Coinfections: Managing a dynamic network of diseases

BY COLIN HEMEZ

When it comes to infectious diseases, the presence of one usually means the presence of many. Differences in environment, socioeconomics, and even genetics all conspire to leave some populations with high burdens of many diseases and other populations with low burdens of few diseases. This inconsistent distribution unfortunately results in many cases of coinfection, where an individual is infected with two or more distinct pathogens. Many HIV-positive individuals develop tuberculosis; several patients with hepatitis B also acquire hepatitis D; lots of those infected with intestinal worms have a more difficult time fighting viral infections like the flu.

Recent evidence suggests that coinfections are most common in regions with high burdens of infectious disease, including underdeveloped nations, tropical regions, and urban slums. In Africa particularly, of about 25 million HIV+ individuals, nearly half are estimated to also be infected with parasitic worms, also known as helminthes.¹ Numerous diseases—including malaria, helminth infections, sexually-transmitted infections, and tuberculosis—are highly comorbid with HIV spread.² In many parts of sub-Saharan Africa, coinfection is even seen as the norm, although specific epidemiological data on the prevalence of HIV, malaria, and helminth is limited and often inconsistent.

Given the great diversity of infectious diseases that exist in different parts of the world, the highly localized patterns with which they occur, and the lack of detailed data on how coinfections alter the disease outcomes of patients, what can health workers and public health officials do now to manage coinfection networks in a rapid and effective way?

Though the precise methods through which to minimize coinfection are often contested, it is indisputable that public health officials have an enormous and diverse number of strategies from which to choose. Some believe the answer lies in distributing more vaccines or prophylactic drugs. Sometimes quarantines are the most effective at preventing disease spread. In some environments, improving a community’s access to clean water could do the trick. But financial and human resources are always limited, and variation in coinfection type, prevalence, and severity all contribute to the effectiveness of various programs. Trying to generalize and universalize public health procedures is difficult because of how complex coinfections can be. The broadest and likely most effective strategy would be to collect detailed and reliable epidemiological data, which can then used by local officials to apply specific strategies to specific scenarios: in other words, collect data, then divide and conquer.

But even at a small scale, coinfections can still be immensely complex. A good example for studying how coinfections play out in a community is the aforementioned situation in sub-Saharan Africa, where coinfection with HIV, malaria, and helminths are widespread.

The coinfection between helminths and HIV demonstrate the key principle that immunological responses to co-infection play a significant role in the severity and spread of disease. Helminths impair cell-mediated or specific immune responses, which are crucial for developing immunity to all infections.³ Cell-mediated responses are responsible for the body’s production of antibodies, which is utilized in vaccination, so people who have been infected with helminths respond less to vaccines. So coinfection with parasitic worms undermines current and future vaccine campaigns against HIV, malaria, and other diseases. Currently, at least one helminth species is endemic (regularly infects the people) of sub-Saharan Africa, with helminth infection prevalence ranging from 20% to over 50% for the region.⁴ As a result, vaccination programs in Africa against all kinds of pathogens often have sub-optimal outcomes. To maximize the efficiency of their programs, public health officials must weigh the importance of targeting each disease. For example, for some areas with high rates of malaria or HIV coinfected with helminths, it may be more prudent to pursue helminth eradication rather than communal vaccination, as helminths decrease the effectiveness of vaccination programs. Or, a simultaneous treat-and-prevent program that offers both vaccination and deworming may be the most effective. To determine which is better must be decided on a local, case-by-case basis.

On another level, it is also important to pursue a better scientific understanding of the coinfection. The immunological effects of helminth infection on HIV risk are poorly understood, especially as they vary depending of the species of helminth involved.³ Helminths interfere with the body’s immune response in order to live for years, decades, and sometimes even lifetimes within a foreign host. The strategies that different helminths use to tinker with immune responses, however, are extremely diverse; they depend on a particular species’s life cycle and its targeted organ. Helminth infections, for the most part, could be either immunosuppressive or immune activating. In cases of immunosuppression, the helminth will secrete molecules into the host’s bloodstream that actively reduce the strength of a normal immune response. This could lead to decreased concentrations of helper T cells, aka CD4+ lymphocytes, in the bloodstream, making HIV transmission (or the establishment of an HIV infection in a previously uninfected person) more difficult. But the helminth infection can also have the opposite effect, increasing CD4+ lymphocyte levels and making it easier for HIV to replicate itself, transmit to another individual, and establish a new infection. The problem of HIV/helminth coinfection demands more basic research into the specific immunological effects of infection by different worm species, as well as localized mapping of helminth species prevalence within sub-Saharan Africa.

A different but similarly consequential coinfection is that between malaria and HIV; this one is slightly more complex. The reason why malaria infection increases the spread of HIV is rooted in the fact that an HIV+ individual’s ability to transmit the virus to another person is strongly associated with the amount of virus she contains in her blood. Specifically, a ten-fold increase in a patient’s viral load is associated with around a 2.5-fold increase in transmission probability.⁵ So infections that increase viral load in HIV-positive patients, either by creating environments in the body that favor virus replication, or by increasing levels of HIV’s preferred cellular host (CD4+ lymphocytes) in the blood plasma, are thus likely to increase HIV transmission and incidence.  The Plasmodium parasites that cause malaria appear to do just this, inducing more rapid HIV replication in the bloodstream and increasing the propensity for individuals coinfected with both HIV and malaria to transmit HIV. Strategies to control malaria in HIV-positive patients (such as rapid malaria diagnosis, treatment with artemisinin combination therapy, and prevention through prophylaxis) are therefore likely to reduce the prevalence of HIV in malaria-endemic regions. Public health officials must keep in mind the codependency between malaria and HIV when targeting either.

Another vitally important and even less intuitive consequence of the body’s immunological response to malaria is that even vaccines against malaria can trigger an increase in HIV transmission. This is because even partial Plasmodium antigens, fragments of the parasite that do not cause illness and are used in vaccines, appear to enhance HIV replication.⁶ This is likely because the immune system still generates a gradual response to the presence of chopped up Plasmodium, which may be less extreme than its response to the live parasite, but still is enough to produce the inflammation that HIV exploits. The macroscopic effect of this microscopic phenomenon is that the large-scale use of some malaria vaccines can lead to spikes in HIV incidence. A strategy that counters this is offering HIV pre-exposure prophylaxis (PrEP) to individuals receiving malaria vaccines, especially in regions with high HIV prevalence, to prevent them from contracting HIV. However this comes with additional costs, which must be weighed against the benefits by public health officials.

Aside from complexity arising from immunological responses in the host, the life cycles of the pathogens involved in coinfection play a large role in disease outcomes where coinfection is the norm. Helminths and Plasmodium parasites both have complex life cycles. Both have numerous life stages, both have multiple infection cycles within the body that invade different tissues, and both are highly dependent on the environment for transmission (helminths because they are often transmitted via the soil in poor-sanitation areas, and Plasmodia because they require the presence of female Anopheles mosquitoes for transmission from one vertebrate host to another). The dynamics of co-infections with worms and malaria are thus likely to be even more complex.

Sometimes the infections can actually have antagonistic effects on each other, with one reducing the likelihood of another’s transmission. For example, a survey of Senegalese children found that individuals with very low-intensity but persistent infections of Schistosoma mansoni, a type of helminth transmitted via contaminated waterways, had a lower risk for malaria infection after controlling for sex and season.⁷ This suggests that schistosomes may keep the host’s immune system in a state of perpetual activation, priming the host to combat a malaria infection when it arises.⁸ However, schistosome infection only showed a protective effect against malaria at an extremely low parasite burden. The study also found that about two-thirds of children who tested positive for S. mansoni infection also had parasite burdens that far exceeded the levels that they believed were beneficial against malaria. At these levels, helminth infection is more detrimental on malarial disease than it is beneficial, and it is not realistic to expect that schistosome prevalence could reduce malaria prevalence in a region. Nonetheless, the finding that S. mansoni appears to be immune activating is an important one, as it could influence the coinfection dynamics between S. mansoni and other pathogens in regions with high schistosome burdens.

The same study also found that school-age children are at the highest risk for coinfection with Plasmodium and one or more helminth species.⁹ Except at the extremely low (and rarely observed) worm burdens that seem to be protective against malaria, schistosome infection exacerbates symptoms of anemia that often result from recurring malarial episodes. Populations at the highest risk of anemia (namely, children and pregnant and nursing mothers) would benefit from integrated strategies that seek to control malaria and helminths simultaneously.

Strategies to control the co-infection network of HIV, malaria, and helminths must be tailored to the specific epidemiological circumstances of local areas. But international cooperation in formulating a disease control program is critical to building a foundation for local programs to build from. Public health officials need to consider the current and future impacts of different interventions, keeping in mind the impact of coinfection on the effectiveness of some programs. Because of the diverse consequences of helminth infections, some countries may benefit more from implementing aggressive anti-helminth campaigns rather than vaccination projects in the short term. Also, widespread data collection is essential for tracking the spread of disease and formulating interventions that meet the demands of local disease burdens. Coinfection networks are complex, and researchers are only just beginning to elucidate them using more accurate and detailed epidemiological data. New insights are sure to come; it is essential that as they do, public health workers integrate them into their fight against coinfection.

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