The changing landscape of HIV-related lung disease: Non-AIDS lung malignancy as a player in the field

Recent epidemiologic work has shown that the type and nature of lung disease experienced by human immunodeficiency virus (HIV)-infected persons have changed with the availability of effective combination antiretroviral therapy (cART).1–3 While the rates of infectious lung diagnoses, particularly opportunistic infections, have declined with cART, non-infectious and non-acquired immunodeficiency syndrome (AIDS) related lung diseases such as chronic obstructive pulmonary disease, pulmonary hypertension and lung cancer are increasing and have greater incidence rates in HIV-infected compared with HIV-uninfected persons.1 Interpretation of findings of diagnostic testing in the current era must therefore adapt to the changing epidemiology of HIV-associated lung disease. In this issue of Respirology, Alcada et al.4 report on important clinical findings related to lung cancer and mediastinal lymphadenopathy found on chest computed tomography (CT) scans done for clinical indication in 271 HIV-infected persons during the current cART era (2004–2009). Their main findings were that 19% of the CT scans had enlarged mediastinal lymph nodes (>10 mm on short axis), and of those with enlarged mediastinal lymph nodes, 33% were diagnosed with a malignancy—10% with a non-AIDS-defining malignancy. Importantly, they found that larger mediastinal lymph nodes were more likely to be associated with a malignancy, while the presence of consolidation on the CT scan made it much less likely that the mediastinal lymph nodes were malignant. These findings of frequent malignant potential highlight the importance of a low threshold for tissue biopsy of enlarged mediastinal lymph nodes, particularly in the absence of radiographical indicators of an infectious aetiology. Compared with bronchogenic lung cancer (small and non-small cell lung cancer), HIV is now an effectively treatable disease with cART. Bronchogenic lung cancer, unfortunately, remains a diagnosis with high rates of mortality, with an overall 16% survival at 5 years and still only 53% 5-year survival with localized lung cancer at diagnosis.5 This is in contrast to HIV, where there is a 93.5% expected 5-year survival with cART.6 Despite improved survival with cART in HIV, there may be cause for concern, with growing literature suggesting HIV infection may be an independent risk factor for bronchogenic carcinoma.7–9 Although investigations of cancer in HIV are limited in ability to control for traditional lung cancer risk factors such as smoking or other exposures, several studies have been conducted which take these factors into account. The risk of lung cancer in HIV-infected persons was assessed in the large California Kaiser Permanente integrated health delivery system, and when controlling for data on smoking, body mass index and alcohol/drug use, the incidence rate ratio was 1.2 (95% CI: 0.9–1.6).10,11 Several smaller studies with prospectively collected data on risk factors for lung cancer show strong trends, despite having few numbers, for lung cancer to be increased in HIV.8,12 A recent meta-analysis of studies of cancer in HIV showed HIV infection was associated with a standardized incidence ratio (SIR) for lung cancer of 2.6 (95% CI: 2.1–3.1).7 Lung cancer in HIV is also seen at younger age,13,14 suggesting an HIV-related risk for its development. There are several reasons HIV-infected persons may be at increased risk for lung cancer. First, cigarette smoking, the primary risk factor for lung cancer, is more prevalent in the HIV population than the general population.15 Additionally, the immune system performs an important function in ridding the body of tumorigenic cells.16 Immune deficiency related to HIV infection may diminish the immune response to malignant foci.7,11,13,17 In support of this hypothesis that immune suppression may allow more cancers, with the availability of cART, the SIR of lung cancer in the HIV-infected population compared with the HIV-uninfected population seems to be declining over time.10,18 Another important aspect of lung cancer in HIV is that HIV infection may be associated with worse outcomes in lung cancer. While data are conflicting, survival with lung cancer in HIV-infected persons may be worse compared with HIV-uninfected persons.8,14,17,19 Additionally, haematotoxicity with chemotherapeutic drugs is more common in HIV-infected persons (likely related to interactions with cART).20 Increased risk of lung cancer and worse outcomes related to lung cancer make reducing risk factors for lung cancer (such as smoking prevention and cessation) and early diagnosis in HIV important for improving outcomes related to lung cancer in the HIV-infected population. HIV-infected persons may benefit from lung cancer screening. Alcada et al. also found that 100% of the non-AIDS-defining lung malignancies associated with enlarged mediastinal lymph nodes was associated with lung nodules. These nodules were presumably present prior to the mediastinal lymphadenopathy, which raises the question of whether early detection would be of benefit in the HIV population. The National Lung Cancer Screening Trial recently showed that low-dose CT screening for lung cancer in an at-risk population (55–74 years old with at least 30-pack-year history of smoking, who had not quit > 15 years prior) was associated with a 20.0% reduction in lung cancer mortality and 6.7% decreased rate of all-cause mortality over 7 years.21 Lung cancer screening in HIV may be beneficial given the high rate of smoking in HIV, early onset of lung cancer of HIV and potential for improved outcomes with early stage disease; however, different screening strategies will likely be needed in the HIV population because of high smoking rates, early onset, and an increased chance of incidental findings and other causes for pulmonary nodules. The findings of Alcada et al.4 are important in understanding the changing spectrum of HIV-related lung disease. Prior studies of mediastinal lymphadenopathy in HIV were performed before the widespread availability and use of cART.22,23 Alcada et al.4 point out that their study found a much lower rate of bacterial pneumonia associated with enlarged mediastinal lymph nodes, suggesting lower frequency of HIV-associated infectious complications; yet these patients remain distinct from the general population, with malignancy, including lung cancer, being found at a young age. Further epidemiologic studies in the cART era may help clarify the true risk of lung cancer associated with HIV infection, and further research will be required to address the utility of lung cancer screening in the this unique population. As HIV infection is controlled with cART, physicians caring for HIV-infected patients will need to remain aware of the changing spectrum of lung disease seen in this population, as interpretation of and response to clinical findings, including radiographical findings, will change as the landscape of HIV evolves.