Tackling a Triple Threat

Helminthic infections and tuberculosis (TB) – not only do these represent two of the most significant global public health concerns (present pandemic excepted), but there is also notable geographic and population overlap between them. Recently, researchers have begun to gain a better understanding of this geographic concordance and the commensurately high rates of coinfection.  A new hypothesis states that helminthic infection may deleteriously impact the management of TB. To clarify their potential interactions, I have examined studies conducted in South Africa to establish the current state of evidence and offer a perspective on the impact that anthelmintic interventions may have on TB control.

Coinfection is common

Most TB and helminthic endemicity occur in the same settings, and coinfection is common. A broad range of countries with high helminthic burdens, such as Malawi and India, have Bacillus Calmette–Guérin (BCG) vaccination results inferior to those seen in regions with lower parasite prevalence (1). A study comparing infant BCG vaccination success demonstrated that “three months post-BCG, 100 percent (51/51) of UK infants made an IFNγ response to M.tb PPD compared to 53 percent of Malawian infants (1).” In the literature, the primary explanation for BCG’s reduced efficacy in lower-income settings is differences in environmental mycobacterial exposure. However, another study offers a compelling alternative explanation: the interaction between helminths and TB. The researchers demonstrate that helminth coinfection correlates with diminished levels of IgM and IgG factors critical in the immune response to TB vaccination (2). The association of helminth infections with the modulation of B cell function in TB is further underscored by post-treatment data from the same paper – following successful anthelmintic treatment, the diminished levels of both IgM and IgG increased. These results support the hypothesis that BCG confers the least protection in areas with high endemic helminth prevalence because the baseline immunity in individuals living in these areas is perturbed by coinfection.

South Africa is a natural context in which to explore the interplay of helminth and TB infection. Although TB represents a serious health problem across the globe, South Africa possesses “the highest TB incidence in the world (3)”. Even discounting the mortality stemming from TB/HIV coinfection, TB represents the top “natural” cause of death in the nation (4). Under these circumstances, progress toward better comprehending and responding to co-pathogens in South Africa’s context may promote better health and health outcomes. Additionally, the association of helminth infections with AIDS and TB in South Africa has been recognized since the nation’s independence, particularly with respect to the triple disease burden borne by the 36.4 percent of the population living below the poverty line. Despite the awareness of their potential interrelatedness, “studies of helminth coinfection with HIV/TB and their deleterious effects are lacking (5)” in South Africa to the detriment of efficient management of a significant public health issue.

A triple threat

If addressing helminth infection positively affects the treatment of TB in South Africa, it will be primarily in terms of its consequences for immune response to TB infection itself – and, due to the high rates of triple infection, its impact on HIV progression.

Let us first consider the impact of helminth coinfection on immune response to TB. Almost two decades ago, researchers suggested that, based on findings in Cape Town, “it is plausible that helminthic infections and Th2 dominance (reflected by IgE, IL-4, IL-13, IL-10) contribute to the high incidence of TB in Third World populations (6).” The potential import of Th2 bias in the context of TB control stems from the fact that, in conjunction with innate immunity, protection against the pathogen requires “an effective adaptive cellular immune response characterized by robust T helper cell type 1 (Th1) T-cell immunity and relative weaker T helper cell type 2 (Th2) T-cell immune responses (6).” Using the tuberculin skin test as a proxy for Th1 response and, consequently, functional immune reaction to TB, a second study underscored this hypothesis by documenting an inverse relationship between Ascaris infections (as reflected by IgE response) and tuberculin skin test-positive status in children from high-risk, poor, urban South African communities (7); that is, the children with intestinal roundworm infections had fewer positive TB skin tests than those who were free of worms.

Though such data could imply that helminths carry a protective effect against TB, that does not seem biologically plausible. It’s far more likely that “helminth exposure/infection may reduce the immune response following M.tb exposure (7).” If this is the case, then there are two potential advantages of deworming:

1. The possible reversal of the demonstrated Th2 bias. A Th1-focused immune response is well-established as critical for an optimal immune response to TB.
2. Improved diagnosis. According to the government of South Africa’s Western Cape Province, “testing for children is done using skin tests and chest X-rays (8).” Given the high prevalence of pediatric TB in South Africa and the methods used to diagnose it, there is enormous potential for undiagnosed TB due to helminths – especially if Western Cape Province’s diagnostic approach is the norm throughout the nation.

But an exploration of the interplay between helminth infection and tuberculosis treatment in the South African context is incomplete without considering a third pathogen: HIV. South Africa ranks among the worst-afflicted countries in the world for both HIV infection and TB. Half of all new TB cases in South Africa are diagnosed in HIV-coinfected patients (9). Given these statistics, any factor that worsens HIV prognosis and progression almost certainly plays a deleterious role in TB prevention and treatment.

The high prevalence of coinfection between helminths and HIV is well-established in South Africa. One study demonstrated a 24.7 percent HIV/helminth coinfection rate, with 42 percent of these patients hosting Ascaris lumbricoides, the “large roundworm” (10). Crucially, the study authors observed a statistically significant association between a CD4 count below 200 cells/μL and a helminth infection.

A second study bolstered the results of the first and addressed a number of its weaknesses by using both egg observation and serology. The researchers in this second group determined that HIV immune responses are impaired by helminth infections in certain susceptible groups of individuals, particularly those who are infected enough to excrete worm eggs and exhibit high serum IgE concentrations (11). Individuals in this subgroup were marked by eosinophilia, and the HIV-positive subjects with high IgE had close to three-fold higher viral loads than those with low IgE. Immune activation is known to be associated with a temporary increase in HIV viral load, even among otherwise well controlled patients; this means that a less robust antiparasitic immunological milieu (as reflected by a low IgE phenotype) could play a role in mitigating this aspect of HIV viral infection.

The worm in the apple

Both eosinophilia and high IgE are classic Th2 responses commonly induced by helminth infections – so there are a number of biologically plausible theories as to how helminth coinfection worsens HIV prognosis. One such theory is that eosinophils increase the number of activated cells that are vulnerable to HIV infection. (How? In large part through their ability to prime CD4 cells, rendering them susceptible to HIV infections.) Findings consistent with this theory have existed in the literature for decades (12). The collective findings from the high IgE groups also concur with the suggestion that chronic helminth infections in adults disrupt peripheral T cell populations (11). This link is underscored by the fact that IgE – and no other immunoglobins – has been “inversely related to helper T cell and suppressor/cytotoxic T cell numbers (13).” Taken as a whole, these results strongly support the idea that the immunological milieu induced by helminthic infection worsens the body’s ability to respond to HIV and, commensurately, to TB.

There are many good reasons to argue for the value of deworming as a stepping stone to more robust TB treatment – primarily its impacts on immunology of both TB and HIV, but other potential advantages as well. The frequency of coinfection offers not just the opportunity to improve treatment of tuberculosis by undercutting its partners, but to directly and simultaneously treat multiple conditions with the same agent. For instance, research has demonstrated the enormous anti-mycobacterial treatment potential of the avermectin family of anti-helminth agents. In the course of one study (12), every avermectin that was evaluated showed mycobactericidal effects, “reducing initial bacterial viability up to six orders of magnitude (12).” What makes these results all the more exciting is the fact that all avermectins tested showed promising bactericidal activity against the multidrug-resistant strain of Mycobacterium tuberculosis, suggesting that we might be able to add avermectins to the small pool of agents we can use to treat TB patients with drug-resistant disease. These medications are especially practical therapeutic options because of the low exposure (AUC/MIC ratios of 10 to 15) needed to achieve clinical effect. A further attraction is that “the specificity of avermectins for mycobacteria would be ideal for selectively targeting the pathogen while minimizing deleterious effects on resident gut flora after oral administration (12).” Ultimately, the authors conclude that “the promising 2 to 8 μg/mL range of MICs for avermectins in liquid cultures is comparable to that of second-line TB drugs, ranging from 1 to 25 μg/ml against M. tuberculosis (12).”

This work is the first demonstration of the antimycobacterial activity of avermectins and, consequently, the potential for simultaneous co-treatment of helminths and TB. Potentially adding some field-based credibility, a follow-up study – once again examining Ascaris in urban South African children – described the anti-mycobacterial potential of anti-helmintic agents as a plausible explanation for its seemingly contradictory results (13). It is possible that sufficiently rapid deworming can clear mycobacterial infection before the appropriate Th1 response reaches culmination – though, of course, further study is warranted.

Finally, beyond their direct positive impacts, deworming programs have often served as entry points to reconstructing and bolstering public health. They provide models, generate confidence in interventions, and help to facilitate partnerships between communities and academic institutions.Intervention research in an informal settlement in Cape Town, for example, demonstrated that a successful school-based deworming program can play a key role in convincing parents and teachers to get involved in health care delivery. All those involved in the intervention, including the children, came to appreciate that health education focused on local problems is beneficial. The researchers also demonstrated – though without fully elucidating why – that synchronized mass deworming programs, especially in densely populated informal settlements, can contribute to overall health. It’s findings like this that have motivated scholars to consider investment in deworming as a practical and affordable way to help “reduce the incidence of infection by HIV and tuberculosis, slow down the progression of the diseases they cause, and improve the efficacy of vaccines against HIV/AIDS and TB (15).”

Many birds, one stone

At least in South Africa, strong evidence exists that helminth infection may exacerbate TB. Most critically, parasitic infections and mycobacteria engender two divergent immune responses. Consequently, a person mounting an appropriate response to a helminth infection undergoes an immunological shift that leaves them increasingly vulnerable to TB. Compounding this situation, the Th2 predominance of the immunologic response to TB can render it more vulnerable to HIV progression. With these immunological consequences in mind, the value of deworming as a potential positive factor for TB control seems clear.

Its potential is only enhanced by emerging evidence that anti-helminth agents may also treat mycobacteria with similar efficacy to second-line anti-mycobacterial drugs – and, of course, that deworming has significant positive effects on overall community health. As South Africa has long believed, and the literature increasingly indicates, helminth infection is very much an equal partner in a deadly triad alongside tuberculosis and HIV. This research, along with corroborating evidence from other African nations, strongly indicates that deworming may soon be a key component of treatment not just for helminths, but also for TB.