Impact of soil-transmitted helminths .
Helminths currently affect over 2 billion people worldwide with a quarter of the world’s population infected at some time in their lives. Sobering statistics from the WHO March 2008 report that 80% of the “Bottom Billion” impoverished population of the world have Ascaris, 60% have Trichuris, and 57% have hookworms. This would only be a problem of pharmacologic distribution if not for an additional report demonstrating that several new studies reported to the WHO claim a 50% failure rate clearing Trichuris and 90% failure rate clearing hookworm. These parasitic infections pose a challenge to tropical physicians who have considered mebendazole and albendazole as adequate treatments for children. This is even more of a challenge for physicians in temperate climates who may be less familiar with these medications. This article presents the recent data and the approach to treatment failure and new therapeutic approaches.
Intestinal parasites cause substantial morbidity and mortality, particularly in children in whom they have detrimental effects on growth and cognitive performance. Parasitic infestation leads to deformity and long-term disabilities and often stigmatizes the child. Parasitized pregnant women are anemic, have increased fetal wastage, and have low birth weight newborns. Though tropical diseases affect a large proportion of the world’s population, less than 1% of new drug development over the past 30 years focused on tropical diseases. Recent philanthropic interest has resulted in research, long tardy, for these diseases.
There are three soil-transmitted helminth infections, Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), and Trichuris trichiura, labeled by the WHO as the “Unholy Trinity.” They are ubiquitous in tropical climates and even temperate rural areas in poverty-stricken communities with poor sanitation (see Table 1). Ascaris and Trichuris increase in prevalence from infancy to puberty and then decrease in adulthood. In contrast, hookworm, the leading cause of anemia throughout the world, continues to increase through life, not reaching a plateau until age 40. This characteristic has a profound effect on women of childbearing age and is associated with small-for-gestation newborns as well as increasing fetal loss.
|Disease||Global prevalence (millions) ||Population at risk (billions)||Estimated global disease burden (disability-adjusted life years in millions)||Vulnerable population|
|Hookworm||576||3.2||1.5–22.1||School-age children, women of reproductive age|
The WHO has classified parasitic infestation by egg intensity to clarify symptomatic and asymptomatic infestations (see Table 2). Children with light worm loads are often asymptomatic, but children form the greatest population of the heavy intensity group. Even children considered asymptomatic may have subtle differences in learning and intellectual achievement .
|Light||1–4999 epg||1–1999 epg||1–999 epg|
|Moderate||5000–49,999 epg||2000–3999 epg||1000–9999 epg|
|Heavy||≥50,000 epg||≥4000 epg||≥10,000 epg|
The clinical presentation relates to parasite migration in the skin, viscera, and gastrointestinal tract. Trichuris and Ascaris are a result of fecal-oral ingestion. Wheezing, dyspnea, nonproductive cough, fever, bloody sputum, chest x-ray infiltrates, and systemic eosinophilia result during pulmonary vascular migration. Once swallowed the larvae mature, and their migration in the gut causes abdominal pain, distention, and malabsorption.
If adult Ascaris migrate into the biliary tree, then pancreatitis, cholangitis, and cholecystitis result. Hepatic abscesses and appendicitis may result from Ascaris migration. In younger children, heavy loads of worms can cause partial or complete bowel obstruction in the ileum. Swelling of Peyer’s patches leads to an increased risk of intussusception and volvulus. Unrecognized obstruction may eventually cause bowel infarction and perforation with resulting peritonitis.
Trichuris may infect any part of the colon, but the parasite prefers the cecum. Eggs release the larvae in the small intestine, and the worms mature in the colon where they tunnel into the mucosa, causing inflammation. Heavy infestation causes a dysentery syndrome severe enough that it may result in rectal prolapse. Impaired growth and anemia are the consequences of chronic infestation.
Hookworm infects through skin penetration. Itching erythematous rash from multiple skin penetrations causes severe pruritus of the skin, usually on the feet or hands. The larvae use the pulmonary vasculature to access the bronchial secretions and then, when swallowed, mature into adults in the gastrointestinal tract. Bronchial migration presents as clinical pneumonitis but may be mistaken for asthma. Pulmonary symptoms are seldom as dramatic as with Ascaris. The significant sequelae of infection relate to intestinal blood loss. As few as 40 worms can reduce the hemoglobin below 11 g/dl. Heavy infestations lead to loss of protein with resulting loss of plasma osmotic pressure and anasarca.
Helminth infestations cause anemia and malnutrition, growth stunting, and cognitive deficits, associated with poor school attendance and performance. Since this occurs in an impoverished area where the diet has limited resource to protein, the consequences of the poor child’s limited diet magnifies the malnutrition. If this occurs in a malaria area, the anemia caused by helminths exaggerates the anemia of malaria.
This is especially crucial for women of childbearing age, since infected women were 2.6 times more likely to have preterm deliveries and 3.5 times more likely to have small-for-gestational age infants. If the woman lives in a malaria-endemic area, the risks of malaria increase the infant mortality.
There are four medications currently available to treat soil-transmitted helminth infections (see Table 3). Benzimidazoles impede the microtubular system, in particular β-tubulin, in the worm. Since this is not a host system, patients tolerate these drugs with minimal side effects. Very few patients report nausea, vomiting, and headache, but allergic reactions with fever are rare. Levamisole and pyrantel pamoate are nicotinic acetylcholine receptor agonists, which paralyze the worms and precipitate their expulsion. Gastrointestinal symptoms, headache, dizziness, fever, and rash are usually mild and self-limited. However, a bulk of paralyzed worms increases the risk of a bowel obstruction.
|Ascariasis||Albendazole*||400 mg once|
|Mebendazole||100 mg twice daily × 3 days or 500 mg once|
|Pyrantel pamoate||11 mg/kg (max 1 g) × 3 days|
|Levamisole||2.5 mg/kg once|
|Hookworm||Albendazole*||400 mg once|
|Mebendazole||100 mg twice daily × 3 days|
|Pyrantel pamoate||11 mg/kg (max 1 g) × 3 days|
|Levamisole||2.5 mg/kg once, repeat after 7 days for heavy infection|
|Trichuris||Mebendazole||100 mg twice daily × 3 days or 500 mg once|
|Albendazole*||400 mg × 3 days|
The most important aspect of treatment is efficacy. Cure rates and egg reduction rates are high for all four drugs when treating Ascaris (see Table 4). Nevertheless, recent studies have documented ineffective and inconsistent treatment of Trichuris and hookworm, whether Ancylostoma duodenale or Necator americanus. The concern is drug resistance, despite lack of previous investigation. Researchers presumed that the drugs were effective in the past because they were effective with the other helminths. Recent studies by veterinarians tested efficacy in mass drug administration to animals in endemic areas. Such studies presumed human efficacy. Subsequent studies done in adults excluded children and pregnant women, the most at-risk populations.
Currently, research established benzimidazoles as safe for children greater than 1 year of age. Teratogenic potential seen in animal studies requires careful assessment of benefit/risk ratio. The WHO does recommend treatment of hookworm in pregnancy due to the adverse effect of anemia which is greater than the risk of the medication . Limited studies show no congenital anomalies or perinatal mortality with the use of albendazole, mebendazole, or ivermectin, although use in the first trimester is still discouraged. Studies have yet to focus on levamisole and pyrantel in pregnancy .
Because of the large burden of disease, prevention needs to be the foremost consideration in improving community health. Sanitation, access to a clean source of water, and careful food preparation limit fecal-oral contamination. Careful disposal of feces decreases exposure to helminthic eggs, and footwear limits hookworm exposure.
The other approach has been to limit morbidity through periodic treatment. The school system has been the logical institution for community treatment. Many studies have employed deworming schoolchildren on an annual basis, while others have focused on women of reproductive age. One recent study focused on community versus schoolchildren treatment justified a strategy that involves the entire community . Community treatment in several studies documents the requirement to reach at least 75% of the at-risk population. Governments willing to institute such programs recognize the cost of $0.02 USD. Several pharmaceutical companies made the drugs affordable. One example, a study done in Zanzibar, examined the co-administration of ivermectin, albendazole, and praziquantel in 5055 children and adults. This mass drug administration benefitted the entire community.
6. Future research and treatment
Considering the high prevalence of soil-transmitted helminths and the established resistance, there is a need for other treatment options. This has provoked enthusiasm for vaccines and drugs with novel mechanisms of action. Unfortunately, there has been little financial incentive for developing human vaccines and novel drugs for poverty-stricken areas, but veterinary medicine has the financial incentive of herd treatment.
The nicotinic acetylcholine receptor is unique to helminths and nematodes, although it appears to be a malaria parasite receptor as well. Since this receptor does not exist in humans, a medication to block this receptor should be effective and well tolerated. A vaccine with an antibody against this receptor seems a logical potential step for research. Tribendimidine is an L-type nicotinic acetylcholine receptor agonist. It is very effective in animals. Clinical trial in humans resulted in approval in China in 2004. Despite the difference in chemical structure and the hypothesized receptor agonist effect, it proved to have the same mechanism of action as benzimidazoles and showed no advantage in humans.
Monepantel is a nicotinic acetylcholine receptor agonist. It is highly effective and licensed for sheep. Researchers initiated studies in humans. It does appear to have a unique mechanism of action since in animals it has been effective in multidrug resistant nematode infections it may also be effective in humans with resistant infestations.
Developing a vaccine requires an antigen. Developers have struggled with which antigen to use that will allow a sufficient and effective antigenic response. Vaccines developed for soil-transmitted helminths are effective in newborn animals. A vaccine to the hookworm antigen, Na-ASP-2, is effective in dogs . Vaccinated while still puppies, they were resistant to hookworm infection. This success led to a limited phase 1 trial in Brazil. Unfortunately, 30% of the patients developed urticaria, and one patient developed anaphylaxis. These reactions stopped the trial. Speculation as to the cause of this intense reaction led to the hypothesis that the study patients had antibodies to the antigen because of previous exposure from residing in an endemic area. Like the puppies, the requirement must to vaccinate human subjects prior to antigenic exposure .
Helminth infections are a common problem. Presumed effectiveness of drugs is a deficient hypothesis. The available medications are not as effective as once thought. The trials of mass treatment of schoolchildren do not exterminate the source of infection or resolve the community exposure. New medication research is essential, especially for Trichuris. Novel treatments such as vaccines may be on the horizon, but safety concerns for humans with previous exposure is an important immunologic problem. Sanitation is still the most important community solution. The recent disaster in Port-au-Prince, Haiti, demonstrated that without sewer systems and potable water, we humans are indeed a vulnerable species.