Asthma and atopy prevalence are not reduced among former tuberculosis patients compared with controls in Lima, Peru

Atopy is epidemiologically associated with asthma, rhinitis and eczema [1‐3]. It is estimated that asthma affects 334 million people worldwide and is one of the top 10 causes of death amongst young adolescents [4]. Allergic rhinitis is also common and often associated with asthma [5]. Some have hypothesized that a reduction in the prevalence of common bacterial infections (including tuberculosis), generally improved sanitation and/or a “westernized” lifestyle may underlie the increased frequency with which atopy and atopic disease are diagnosed [6, 7]. The “hygiene hypothesis” suggests that exposure to bacterial infections and toxins, which was common at the turn of last century and is still present in many developing countries today, provides an “infectious milieu” that reduces the development of atopy and atopic disease [8].

Tuberculosis is a common infectious disease that disproportionately affects people in developing countries [9, 10]. Whilst tuberculosis remains the biggest infectious disease killer on the planet, being responsible for an estimated 1.6 million deaths in 2017, the immunological effects of M. tuberculosis infection may influence the risk of developing atopy and atopic disease [11]. Tuberculosis is associated with a T-helper 1 (T_H1) lymphocyte immune response dominated by cytokines such as interferon-γ [12]. There is evidence from observational studies of an inverse association between tuberculosis infection, as measured by a positive tuberculin skin test, and the presence of atopy, defined as measured an elevated serum IgE and/or a T_H2 cytokine profile [13]. Furthermore, animal models using M. vaccae vaccination demonstrated that mycobacterial infection may inhibit features of allergic asthma [14]. Subsequent population-based studies have demonstrated a variable protective effect from mycobacterial exposure, either Bacille Calmette-Guérin (BCG) vaccination or M. tuberculosis infection, with the most consistent protective effect observed in those with a genetic pre-disposition to atopic disease [15‐17].

Evidence of the effect of tuberculosis disease (as opposed to infection) on the risk of atopy or atopic disease is limited. Ecological studies have suggested a reduced risk of atopy and symptoms of asthma among populations with higher tuberculosis notification rates [18]. However, this has not been confirmed in studies of individuals with and without tuberculosis. In this study we determine the rate of atopy among a cohort of patients with laboratory confirmed tuberculosis using the gold standard of skin prick testing. The measurement of exhaled nitric oxide (FeNO) may provide some additional insight into the pathophysiology, as nitric oxide (NO) is produced in the respiratory tract by activated inflammatory cells such as alveolar macrophages and is known to be elevated in asthma. Interestingly, NO has also been found to have important anti-mycobacterial effects in murine models [19]. Human studies suggest that patients with active pulmonary TB have lower FeNO levels early in their disease [20], which perhaps represents a deficient respiratory inflammatory response, but further data is needed. The objective of this study was to determine whether individuals with a confirmed history of tuberculosis have a reduced risk of atopy and of atopic diseases compared with people without a history of tuberculosis.

A description of enrolment of participants with prior tuberculosis has been published previously [30]. For the group without tuberculosis, we randomly selected 296 residents of the study area and 161 (54%) agreed to participate in the study. In total, the enrolled study population included 177 patients with a recent history of treated, laboratory-confirmed tuberculosis and 161 individuals without prior tuberculosis selected from the general population. The characteristics of the study population are described in Table 1. Those with prior tuberculosis tended to be younger (median age 29.0 compared to 37.6 years), included a higher proportion of males (57.6% vs 30.4%) and were more likely to be university educated (14.7% vs 3.7%) compared to those without prior tuberculosis. Participants in both groups were predominantly of mixed race (“mestizo”). The body mass index (BMI) was similar between groups as were the reported exposures to cigarette smoke, indoor air pollution and occupational dust.

We found a suggestion that people with prior tuberculosis had less atopy, as indicated by a positive skin prick test, than those with no history of tuberculosis. However, we did not find evidence of a decreased prevalence of any diseases associated with atopy, that is, allergic rhinitis and various manifestations of asthma, among people with recent tuberculosis.

Atopy is an IgE mediated immediate hypersensitivity response that occurs following exposure to environmental allergens [31]. Although others have observed that tuberculosis is associated with reduced manifestations of atopic disease, most previous studies have focused on the the consequences of latent tuberculosis infection rather than active tuberculosis [32, 33]. In contrast to previous studies, this study focused on patients with recent, laboratory confirmed, tuberculosis. The human immunological response to tuberculosis is complex, with important distinctions between latent infection and active disease [34]. People with active tuberculosis have increased numbers of circulating regulatory CD4 T cells (that express CD25 + FoxP3+) and a greater IFN-γ response, compared to those with latent infection [35, 36].

Peru is a middle-income country of South America that has high rates of asthma and allergic rhinitis despite routine BCG vaccination at birth [37]. Whilst the BCG vaccine is administered to reduce the risk of tuberculosis (particularly extrapulmonary disease among infants), limited evidence suggest that it may also reduce the risk of allergic rhinitis [17]. The average ambient temperature in Lima ranges between 16 and 32 °C year-round with high humidity, conditions optimal for mite reproduction [38]. The Peru Urban to Rural Asthma (PURA) study recently found that there were higher rates of asthma (12% versus 3%) and allergic rhinitis among 13–15-year-old children living in (urban) Lima than in a regional town on the north coast (Tumbes) [39]. In this context, it is noteworthy that both tuberculosis and house dust mites, may benefit from the environmental milieu found in the urban slums of Lima, Peru. The impact of tuberculosis disease on the risk of having asthma and related disorders has not been explored in epidemiological studies, other than in ecological analyses. Although the International Study of Asthma and Allergies in Childhood (ISAAC) [40] found that the prevalence of asthma in children was inversely related to the incidence of tuberculosis in 55 countries [41]. Our findings suggest that this question merits further study [42, 43].

We did not find any significant association between prior tuberculosis and any asthma-related outcomes, including wheezing, bronchodilator responsiveness, or exhaled nitric oxide (FeNO) concentration. It has been observed that people with prior tuberculosis may be more likely to have airflow obstruction [30]. Our FeNO findings imply that this is not mediated by eosinophilic inflammation. Any potential protective effect of tuberculosis on “atopic asthma”, may be lost due to lung damage and respiratory sequelae mediated through neutrophilic inflammation and other mechanisms [44]. This is counter to the idea of a reduced burden of atopic disease in settings where infectious diseases are common (the “hygiene hypothesis”). In fact, our findings suggest quite high rates of both atopy and atopic disease in this middle-income country. It would therefore not appear correct to ignore the possibility of atopic disease in patients with a history of tuberculosis. As this group has a greater risk of airflow obstruction and an equal risk of atopic disease (compared to community controls), respiratory health among former tuberculosis patients appears to be important. This may be an unmet need, especially in settings where the routine follow-up of tuberculosis patients does not occur or where linkage to (respiratory) specialist care is difficult.

As this was a cross-sectional study, we cannot comment on the temporal association between tuberculosis exposure and atopy or atopic disease. Our findings may also have been influenced by non-responder bias due to the relatively low participation rates. As only successfully treated tuberculoisis patients were recruited it is possible that patients with an unfavourable treatment outcome may have had different responses, but this has limited biological plausibility. We meticulously assessed and corrected other common factors that may have introduced bias, such as smoking and occupational dust exposure. Other study strengths include the recruitment of a well defined study population with controls subjects from the same community. All patients had laboratory confirmed tuberculosis, eliminating the risk of recall bias regarding the exposure. The population-based random sampling of controls participants from the same communities provided robust internal controls to assess the impact of tuberculosis on atopy and atopic outcomes, independent of other environmental, genetic and lifestyle factors. Another strength was the comprehensive assessment of atopy and atopic disease with standardized questionnaires and objective testing.

The apparent dissociation between atopy and atopic disease, in their relationship to tuberculosis, emphasizes the importance of understanding the biological mechanisms that underpin this possible inverse association. Further work is required to elucidate these mechanisms.