Pulmonary infections with mycobacteria and Pneumocystis jirovecii
as well as recurrent pneumonia caused by bacterial agents such as Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcus aureus, and Chlamydia pneumoniae
are common among PWA 13
. Given accumulating evidence that smoking may not explain all of the increased lung cancer risk among PWA 2-4
, we evaluated whether pulmonary infections could explain part of the association. Consistent with this hypothesis, we found that individuals with recurrent pneumonia had a significantly increased risk of lung cancer. Notably, lung cancer risk was significantly elevated 5-10 years after a recurrent pneumonia diagnosis, thus arguing against reverse causality (i.e., that pneumonia arose as a manifestation of lung cancer). Additionally, our previous observation that the excess risk of lung cancer was especially strong among young PWA 4
indicated a role for additional co-factors among young individuals. Our current observation that recurrent pneumonia was associated with increased lung cancer risk among younger, but not older, PWA supports the conclusion that pulmonary infections might explain the high lung cancer risk among young PWA.
Ascertainment and reporting of AIDS-defining pulmonary infections may have varied across both calendar time and between the AIDS-onset period and the years of subsequent follow-up, which could bias our results. However, our observations that the incidence of recurrent pneumonia among PWA was similar between the pre-HAART and the HAART eras and that the recurrent pneumonia-lung cancer association did not differ by calendar time or AIDS-relative time, argue against a major bias arising from changes in ascertainment or reporting of recurrent pneumonia.
The lack of a significant relationship between AIDS-associated tuberculosis and lung cancer risk contrasts with previous reports of an association among individuals without HIV infection 11, 21, 22
. Our observation of an increased risk of lung cancer within one year following a tuberculosis diagnosis suggests a non-causal association and points to the role of either an ascertainment bias (i.e., detection of lung cancer by chest radiographs among persons with tuberculosis) or reverse causality (i.e., that subclinical lung cancer facilitated the reactivation of latent tuberculosis infection).
Cigarette smoking increases the risk of pulmonary infections such as recurrent pneumonia and tuberculosis 23
. Therefore, confounding by smoking could explain, in part, the association of recurrent pneumonia with increased lung cancer risk. Indeed, our analyses that incorporated indirect adjustment for smoking indicated that a 10% difference in the prevalence of smoking between PWA without pneumonia and individuals with recurrent pneumonia could account for the significantly elevated lung cancer risk. Nonetheless, we note that effect estimates for the recurrent pneumonia association remained elevated, although not statistically significantly so, across a range of hypothetical smoking prevalence estimates, indicating that confounding by smoking may not explain all of the elevated risk. Likewise, the lack of association between lung cancer and tuberculosis, which is also related to smoking, also argues against confounding by smoking being the entire explanation for the recurrent pneumonia association.
The pulmonary infections we evaluated—tuberculosis, PCP, and recurrent pneumonia—are more common among HIV-infected individuals with low CD4 T-cell counts than those with relatively higher CD4 counts 13
. Although recurrent pneumonia was associated with both low CD4 counts and lung cancer, lung cancer risk was previously noted to be unrelated to CD4 count at AIDS onset among PWA overall 4
. The low range of CD4 counts among PWA in our study may have masked an association between immunosuppression and lung cancer risk. Indeed, a recent study among HIV-infected individuals reported strong associations of immunosuppression with increased lung cancer risk 24
. Likewise, we previously found that lung cancer risk increased significantly from 5 years before to 5 years after AIDS onset, which could be an alternative measure for the degree of immunosuppression, or perhaps an indicator of recurrent or persistent pulmonary inflammation 4
The limitations of our study should be noted. Importantly, our assessment of pulmonary infections was based on AIDS registry data, not on our own direct assessment of infection status. Additionally, we did not have information on the smoking behaviors of PWA. Our analyses that incorporated indirect adjustment for smoking showed that confounding by smoking could potentially explain part of the significant association of recurrent pneumonia with increased lung cancer risk. Furthermore, we could not adjust for either duration or intensity of smoking. Therefore, the possibility of residual confounding by smoking cannot be ruled out. Our study also has several strengths, including a large sample size, population-based surveillance, and prospective evaluation of the association of pulmonary infections with lung cancer.
In conclusion, lung cancer risk was significantly elevated among PWA who had recurrent pneumonia, suggesting a role for pulmonary infections and inflammation in lung carcinogenesis. Additional studies utilizing biological markers for pulmonary infections and inflammation, along with detailed information on smoking behaviors, are needed to further characterize the mechanisms of increased lung cancer risk among PWA.