberculosis; VZV, varicella zoster virus.

Importantly, children with perinatal HIV exposure who are negative (CPHEN) have increased risk for pulmonary infections. In an urban center in Zambia with high-density living and high levels of poverty, mortality among CPHEN hospitalized with pneumonia (21%) is nearly twice that of children unexposed to HIV (11%), though these estimates are substantially lower than mortality in children with HIV (40%).^10,31 Interestingly, PCP was present in 11% of CPHEN compared to only 1% of unexposed children, most of whom were infants.

Pulmonary infections

Large epidemiologic studies in the general population support that acute pulmonary infections are associated with poorer pulmonary health outcomes later in life. In a contemporary cohort of PWH, respiratory viruses, often with M.tb or Pneumocystis coinfection, were associated with decline in pulmonary function during acute infection followed by improvement over the ensuing year.³² Among PWH who have documented bacterial pneumonia or TB, 31% have preserved ratio impaired spirometry (PRISm) at least three months after completing treatment.³³ Emerging data suggest that PTLD is an important consequence of pulmonary TB in PWH, and up to 33% of PWH in LMICs have findings consistent with PTLD after TB cure.³⁴ PWH with prior PCP have increased evidence of restriction and diffusion impairment on pulmonary function testing.³⁵ Though not necessarily reflective of prior CMV pneumonia, CMV seropositivity is associated with worse lung function in adolescents with HIV³⁶, and greater COPD mortality and lung function decline in adults without HIV.^37,38

Tobacco smoking

Cigarette smoking is a key risk factor for acute infectious pulmonary diseases such as pneumonia, as well as COPD that is more severe at younger ages. While this is most relevant in high-income countries, where smoking is more prevalent among PWH compared to people without HIV,³⁹ cigarette smoking and secondhand smoke exposure are increasing in prevalence in LMICs and may become increasingly important risk factors in these settings.⁴⁰ In a simulation modelling study among PWH with assumed virological suppression in South Africa, tobacco smoking decreases life expectancy more than HIV.⁴¹ PWH who smoke are at higher risk for COPD and lose lung function faster than PWH who do not smoke.^42,43 Similarly, smokers with HIV experience greater lung damage than smokers who do not have HIV, despite differences in quantity of tobacco exposure.⁴⁴ Pathophysiologic drivers of accentuated smoking-related lung damage among PWH are not fully understood; recent data suggest that smoking can inhibit CD8+ T-cell trafficking from airway mucosa into airspaces after they are recruited to the lungs in the setting of HIV. The resulting increase in CD8+ T-cells in the airway mucosa may be responsible for accelerated inflammation and remodeling, thereby leading to COPD in PWH.⁴⁵

Air pollution

Similar to their enhanced susceptibility to tobacco-related pulmonary disease, PWH may also experience heightened susceptibility to air pollution-associated pulmonary disease. Air pollution is responsible for >8 million deaths annually,⁴⁶ and has surpassed tobacco as the leading cause of pulmonary disease in most of the world.⁴⁷ Air pollution sources and concentrations vary geographically, with traffic- and industry-related pollutants as predominant exposures in urban areas and biomass-related pollutants as predominant exposures in rural areas and LMICs.⁴⁸ However, with the ongoing global focus on reducing household air pollution, ambient air pollution is now responsible for more than half of global air pollution-related mortality.⁴⁶

Air pollution is responsible for a wide range of pulmonary health effects across the lifespan from in utero through adulthood. Air pollution drives accelerated lung function decline, structural lung abnormalities, development of and exacerbations of chronic pulmonary disease, impaired lung growth in early life, increased lung cancer risk, and susceptibility to and severity of pulmonary infections. There is no documented safe exposure threshold.

Potential heightened susceptibility to air pollution-related pulmonary disease among PWH is an area of ongoing research. Importantly, air pollution exposure is associated with increased TB incidence and impaired immune response to TB infection. Additionally, personal exposure to short-term air pollution levels that exceed World Health Organization (WHO) standards are associated with increased odds of respiratory symptoms among PWH but not people without HIV.⁴⁹ The growing global environmental health crisis is hindering ongoing progress in improving pulmonary health among PWH. A wider lens on this underappreciated driver of poor pulmonary health is crucial to sustaining progress in improving life expectancy and quality of life among PWH globally.

Sex differences

Although HIV is more common among men in high-income settings, women and girls account for nearly two-thirds of new HIV diagnoses in sub-Saharan Africa, and comprise over half of PWH worldwide.⁵⁰ Importantly, research characterizing HIV-associated pulmonary disease has occurred within cohorts of predominantly men.⁵¹ However, recent studies provide illuminating preliminary data. Among largely non-smoking Ugandan adults, women with HIV experienced greater FEV1 decline compared to women without HIV, but similar differences were not detected in men.⁵² Among Ugandan PWH, women had 3-fold increased odds of obstructive lung disease compared to men.⁵³

Based on data supporting an influence of sex on pulmonary disease in the general population, it is likely that women and girls with HIV face accentuated pulmonary disease risk. Women who smoke have higher COPD risk,⁵⁴ worse lung function,⁵⁵ more exacerbations,⁵⁶ faster disease progression,^57,58 and higher lung cancer risk⁵⁹ compared to men who smoke, even at similar levels of tobacco exposure. While global COPD mortality is declining among men, mortality among women is rising.⁶⁰ Women tend to have small airways-focused lung damage and a bronchitis phenotype while men have more emphysema-predominant disease.^55,61,62 Genetic variants associated with lung development and/or function are located on the X-chromosome and may be relatively over-expressed among women^63,64 or exhibit sex-specific DNA methylation patterns.⁶⁵ Ovarian sex hormones play a less elucidated role in lung homeostasis.⁶⁶ Sex steroid receptors are present in lung tissue, and lung function varies physiologically across the menstrual cycle.⁶⁷ At steady state, estrogens maintain alveolar structural stability⁶⁸ and progesterone promotes airway smooth muscle relaxation.⁶⁹ However, estrogens can be pro-inflammatory and induce airway proteases, which may drive higher tobacco metabolite levels in lung tissue of female smokers.⁷⁰ Nonetheless, decreased 17β-estradiol at menopause is associated with worse lung inflammation.⁷¹ Lastly, earlier age at menopause is associated with lung dysfunction,⁷² and women with HIV may experience more advanced reproductive aging.⁷³

Social determinants of health

Social determinants of health (SDoH) are defined by the WHO as “conditions in which people are born, grow, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life.”⁷⁴ SDoH are key contributors to inequities and suboptimal outcomes in healthcare, including at the intersection of HIV and pulmonary disease.^4,75,76 These nuanced factors, including disparities in economic circumstances, stigma, access to care and other social conditions are challenging to measure, model, and map, resulting in limited effective interventions and resource allocation. These factors along with known biological risk factors for pulmonary disease have historically been studied in isolation. There is a gap in the understanding of how biologic and social factors comprise a bio-social feedback loop to influence the risk of acute and chronic pulmonary conditions among PWH. Importantly, most PWH live in LMICs where there is a greater prevalence of non-communicable chronic diseases, air pollution, undernutrition, substance use and poverty; SDoH are therefore tightly woven into the fabric of risk factors and disease burden for PWH. For instance, in LMICs, women are responsible for meal preparation, often over open-flame stoves, which increases pollution-associated COPD risk.⁷⁷ Additionally, socioeconomic disadvantage and lower education – more common among women, particularly in resource-constrained settings⁷⁸ – are also associated with increased COPD risk.⁷⁹ Even in high-income settings, PWH have an increased risk of COPD that seems to be driven by smoking and socioeconomic disadvantage.⁴² Because these biologic and social factors often co-exist, they may interact in complex ways to adversely impact outcomes of acute and chronic pulmonary conditions, suggesting the presence of syndemics.^80–82 Syndemic theory has the potential to lead to novel, tailored, multipronged interventions for PWH who have pulmonary conditions. These can be implemented sequentially to elucidate whether intervening on multiple syndemic components can result in greater overall impact than intervening on isolated risk factors, better informing priorities for and directing resources toward improving pulmonary health outcomes, especially among marginalized communities.

DIAGNOSIS AND MANAGEMENT

Pulmonary Infections

Pulmonary infections may co-occur in PWH, especially in the setting of low CD4+ T-cell count,⁸³ necessitating a broad differential diagnosis and evaluation when feasible. Although often overlapping, signs and symptoms may help narrow the differential diagnosis and direct the order and priority of diagnostic testing. For instance, as one of the most common opportunistic infections in PWH, PCP may lead the differential diagnosis among individuals who have a low CD4+ count and present with subacute development of dyspnea, non-productive cough, fatigue, malaise, weight loss, and low-grade fever over several weeks. People with PCP may have other indications of immune deficiency, including oral thrush, and often have diffuse bilateral infiltrates on chest radiography,⁸⁴ though findings such as ground glass opacities on computed tomography (CT) are more sensitive.⁸⁵ In advanced disease, presentation can include acute dyspnea, potentially indicating development of a pneumothorax. Other fungal infections, such as coccidiomycosis, histoplasmosis, cryptococcosis, toxoplasmosis, and talaromycosis may present with disseminated disease or be localized to the lungs.⁸⁶ Bacterial and viral pneumonia tend to have a more acute onset over several days, and people may present with cough (often productive), dyspnea, fever and chest pain. While bacterial pneumonia is more often characterized by focal or lobar infiltrates on chest radiography, viral pneumonia, including COVID-19 pneumonia, may present with diffuse, bilateral infiltrates. Pulmonary tuberculosis typically presents with weeks to months of a productive cough that may progress to hemoptysis, dyspnea, fevers, night sweats, weight loss and fatigue; chest radiography may demonstrate upper lobe infiltrates, cavitation, and calcified lymph nodes, but with greater immunosuppression, atypical findings of miliary disease and focal or lobar infiltrates are more likely.

A multimodal approach to microbiologic diagnosis is necessary and includes the evaluation of sputum, bronchoalveolar lavage, blood, and/or urine samples. PCP is diagnosed by visualizing cytologic or immunostained Pneumocystis cysts or trophozoites by microscopy or using molecular detection techniques for Pneumocystis DNA in respiratory samples.^87,88 Lower respiratory tract samples are preferred, but improved polymerase chain reaction (PCR) techniques allow for use of less invasive nasopharyngeal and oral samples.^89,90 As an adjunct, a negative serum (1–3)-β-D-glucan (BDG) is associated with a post-test probability of disease of ≤5% among those with a pre-test probability of PCP <50%.⁸⁹ Pneumocystis and other fungal pneumonias are often under- or misdiagnosed (e.g. histoplasmosis misdiagnosed as TB), especially in LMICs due to limited diagnostic capacity, despite the WHO deeming these diagnostic tests essential.^86,91,92 Microscopy and culture of respiratory samples, and often blood samples, are important in the evaluation of bacterial and mycobacterial infection, but these approaches are frequently unrevealing.^32,93 Though less commonly used for bacterial pathogens, molecular detection methods are critical for the detection of M.tb. The GeneXpert MTB/RIF, an automated nucleic acid amplification test, detects presence of M.tb and rifampin resistance, a proxy for multi-drug resistance, in <2 hours. This platform is used worldwide in M.tb diagnosis and is highly specific, but sensitivity may be suboptimal, especially in smear-negative and HIV-associated TB. The WHO-recommended GeneXpert MTB/RIF Ultra is a next-generation assay that runs on the same platform; it has greater sensitivity for M.tb detection and improved determination of rifampicin resistance in the aforementioned groups but lower specificity attributed to detection of non-viable or non-replicating bacilli.⁹⁴ Urine lipoarabinomannan (LAM) testing may be a useful adjunct for diagnosing TB in PWH with severe immunocompromise. Molecular detection methods are increasingly available for respiratory viral pathogens. Pneumonia due to CMV is challenging to diagnose; detecting CMV inclusion bodies in lung tissue is considered diagnostic while detecting CMV in body tissues/fluids using molecular, microbiological or immunohistochemical testing can support a diagnosis of CMV pneumonia in an appropriate clinical context.

Immune reconstitution inflammatory syndrome (IRIS)

Timing of ART initiation is important when managing pulmonary infections in people newly diagnosed with HIV. Immune reconstitution with ART is critical in the successful treatment of infections but can also worsen infections present at the time of ART initiation. Paradoxical IRIS is the worsening of preexisting infection that is being adequately treated due to an overexuberant immune response to persistent antigen. Unmasking IRIS is the development of symptoms related to an undiagnosed infection once immune recovery allows the host to mount the appropriate immune response. The timing of IRIS after ART initiation can range from weeks to months.⁹⁵ Pathogens commonly associated with IRIS related to pulmonary infections include M.tb, Pneumocystis jirovecii, disseminated Mycobacterium avium intracellulare, CMV, and cryptococcus. The incidence of IRIS among PWH newly starting ART is ~10%, and mortality is significantly higher among those who develop IRIS than those who do not.

IRIS should be considered in PWH with low pre-ART CD4+, a robust virologic and immunologic response to ART, symptoms consistent with unmasking of a new infection or worsening of a preexisting infection after initial improvement, and a temporal relationship between starting ART and clinical decompensation. Clinical characteristics associated with IRIS depend on the underlying infection, but are generally self-limiting. For example, TB-associated IRIS may include fever, worsening pulmonary infiltrates, lymphadenopathy, pleural effusions, enlarging tuberculomas, and development or worsening of extra-pulmonary disease. IRIS associated with PCP often presents with recurrence of fever, cough, dyspnea, hypoxemia, and worsening pulmonary infiltrates.

To minimize risk of IRIS, ART must be initiated as soon as possible after HIV diagnosis, before significant immunocompromise develops. Concurrent diagnosis of HIV and TB is an exception to this recommendation. To reduce risk of TB-associated IRIS, ART initiation should be delayed 2–8 weeks after anti-TB treatment initiation; those with CD4+ <100 cells/μL should receive four weeks of prednisone along with anti-TB treatment if ART is initiated within the first 30 days of ant-TB treatment.⁹⁶ Among those with non-TB causes of IRIS, a short course of systemic steroids (typically prednisone 1mg/kg daily, tapered as symptoms improve) can be a helpful adjunct to suppress the overexuberant inflammatory response if symptoms become severe.

Immunological non-response

Once ART is initiated and virologic suppression is achieved, CD4+ T-cell count improves rapidly over a few months and continues to improve slowly for up to a decade with normalization of CD4+ to >500 cells/μL in most PWH. However, a subset who achieve virologic suppression do not experience CD4+ count normalization. This immunological non-response is most often defined as CD4+ count <350 or <200 after ≥24 months of virologic suppression or CD4+ count <350 after ≥24 months of ART.⁹⁷ Prevalence is challenging to quantify but is estimated to be 9–45% of PWH. Immunologic non-response is more common among PWH who initiate ART at lower CD4+, particularly <200 cells/μL. Immunologic non-responders experience higher AIDS and non-AIDS related morbidity and mortality than PWH whose CD4+ count normalizes.⁹⁸

The pathobiology driving immunological non-response is complex, interactive, and incompletely understood. Purported mechanisms include decreased hematopoiesis, thymic dysfunction, ongoing HIV replication, persistent immune activation, altered cytokine production, and host genetic and/or metabolic factors, all of which lead to inadequate production and/or increased destruction of CD4+ T-cells.⁹⁹ Interventions to increase CD4+ count – including ART intensification, additional immunomodulatory therapies, and cytokine-based therapies to boost lymphocyte differentiation and maturation, such as interleukin(IL)-2 and IL-7 – do not improve clinical outcomes and are not recommended.⁹⁹ By virtue of persistently reduced CD4+, PWH with immunologic non-response experience heightened risk of clinical progression (and infectious complications) compared to PWH for whom CD4+ normalizes on ART. However, because CD4+ alone does not accurately reflect risk of infectious complications, it is paramount to ensure strict adherence to guidelines for prophylaxis, including considerations for PWH on ART with an undetectable viral load and CD4+ count 100–200 cells/μL, and for vaccinations and preventative anti-infectives, as below.

Prophylaxis and prevention

Immune reconstitution with ART should be combined with prophylaxis, immunizations, and smoking cessation to prevent pulmonary infections in PWH. The most recent US-based guidelines recommend trimethoprim-sulfamethoxazole as the first-line agent for PCP prophylaxis for PWH who have CD4+ <200 cells/μL or <14%. Trimethoprim-sulfamethoxazole is superior to dapsone-based regimens, aerosolized pentamidine, and atovaquone for PCP prophylaxis and confers a mortality benefit compared to no prophylaxis.¹⁰⁰ However, trimethoprim-sulfamethoxazole is also the most toxic regimen, and no randomized controlled trials (RCTs) have compared efficacy of lower doses with the recommended daily double-strength tablet. PCP prophylaxis can be discontinued when CD4+ is ≥200 cells/μL or ≥14% for >3 months with ART, or potentially when CD4+ is 100–200 if HIV RNA remains undetectable.^101,102 PWH, including pregnant and breastfeeding women, who have a positive screening test for latent tuberculosis infection (LTBI) and in whom active TB is excluded should receive TB preventive treatment. Regimens include 12 weeks of once-weekly isoniazid, pyridoxine and rifapentine (3HP) or daily isoniazid, pyridoxine and rifampin.¹⁰¹ Rifamycin-based regimens have better safety, improved completion, and are at least as effective as isoniazid for TB prevention among PWH.¹⁰³ However, many antiretrovirals interact with rifamycins, which may necessitate a change in ART or use of 6–9 months of daily isoniazid with pyridoxine as an alternative. PWH with CD4+ <200 cells/μL and negative screening test(s) for LTBI should be retested after attaining CD4+ ≥200. These recommendations pertain to high and low TB incidence settings given the high prevalence of LTBI among PWH, especially PWH with origins from TB-endemic countries.¹⁰⁴

The U.S. Advisory Committee on Immunization Practices^105,106 recommends all routine vaccinations to protect against pulmonary infections in PWH. These include pneumococcal vaccination with PCV13 and PPSV23 (ages 6–64 years), the new RSV vaccine (young children, ages >60 years and/or chronic pulmonary disease), and Haemophilus influenza (Hib; ages <60 months) vaccination. Due to a higher risk for invasive Hib disease among children with HIV, those who are 12–59 months and who received ≤1 dose of Hib vaccine before 12 months of age should receive 2 additional doses; those who received ≥2 doses before 12 months of age should receive one additional dose. Hib vaccination is not recommended for adults with HIV. Annual vaccination against influenza and SARS-CoV-2 is recommended. Household and other close contacts of PWH should be immunized to enhance the effectiveness of immunizations.

Drug-drug interactions

Drug-drug interactions are important for clinicians to keep in mind when prescribing anti-tuberculosis and COVID therapies.¹⁰⁷ Rifamycins, which are important for the treatment of latent and active tuberculosis, interact with many antiretrovirals.¹⁰⁸ While rifampicin and rifapentine should not be co-administered with most antiretrovirals, rifabutin can be co-administered with many with close monitoring and alteration of rifabutin dosing. Considerations for COVID therapies include caution with co-administration of corticosteroids (see Drug-drug interactions section below), ruxolitinib, and nirmatrelvir/ritonavir (currently sold as Paxlovid).

Non-infectious Pulmonary Conditions

COPD

Diagnosis of COPD is based on spirometric findings of airflow obstruction (forced expiratory volume in one second to forced vital capacity ratio [FEV1/FVC] <0.7 after bronchodilator) along with: dyspnea that is persistent, progressive over time or worse with exertion; recurrent wheeze; chronic cough that may be productive and intermittent; recurrent lower respiratory infections; risk factors including tobacco smoke, indoor smoke, or occupational dust, vapor, fume and gas exposure; and/or host factors such as low birthweight, genetic factors, and childhood respiratory infections.¹⁰⁹ PWH may have a greater symptom burden for a similar degree of lung function impairment compared to people without HIV.¹¹⁰

Despite increased risk for chronic pulmonary conditions, there are no specific recommendations for chronic pulmonary disease screening or case-finding among PWH without respiratory symptoms.^109,111 Although screening for chronic pulmonary diseases is not effective in the general population, recent studies support the role of case-finding strategies to identify people at-risk for COPD and asthma.^112,113 In a Canadian RCT, individuals with undiagnosed COPD or asthma who were identified by case-finding based on presence of respiratory symptoms and were subsequently randomized to pulmonologist-directed care had less healthcare utilization for pulmonary illness, lower symptom burden, and improved quality of life compared to those in usual care.¹¹² A similar approach to identifying symptomatic PWH and performing spirometry with handheld devices may confer benefits in LMICs; but, such approaches have not been studied in these settings.¹¹⁴

Similarly, there are few COPD management approaches specific to PWH, and PWH are significantly underrepresented in studies of COPD therapeutics or management strategies, including advanced COPD treatment strategies such as endobronchial valves and lung volume reduction surgery. Patient-centered goals include improving quality of life and functional status, mitigating symptom burden, reducing exacerbations, and improving survival.¹⁰⁹ Pharmacologic therapy comprises ≥1 of the following: inhaled bronchodilators short- and long-acting β2 agonists (SABAs and LABAs, respectively), short- and long-acting muscarinic agonists (SAMAs and LAMAs, respectively), and inhaled corticosteroids (ICS). In recent years, Global Initiative for Chronic Obstructive Lung Disease COPD guidelines support prioritizing long-acting bronchodilators and minimizing ICS use unless there are concomitant features of asthma or presence of peripheral eosinophilia. Minimizing ICS use in PWH is critical, as ICS use in COPD is associated with a nearly 40% increased risk of pneumonia¹¹⁵ and >2-fold increased risk of TB.¹¹⁶ Importantly, the number needed to harm to cause one additional TB event is lower for people with COPD treated with ICS in TB-endemic areas than in non-endemic areas.¹¹⁶ Additionally, vigilance for drug-drug interactions with ICS use is critical (see below). Other important components of COPD management include immunization against respiratory pathogens, smoking cessation, oxygen supplementation, non-invasive positive pressure ventilation, and pulmonary rehabilitation, as appropriate.¹⁰⁹

Asthma

Asthma, a chronic disorder of the airways, encompasses complex interactions of variable and recurring respiratory symptoms, airflow obstruction, airway hyper-responsiveness and inflammation.¹¹⁷ Asthma diagnosis requires a history of consistent symptoms, including wheezing, chest tightness, dyspnea and cough, in combination with variable airflow limitation, and, in some cases, bronchodilator responsiveness or airway hyper-responsiveness on pulmonary function testing. Signs and symptoms vary in intensity over time, making asthma challenging to diagnose. Asthma symptoms may become more apparent after immune reconstitution. Studies of asthma among PWH often define asthma based on self-report; incorporating respiratory symptoms, pulmonary function and asthma therapies in the definition may improve diagnosis. Among people hospitalized for asthma exacerbations, PWH may have greater use of non-invasive positive pressure ventilation and longer lengths of stay.¹¹⁸ Yet, overall data are inconclusive, and it remains unclear whether HIV is associated with an increased risk or severity of asthma.

As with COPD, there are few asthma management considerations that are unique to PWH, and management should be guided by published recommendations.¹¹⁷ Because airway inflammation is a prominent feature of asthma, ICS play an important role in therapy along with SABAs and LABAs. These are stepped up in frequency and dose to achieve and maintain control of asthma symptoms. For severe asthma, referral to a specialist and consideration of serologic IgE and aeroallergen testing as well as addition of a LAMA, monoclonal antibody/biologic injection or sublingual allergen immunotherapy may be indicated for select individuals. Importantly, PWH were excluded from clinical trials examining biologics in atopic disease, but subsequent reports support that dupilumab and other monoclonal antibodies and biologic injections may be effective treatments for moderate-to-severe Th2-high asthma among PWH.¹¹⁹ Safety profiles are less elucidated, and HIV RNA and CD4+ count should be monitored closely with declines of 30% in CD4+ prompting consideration of discontinuation of these therapies.

Venous thromboembolic disease (VTE)

Even in the contemporary ART era, PWH have a 2–10 fold increased risk of pulmonary embolism and deep venous thrombosis than the general population.¹²⁰ Common provoking factors, including recent hospitalization, immobilization, infection, smoking and injection drug use as well as HIV-related factors such as viremia seem to play a role in this heightened risk.¹²¹ Importantly, regardless of whether VTE is provoked or unprovoked, the risk of recurrent VTE remains higher among PWH than those without HIV.¹²² Recurrence risk may decrease with greater CD4+ T-cell recovery after the index VTE event. Overall, management follows guidelines for the general population.¹²³

Pulmonary hypertension

Pulmonary arterial hypertension is 5,000x rarer among PWH (0.5% prevalence) than in the general population.¹²⁴ Notably, prevalence has not changed with expansion of ART access and is likely underestimated, particularly in LMICs. While exact mechanisms by which HIV causes pulmonary hypertension remain unclear, soluble HIV viral proteins drive perturbations related to the pulmonary vasculature that are linked with development of pulmonary hypertension. Clinical presentation can be nonspecific and includes dyspnea, edema, nonproductive cough, fatigue and syncope, often resulting in lag-times of up to two years before diagnosis. While transthoracic echocardiography plays a role in evaluation and management of pulmonary hypertension, pulmonary arterial catheterization is required for definitive diagnosis and for initiation of targeted therapies. Overall management is guided by general treatment algorithms, taking drug-drug interactions into consideration.

Sarcoidosis

There are case reports of PWH developing sarcoidosis after ART initiation, most of which have occurred >1 year after ART was started.¹²⁵ Some, but not all, cases were among PWH with a prior diagnosis of sarcoidosis that was clinically quiescent prior to HIV diagnosis and ART initiation. Sarcoid-related granuloma formation is reliant upon CD4+ T-cells, suggesting that an IRIS-like syndrome may underlie clinical worsening of previously subclinical sarcoidosis or new development of sarcoidosis following immune reconstitution in some PWH. Though rare, the management of “IRIS-associated sarcoidosis” is the same as sarcoidosis in the general population.

Lung cancer

Lung cancer is the leading cause of non-AIDS-defining cancer and cancer death among PWH.¹²⁶ With the advent of ART, lung cancer incidence decreased over time among PWH, but continued high prevalence of tobacco use together with HIV-associated immune dysfunction remain associated with an increased risk of lung cancer among PWH compared to people without HIV. As in the general population, adenocarcinoma followed by squamous cell carcinoma are the most common types of lung cancer in PWH. Similar to other age-related comorbidities (e.g., COPD), lung cancer is often diagnosed at younger ages in PWH.¹²⁷ Generally, lung cancer therapy recommendations are similar for people with and without HIV. Although PWH were also excluded from trials of immune checkpoint inhibitors (ICIs), retrospective studies suggest that safety profiles and anti-tumoral efficacy of ICIs are comparable for people with and without HIV; however, the safety profile of ICIs combined with chemotherapy or tyrosine-kinase inhibitors is not yet known in PWH.¹²⁸ Risk of pneumonia and other poor short-term outcomes related to therapies including surgical resection are comparable across HIV status.¹²⁹ While data on the effect of HIV on lung cancer survival are conflicting, PWH who have an AIDS-defining illness or low CD4+ counts may have worse survival.¹³⁰

Lung cancer screening has additive benefit to smoking cessation in lung cancer prevention, and should be performed using a shared decision-making approach.¹³¹ Current lung cancer screening recommendations perform similarly among people with and without HIV, but may be underutilized in PWH.¹³² Ongoing research is focused on optimizing implementation of lung cancer screening recommendations among marginalized groups, including PWH.¹³³

Drug-drug interactions

Most corticosteroids interact with ART regimens that include CYP3A4 inhibitors (e.g. ritonavir, cobicistat) to cause hypercortisolism.¹⁰⁷ Beclomethasone is the preferred ICS for chronic pulmonary diseases among PWH who are using protease inhibitors because of its minimal interaction. In addition, salmeterol (LABA), should be avoided among PWH taking protease inhibitors or elvitegravir/cobicistat. Many anticoagulants, antiplatelets, and agents targeting pulmonary hypertension also interact with ART regimens, requiring close monitoring and alteration of either the drug dosage, timing or regimen altogether.

Smoking cessation

Achieving sustained smoking cessation is paramount to improving pulmonary health. For instance, it is estimated that in South Africa alone, if 10–25% of virologically suppressed PWH aged 30–59 years stopped smoking, 190,000–460,000 life-years would be gained.⁴¹ Attenuated but similar results were estimated for the US.¹³⁴ Among people who smoke, PWH may be more likely to initiate cessation interventions than people without HIV.¹³⁵ Historically, PWH have low smoking quit rates with traditional combination behavioral and pharmacological interventions.¹³⁶ Trials of varenicline for cessation largely support early benefit and benefit in achieving long-term abstinence.¹³⁷ Promising smoking cessation strategies among PWH include comprehensive approaches and clinic-level interventions rather than individual-level interventions.^138,139 Integrating smoking cessation interventions with mental health and substance use services, providing greater social support, and addressing other comorbid conditions in a holistic approach to smoking cessation may confer added benefits.¹⁴⁰

Pulmonary rehabilitation (PR)

PR is beneficial for people with chronic pulmonary diseases, particularly when dyspnea is a predominant feature. PR involves respiratory muscle strengthening through breathing and core exercises, education, and behavior change, often in a group setting. In COPD, PR significantly improves quality of life by reducing dyspnea and fatigue, improving exercise capacity, and providing a sense of control over the disease process.¹⁴¹ For these reasons, PR is a core recommendation,¹⁰⁹ but few studies have focused on PWH. Exercise training alone improved endurance, aerobic fitness and lean body mass in a pilot study enrolling children with HIV.¹⁴² For PTLD, preliminary data demonstrate improvements in dyspnea scores and mental health parameters. Unfortunately, PR is not widely available, especially in LMICs where the burden of chronic pulmonary disease is highest.¹² PR remains a promising therapeutic intervention that should be offered to PWH with chronic pulmonary disease and warrants further investigation, including to optimize implementation.

EMERGING THERAPIES

Routine antimicrobial use

Among children (ages 6–19 years) with perinatally-acquired HIV and impaired lung function in the BREATHE Trial in sub-Saharan Africa, weekly azithromycin is associated with reduced acute respiratory exacerbations but not improved lung function.¹⁴³ Azithromycin has potent anti-inflammatory properties in addition to antimicrobial properties. In a subset of these children, higher baseline exhaled nitric oxide (eNO) is associated with greater risk of acute respiratory exacerbation, suggesting that eNO may be useful in identifying children with HIV who might benefit from closer monitoring and proactive interventions.¹⁴⁴

Preliminary data also support that doxycycline, an antibiotic with anti-inflammatory properties, has potent activity as a matrix metalloproteinase (MMP) inhibitor and may have a role in emphysema therapy. In pre-clinical models of cigarette-exposed mice, doxycycline decreased expression of MMPs and pro-inflammatory markers in the lungs.¹⁴⁵ In a phase 2 trial of doxycycline in PWH who have emphysema, doxycycline may improve emphysema. As a result, the ongoing, multisite, double-blinded RCT entitled Doxycycline for Emphysema in People Living with HIV (DEPTH; NCT05382208) is examining the effect of twice daily doxycycline on emphysema and lung diffusing capacity (DLCO).

Use of medications with evidence-based cardiovascular benefits

Prompted by promising pre-clinical data, albeit conflicting clinical data, angiotensin-receptor blockers and statins have been examined for their potential role in mitigating chronic pulmonary disease among PWH. A multicenter RCT of losartan enrolled 220 adults with mild-moderate emphysema, finding no difference in emphysema progression.¹⁴⁶ A substudy of LIFE HIV (NCT02049307), a 12-month RCT of daily losartan versus placebo among 108 PWH, found that losartan improved levels of surfactant protein D among those with CD4+ >350 cells/μL.^147,148 In a pilot RCT of 24 weeks of rosuvastatin (n=11) vs placebo (n=11) among PWH with abnormal pulmonary function, those in the rosuvastatin arm had slowed worsening of airflow obstruction, improved DLCO, and lower levels of monocyte activation (sCD14) and endothelial dysfunction (endothelin-1).149 Together these results suggest that medications with evidence-based cardiovascular indications may have potential in the prevention or treatment of chronic pulmonary diseases among PWH, possibly via pathways of inflammation important in HIV. Future, well-powered RCTs are necessary to confirm these findings.

SUMMARY AND FUTURE CONSIDERATIONS

In light of their multifaceted immunocompromised condition, PWH are at high risk of experiencing acute and chronic pulmonary conditions. Early ART initiation can mitigate this risk. However, PWH in LMICs bear a disproportionate burden of pulmonary disease in light of greater exposure to frequently overlapping risk factors. Implementing current best practices while expanding research to address gaps in the prevention, diagnosis and treatment of acute and chronic pulmonary conditions among PWH in LMICs is an important step to mitigating health disparities. Additional knowledge is needed to inform tailoring interventions for PWH, such as case-finding, lung cancer screening, smoking cessation, reduction of air pollutant inhalation, and emerging therapies. Ongoing national and international cohorts of PWH, including the MACS/WIHS Combined Cohort Study, Veterans Aging Cohort Study, CFAR Network of Integrated Clinical Systems (CNICS), NA-ACCORD, Pediatric HIV/AIDS Cohort Study (PHACS), IMPAACT, the IeDEA Cohort Consortium and others are robust resources that provide an excellent foundation to begin to tackle these gaps. As children, adolescents and adults age with HIV with more effective ART regimens, chronic pulmonary conditions will become increasingly important to address in order to maximize longevity, well-being and quality of life for PWH.

CLINICS CARE POINTS.

• Early initiation of antiretroviral therapy can decrease the risk of pneumonia, other pulmonary infections and chronic pulmonary conditions.

• Greater vaccination, smoking cessation, reduction of inhaled pollutant exposures and implementation of PR programs are imperative to decrease the risk for acute and chronic pulmonary complications among PWH.

• SDoH are important contributors to pulmonary disease in PWH, and should be addressed in preventing, diagnosing and treating pulmonary diseases.

• There are important considerations for interactions of specific classes of medications with ART in the treatment of acute and chronic pulmonary disorders.

• Ongoing research seeks to advance the care of chronic pulmonary disorders with a specific focus on mitigating the burden of disease among PWH.

Key Points:

• Early initiation of antiretroviral therapy is a cornerstone in the management of people with HIV across the lifespan that substantially decreases the risk of pneumonia, other pulmonary infections and chronic pulmonary conditions.

• The burden of acute and chronic pulmonary conditions is greatest among people with HIV living in low- and middle-income countries where there is a disproportionately increased risk of exposure to risk factors for pulmonary disease and fewer resources for diagnosis and treatment.

• Interactions of antiretrovirals with medications for treating acute and chronic pulmonary disorders are crucial for clinical providers to consider when selecting and prescribing medications.

• Greater vaccination, smoking cessation, reduction of inhaled pollutant exposures, implementation of pulmonary rehabilitation programs, and addressing social determinants of health are important components in decreasing the risk for acute and chronic pulmonary complications among people with HIV.