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CROI 2014: Chronic Lung Disease Is Prevalent and Under-diagnosed in People with HIV

Even though the incidence of most HIV-related respiratory complications and opportunistic infections have declined dramatically since the advent of effective antiretroviral therapy (ART), 4 studies presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) last month in Boston showed that people living with HIV are still at increased risk of serious progressive lung complications, including under-diagnosed chronic obstructive pulmonary disease (COPD) and emphysema.

A number of factors -- such as smoking, which is common in many cohorts of HIV positive people -- contribute to this. Nevertheless, HIV itself was still independently associated with increased risk of lung disease in some studies, while in another, HIV-related inflammation sped the rate and increased the severity of lung damage when people smoke.

Since most study participants were on treatment, it was difficult to conclusively show the effect of ART in reducing the risk of chronic pulmonary complications, However, some of the studies did find a protective effect from having a higher CD4 T-cell count. One study found an association between lung disease and low nadir (lowest-ever) CD4 counts when starting ART, while others showed that chronic lung disease was associated with ongoing systemic immune activation. In one study the rate of decline in lung function did tend to be greater in those with higher HIV viral loads.

Do these associations suggest that HIV is directly causing lung disease?

According to Kristina Crothers of the University of Washington, who presented one of the large cohort analyses, after carefully collecting detailed histories and adjusting for all the major confounders including smoking, "We’re still seeing a residual effect of HIV infection...We don't know what’s going on in the lung. There may be some compartmental replication of HIV in the lung, particularly in the setting of chronic lung disease, that may be contributing to and driving some of this pathogenesis. Those are some of the next questions to answer."

HIV and the Lungs

"It’s been established in a number of studies from years back that untreated HIV has long been associated with macrophage and lymphocyte activation, secretion of a number of pro-inflammatory cytokines and chemokines, loss of antigen-specific CD4 cells, accumulation of CD8 cells in the alveolar space, and altered pulmonary immunity leading to susceptibility to opportunistic infections," said Marshall Glesby of Weill Cornell Medical College, giving some background at a themed discussion he moderated on the pulmonary complications of HIV infection.

Even without opportunistic infections, HIV infection and related inflammation in the lung was sometimes associated with a clinical syndrome, lymphocytic interstitial pneumonia (LIP) -- a sort of non-specific pneumonitis that could present with shortness of breath and wheezing and hypoxemia (low blood oxygen), along with lymphadenopathy and other non-pulmonary symptoms. At one time, HIV-related LIP complicated the diagnosis of tuberculosis (TB) by chest X-ray in adults living with HIV and it was a particularly frequent condition in perinatally infected children.

An ACTG study based on longitudinal bronchoscopies demonstrated that after initiating ART, there is a reduction in HIV viral load in the lung’s alveolar cells, a decrease in CD8 cell infiltration, reduced activation of lymphocytes and macrophages, and a decrease in pro-inflammatory cytokines and chemokines. ART has also clearly been associated with reduced incidence of multiple opportunistic infections and malignancies that affect the lungs in the era of more effective HIV therapy (with the exception of TB in some settings).

Nonetheless, "there is increased concern [about] COPD, pulmonary hypertension, and lung cancer," said Glesby, "and some of this is driven by very high rates of smoking in most HIV-infected populations."

In fact, smoking rates remain higher in HIV positive populations -- 39% to 59% in HIV outpatient settings in the U.S. versus 19% in the general U.S. population, according to one recent review. But as the studies presented at CROI point out, smoking is not the only thing leading to or exacerbating chronic lung disease in people living with HIV.

COPD is characterized by persistent airflow limitation that cannot be fully reversed once it has become established. It is typically progressive and associated with an enhanced chronic inflammatory response in both the airways and lung parenchyma (functional tissue). Symptoms include dyspnea (shortness of breath), chronic cough, and sputum production.

Most studies use a COPD diagnostic definitions based on spirometry, a pulmonary function test that measures the amount (volume) and speed (flow) of air that can be inhaled and exhaled. The "GOLD" definition of COPD is based on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) after administration of a bronchodilator. Essentially, people with COPD have a significantly reduced ratio of FEV1 to FVC compared to a healthy person.

"It’s thought that the airflow limitation can be a consequence of both small airway disease with airway inflammation, airway fibrosis, and luminal plugs causing increased airway resistance -- as well as destruction of the lung parenchyma with loss of alveolar attachments and decrease of elastic recoil," Glesby explained.

Emphysema is a type of COPD, defined anatomically based on the destruction of the alveolar-capillary units where blood and air meet in the lung. It is commonly defined on autopsy, but in a living person the gold standard of diagnosis is by high-resolution chest computed tomography (CT), though sometimes it may be evident on a chest X-ray. A number of studies have previously suggested that HIV positive smokers may have accelerated lung destruction compared to uninfected controls, with a potentially earlier age of onset and a lower smoking threshold for the development of emphysema.

Acute exacerbations of COPD are eventscharacterized by a worsening of the patient’s respiratory symptoms beyond the normal day-to-day variations and that leads to a change in medications.

"[Acute exacerbations] are thought to often be triggered by viral upper respiratory tract infections," said Glesby. "And there are multiple consequences, including an accelerated decline in lung function, decreased quality of life, increased mortality, and the obvious economic costs associated with these exacerbations."

HIV as a Risk Factor for Emphysema

The first poster presented at the themed discussion, by Engi Attia of the University of Washington, was a cross-sectional analysis of HIV positive and negative individuals enrolled in the Examinations of HIV-associated Lung Emphysema (EXHALE) cohort, a pulmonary sub-study of the Veterans Aging Cohort Study (VACS).

The study was performed to determine whether HIV is an independent risk factor for emphysema, and whether the severity of emphysema or its distribution differed by HIV status. The researchers also looked at whether there was an association between emphysema and biomarkers of HIV severity and related systemic inflammation, such as nadir CD4 count, interleukin 6 (IL-6, one of the most important inflammatory cytokines), soluble CD14 (a marker of chronic inflammation associated with HIV infection), and D-dimer (a small protein fragment that is a sign of altered coagulation).

The EXHALE cohort included 114 HIV positive and 89 HIV negative participants, and people with pulmonary diseases other than COPD were excluded. Emphysema severity and distribution were determined by chest CT at enrollment. Covariates in the multivariate analysis included demographics, COPD, prior pneumonia, smoking history (former, current, and cumulative), as well as use of marijuana and injected drugs.

"We found that HIV-infected individuals had significantly greater emphysema severity," said Attia. "They also had significantly greater diffuse emphysema, which we believe is driven by the increased lower lung zone and diffuse involvement."

• In the multivariate logistic regression models, HIV infection was significantly associated with emphysema in the unadjusted odds ratio (OR), but not in the adjusted OR.
• HIV was, however, an independent risk factor for emphysema after adjusting for smoking (significant in both unadjusted and adjusted OR).
• When elevated soluble CD14 (>75th percentile) was added this model, there was a marked attenuation of this association.
• Among HIV positive participants, factors significantly associated with emphysema included:

o   Nadir CD4 of less than 200 cell/mm³;

o   Soluble CD14 >75th percentile;

o   Pack-years of smoking.

Prior pneumonia was also a significant risk factor for emphysema before adjustment in their model, but the researchers were unable to include it in their multivariate models because they had difficulty determining the temporal association between HIV infection, pneumonia, and emphysema development.

"Taken together, the emphysema distribution and association with biomarkers among those with HIV suggests that there may be a systemic or a vascular-based mechanism linking HIV with emphysema," said Attia.

Factors Associated with COPD in Smokers

The second poster, presented by Alain Makinson of University Hospital in Montpellier, France, described risk factors associated with COPD in people living with HIV who smoke. 90% were active smokers and the rest had stopped smoking less than 3 years before inclusion in the study. 

This cross-sectional prevalence study was nested in the larger ANRS HIV-CHEST study, a CT screening study at 14 centers in France looking for lung cancer in HIV positive subjects at higher risk. Participants were also screened for COPD by spirometry. The study included 334 people (17% women) aged 40 or older (median 50 years) with a history of at least 20 pack-years of smoking (median 30), a CD4 nadir <350 cells/mm³ (median 178 cells/mm³) and a current CD4 cell count over 100 cells/mm³ (median 574 cells/mm³). Most (88%) were on ART with undetectable viral load). 35% had a notable history of cannabis use.

• COPD was diagnosed in 83 participants (25%), and was previously unknown in 62 (75%) of them.
• 54% of those with COPD had mild disease (GOLD grade 1) and 41% had moderate COPD (GOLD grade 2).
• 2 factors were significantly associated with COPD:

o   Age (OR 2.34);

o   Most recent CD4 count, with a 100 cells/mm³ increase negatively associated with, or protective against, COPD (OR 0.90).

• There was a trend towards an increased risk of COPD associated with history of cannabis use, lean body mass index, history of lung infection or Pneumocystis pneumonia, but these did not reach statistical significance.
• Increased smoking (over the baseline smoking history) and hepatitis C coinfection were not associated with COPD in the multivariate analysis.

"We found that there is a high prevalence of COPD with under-diagnosis," said Makinson. He added that this points to the need to screen for COPD to increase early diagnosis in smoking HIV positive patients age 40 years and older -- something that is already recommended by the "GOLD" standards for the general population.

"Tobacco and cannabis smoking cessation should be highly prioritized," he added. "The cannabis and COPD association should perhaps be further studied in HIV-infected populations, and higher CD4 counts seemed protective in our study."

HIV and Acute Exacerbations of COPD

As already noted, acute exacerbations of COPD often lead to very rapid decline. In order to determine the risk factors for such exacerbations, another study by Allison Lambert of Johns Hopkins University and colleagues evaluated risks in participants with COPD from the prospective ALIVE (AIDS Linked to the Intravenous Experience) cohort.

The investigators identified 167 participants with COPD, and then assessed for acute exacerbations during semi-annual visits. Acute exacerbation was defined as a self-reported worsening of breathing or and event requiring treatment with either antibiotics or steroids.

Participants were middle-aged (median age 53 years) and primarily African American (89%). Almost one-third (32%) were HIV positive and 72% of them were on ART. About half had HIV RNA <50 copies/mL and their median CD4 count was 312 cells/mm³. 90% were current smokers and 8% were former smokers; 36% were currently using injection drugs while 64% were former users.

• Participants attended a median of 3 visits over the course of a year and a half.
• 53 events were observed among 36 participants.
• HIV was an independent risk factor for acute exacerbation of COPD.
• HIV positive participants had a 2.5-fold increase in their odds of COPD exacerbation compared to those without HIV.

This study also looked at whether there was an effect of viral load on acute exacerbations of COPD, and found that HIV positive people with both undetectable and high viral load had increased odds of acute exacerbations compared to people without HIV infection. Inclusion of prior COPD exacerbation -- which strongly increases future exacerbation risk -- attenuated the HIV effect.

Do HIV and Immune Activation Accelerate COPD Progression?

Building on findings from the ALIVE study suggesting that COPD may be increased in people with HIV, particularly if they have a high viral load or a low CD4 cell count, the fourth study aimed to determine if the rate of decline in lung function was increased in HIV positive versus negative participants, and whether plasma IL-6, soluble CD14, and D-dimer were associated with lung function over time.

The study again involved participants in the EXHALE cohort, and included 168 HIV positive and 147 HIV negative enrolled from 2009 to 2012. The HIV positive patients were slightly older than the uninfected patients (median 55 vs 53 years). Participants were well matched for current smoking status (64% and 57%, respectively). Median pack-years was about 25 in both groups and did not differ by HIV status. Most of the HIV positive participants were on ART with a median CD4 count of 400 cells/mm³.

Spirometry with bronchodilator was performed on participants at baseline and then again approximately every 6 to 12 months.  Biomarker values were obtained at baseline and analyzed either as continuous measures or dichotomized above or below the group median. The analysis adjusted for age, body mass index, smoking pack-years, and CD4 count.

• This study found no increase in the prevalence of COPD by HIV status.
• However, the rate of decline in FEV1 was significantly greater in people with HIV compared to HIV negative patients.
• In cross-sectional analyses at baseline, HIV positive patients with higher levels of IL-6, sCD14, and D-dimer had a significantly lower baseline value of FEV1, as well as FEV1/FVC ratio.
• In the longitudinal analysis, HIV positive patients with a high sCD14 level at baseline had a significantly greater decline in FEV1 over time.

"FEV1 decline is accelerated in these HIV-infected individuals, and among those with HIV, an elevated level of sCD14 is associated with a more rapid decline in FEV1," said presenter Kristina Crothers. "So we think that these data suggest that selective immune activation may play a role in COPD progression, particularly in the setting of HIV infection."

4/25/14

References

MJ Glesby. Pulmonary Complications of HIV Infection Session. Themed Discussion. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6.

EF Attia, MB Goetz, MC Rodriguez-Barradas, et al.  HIV Infection and Related Biomarkers Are Independent Risk Factors for Radiographic Emphysema. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 775.

A Makinson, M Hayot, S Eymard-Duvernay, et al. Factors Associated With Chronic Obstructive Pulmonary Disease in a High-Risk HIV-Infected Cohort. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 776.

AA Lambert, GD Kirk, J Astemborski, et al. HIV Infection Increases Risk of Acute Exacerbations of COPD. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 773.

K Crothers, CV Rodriguez, C Wongtrakool, et al. Association of HIV Infection and Immune Activation With Decline in Lung Function. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 774.