Neglected tropical diseases: should we wage war on them or not?

Should we aggressively attack the diseases that most clinicians treating adult patients have put in the back of their heads? When I was a trainee an instructor (I got my training in the army so all teachers were instructors and when I went from being an Assistant Professor to a Professor in the army terminology I went from instructor class 2 to instructor class 1) very emphatically said that the current medical emergency in the country warranted a mass deworming of the population. This would significantly reduce all medical diseases in the population. This was in the late 70s. The remark drew a laugh from most other teachers and consultants who then turned their attention to heart disease and hypertension and diabetes and such like. In the article I am citing we are learning of the efficacy of mass treatment with ivermectin and azithromycin and giving combination of drugs as well.

Expanding the War on Neglected Tropical Diseases
Peter J. Hotez, M.D., Ph.D., Alan Fenwick, Ph.D., and David H. Molyneux, D.Sc.

Of the seven major neglected tropical diseases three are soil transmitted helminth infestations ( ascariasis, trichuriasis and hookworm) and three worms that live in the blood or lymphatics or tissues; schistosomiasis, lymphatic filariasis, and onchocerciasis and then there is trachoma. The collateral and extended effects of preventive chemotherapy, many of which were unanticipated, have reduced disease burdens and saved lives on a scale that appears to have exceeded the intended impact

The concept of integrated programs of mass drug administration (also referred to as preventive chemotherapy) was first proposed in the early 2000s, and such interventions now reach more than 1 billion people per year in low- and middle-income countries of Africa, Asia, and Latin America.1 Implementation of the World Health Organization (WHO) preventive chemotherapy strategy has resulted in substantial reductions in the disease burden and disability-adjusted life years (DALYs, or lost years of healthy life) — as much as a 46% decrease in DALYs — attributable to the seven NTDs, allowing some countries to achieve their elimination targets for trachoma, lymphatic filariasis, and onchocerciasis. Moreover, it has led to cost savings for the world’s poorest people, by reducing catastrophic health expenditures. I would like to refresh your memories on the subject of ascariasis, trichuriasis, pinworm and hookworm.

ASCARIS. 

Ascaris lumbricoides is the largest intestinal nematode (roundworm) parasitizing the human intestine and is one of the most common helminthic human infections worldwide. It is also a  parasite of pigs and a very similar one infests human beings as well.  Transmission of ascariasis occurs primarily via ingestion of water or food contaminated with Ascaris eggs. Most patients with A. lumbricoides or A. suum infection are asymptomatic. When symptoms do occur, they occur most often during the adult intestinal worm stage (as intestinal, hepatobiliary, or pancreatic manifestations) but may also occur during the larval migration stage (as pulmonary manifestations).

Infestation is most common among children from 2-10 years of age with a sharp drop after the age of 15 years. Areas where toilet facilities are limited to the use of open fields or a hole in the ground  transmission is more likely. Warm climate increases survival of the eggs and the rainy season washes human excreta into the drinking water or vegetable fields. Proximity of pigs and the use of pig manure add to the likelihood of infestation.

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This picture shows a roundworm larva and a larva which is hatching. Given below is the life cycle.

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Adult worms (females 20 to 35 cm; males 15 to 30 cm) (1) live in the lumen of the small intestine. A female may produce approximately 200,000 eggs per day, which are passed with the feces (2). Unfertilized eggs may be ingested but are not infective. Fertile eggs embryonate and become infective after 18 days to several weeks (3), depending on the environmental conditions (optimum: moist, warm, shaded soil). After infective eggs are swallowed (4), the larvae hatch (5), invade the intestinal mucosa, and are carried via the portal, then systemic circulation to the lungs (6). The larvae mature further in the lungs (10 to 14 days), penetrate the alveolar walls, ascend the bronchial tree to the throat, and are swallowed (7). Upon reaching the small intestine, they develop into adult worms (1). Between two and three months are required from ingestion of the infective eggs to oviposition by the adult female. Adult worms can live one to two years. Larvae may migrate to brain or kidney.

Loeffler’s Syndrome is an eosinophilic pneumonitis which occurs when the larvae migrate through the lungs in previously unexposed individuals. It is not commonly diagnosed. Pulmonary manifestations associated with migration of Ascaris larvae include dry cough, dyspnea, fever, wheezing, substernal discomfort, and blood-tinged sputum. Over half of patients have crackles and wheezing in the absence of focal consolidation. Urticaria occurs during the first five days of illness in about 15 percent of cases. Hepatomegaly may develop. Lymphadenopathy is generally not observed. Symptoms generally subside within 5 to 10 days; the syndrome is usually self-limited and very rarely fatal.

Eosinophil levels are usually 5 to 12 percent but can be as high as 30 to 50 percent. Eosinophilia is masked by administration of steroids. Sputum analysis may demonstrate eosinophils and Charcot-Leyden crystals. These crystals are also observed in other eosinophilic parasitic lung infections. Chest radiography may demonstrate round or oval infiltrates ranging in size from several millimeters to several centimeters in both lung fields. These findings are more likely to be present when blood eosinophilia exceeds 10 percent. The infiltrates are migratory and may become confluent in perihilar areas; they usually clear after several weeks. The diagnosis may be definitively established via visualization of Ascaris larvae in respiratory secretions or gastric aspirates  although this is rarely possible. Examining the stool for larvae at this stage is of no value,

Symptomatic pulmonary involvement is rare among individuals in highly endemic areas with ongoing exposure. Treatment is symptomatic as anthelmintic therapy will not alter the course of the disease. If you need to use steroids rule out strongyloides first or multi organ failure can ensue.

Intestinal infestation is usually asymptomatic. Complications of ascariasis include intestinal obstruction, malnutrition, hepatobiliary involvement, pancreatitis, and other manifestations. in heavily infested areas ascariasis may be the most common cause of acute surgical emergencies in the abdomen.

The diagnosis of ascariasis is generally established via stool microscopy for evaluation of Ascaris ova (the eggs of A. lumbricoides and A. suum are indistinguishable). Characteristic eggs may be seen on direct examination of stool or following concentration techniques. Ova can be detected 40 days after infestation.

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Wet mount of ascaris ovum.

Examination of the stool.

  • The Kato-Katz method is the most common technique for stool preparation; it involves filtering a stool sample followed by staining using materials provided in a kit. It is the method recommended by the World Health Organization (WHO) and is the most widely used technique due to its simplicity, low cost, and capacity to facilitate detection of multiple parasite species. Examine three stool samples.
  • The FLOTAC method is generally considered the most sensitive stool preparation technique but requires a centrifuge, which limits its utility in some settings. In settings with high prevalence of ascariasis, the sensitivity of Kato-Katz and FLOTAC are comparable.
  • PCR using next-generation sequencing techniques are increasingly becoming available and are able to detect soil-transmitted helminths including T. trichiura. The utilization of such methodologies has the ability to improve species specificity and limits of parasite detection. Sensitivity and specificity vary according the specific test used; one study showed that, compared with microscopic examination of fecal samples, the sensitivity and specificity of a multiplex PCR were 87 and 83 percent, respectively

Treatment.

In a systematic review and network meta-analysis, average cure rates for treatment of A. lumbricoides with albendazole, mebendazole, and pyrantel pamoate were 96, 96, and 93 percent, respectively. The highest estimated egg reduction rate was for albendazole (99 percent), followed by mebendazole and pyrantel pamoate (98 and 94 percent, respectively). There were no significant differences among the treatments. In pregnant women use pyrantel pamoate.

ENTEROBIASIS (PINWORM)

Humans are the only natural host. Infection occurs in all socioeconomic groups; transmission is most efficient when people are living in closed, crowded conditions and is common within families. Enterobiasis is observed most frequently among school children aged 5 to 10 years; it is relatively uncommon in children <2 years old.

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TRICHURIASIS (WHIPWORM)

Trichuriasis occurs most commonly in tropical climates. It is estimated that approximately one-quarter of the world population carries this parasite. In communities where trichuriasis is endemic, infection may be present in more than 90 percent of individuals, but the majority of the total worm burden is generally carried by fewer than 10 percent. T. trichiura is frequently observed in association with other geohelminths such as Ascaris lumbricoides, since these pathogens thrive under similar conditions.

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Most infections with T. trichiura are asymptomatic. Clinical symptoms are more frequent with moderate to heavy infections. Stools can be loose and often contain mucus and/or blood. Nocturnal stooling is common. Colitis and dysentery occur most frequently among individuals with >200 worms, and secondary anemia may be observed. Infected individuals may have a peripheral eosinophilia of up to 15 percent. There may be pica and finger clubbing.

Rectal prolapse can occur in the setting of heavy infection, and embedded worms may be visualized directly in the mucosa of the inflamed rectum.

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 White adult worms can be seen on the prolapsed rectum.

Treatment is with albendazole and mebendazole. Ivermectin has limited value.

HOOKWORMS.

There are two major species of hookworm that cause human infection: Ancylostoma duodenale (in Mediterranean countries, Iran, India, Pakistan, and the Far East) and Necator americanus (in North and South America, Central Africa, Indonesia, islands of the South Pacific, and parts of India).

How do we pick up hookworms? Larvae migrate through the skin. Human fecal contamination of soil and favorable soil conditions for larval hatching and survival (moisture, warmth, shade) ensure that the larvae are present in the soil, and contact of human skin with contaminated soil provides the last step for the larvae to reach the intestine. Individuals who walk barefoot or with open footwear in fecally contaminated soil are at risk for infection; risk groups include native residents of endemic areas, tourists, and infantry troops.

The life cycle of the hookworm.

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The potential manifestations reflect the four phases of hookworm infection:

  • Dermal penetration by infecting larvae: a focal maculopapular pruritic patch “the ground itch”.
  • Transpulmonary passage: usually insignificant. Bronchopulmonary lavage in volunteers showed only bronchial erythema and eosinophilia.
  • Acute gastrointestinal symptoms: Nausea, diarrhea, vomiting, midepigastric pain (usually with postprandial accentuation), and increased flatulence have been observed in individuals with naturally acquired infections
  • Chronic nutritional impairment: hookworms cause blood loss during attachment to the intestinal mucosa by lacerating capillaries and ingesting extravasated blood. This process is facilitated by the production of anticoagulant peptides that inhibit activated factor X and factor VIIa/tissue factor complex and inhibit platelet activation. Each N. americanus and A. duodenale worm consumes about 0.3 mL and 0.5 mL of blood per day, respectively. The daily losses of blood, iron, and albumin can lead to anemia and contribute to impaired nutrition, especially in patients with heavy infection.

Diagnosis is confirmed by examining the stool. Treatment is with albendazole, mebendazole, pyrantel and  pamoate and ivermectin and oral iron therapy and a high protein diet.

Extended Targets of Medications Used for Preventive Chemotherapy against NTDs.

The primary drugs used for preventive chemotherapy, included albendazole or mebendazole, ivermectin, praziquantel, and azithromycin. They affected conditions beyond their originally intended targets. Now, nearly 15 years after mass drug administration for NTDs was first proposed, the existence of such collateral benefits can be verified.

In an Australian aboriginal community, a single dose of ivermectin (200 μg per kilogram of body weight) delivered in two community mass drug administrations 12 months apart not only prevented ascariasis, trichuriasis, and hookworm infections, but also significantly reduced the prevalence of strongyloidiasis. A similar effect on strongyloidiasis was achieved in Cambodia with a single mass ivermectin administration. Ivermectin also reduces the prevalence of loiasis (human Loa loa infection) in places where both onchocerciasis and loiasis are endemic. A recently published clinical trial suggests that ivermectin could help reduce the prevalence of mansonelliasis in the Amazon, although it’s less clear whether this effect could be replicated in Africa. In addition, mass administration of albendazole appears to have reduced the prevalence of oesophagostomiasis (Oesophagostomum bifurcum infection) in humans, even to the point of elimination in northern Ghana and Togo. Mass administration of single-dose praziquantel for schistosomiasis also appears to be effective for the treatment of opisthorchiasis (in Southeast Asia) and human tapeworm infections.

Furthermore, preventive doses of ivermectin reduced the incidence of  scabies and yaws. Scabies (and its associated secondary bacterial infections, especially impetigo) has one of the largest public health effects among the NTDs. Beginning in 2012, large-scale studies, including randomized clinical trials, conducted in the South Pacific and Africa showed the benefits of mass administration of ivermectin for scabies.  Similarly, mass administration of azithromycin designed for trachoma elimination has shown enormous promise for the treatment and elimination of yaws. A major study from Papua New Guinea in 2015 found that mass azithromycin administration substantially reduced the prevalence of yaws, as did a single round of such treatment in Ghana.

More recent studies have shown that plasma containing ivermectin has the capacity to reduce transmission of Plasmodium vivax malaria, thanks to the drug’s effects on the viability of both anopheles mosquito vectors and the malaria parasites themselves. In Kenya, among adults treated with both high-dose ivermectin and dihydroartemisinin–piperaquine, blood containing ivermectin was shown to reduce survival of Anopheles gambiae mosquitoes that fed on it, which suggests that this approach could also help in controlling P. falciparum malaria.

In 2009, in a trachoma-endemic area of Ethiopia, mass azithromycin administration was found to be associated with dramatic reductions in overall child mortality. The public health effect of azithromycin on trachoma occurs primarily in the first 3 months after the distribution of the drug, which suggests that azithromycin could have substantial benefits if administered to populations more frequently than once, or even twice, per year. A follow-up MORDOR II study is planned for Burkina Faso to test these, and other, ideas.

There are new anthelmintic agents, such as tribendimidine (for foodborne trematodiases and soil-transmitted helminth infections); the addition of either tribendimidine or oxantel pamoate to albendazole,  increases the efficacy of treatment for trichuriasis and hookworm; and moxidectin (recently approved by the Food and Drug Administration) has been approved in place of ivermectin in some settings. A further proposed addition is nitazoxanide to target the intestinal protozoa giardia and cryptosporidium. Finally, recent studies have indicated that chemoprophylaxis with single-dose rifampin in household contacts of people with leprosy may reduce leprosy transmission and prevalence in some settings.

One concern regarding mass drug administration, especially with azithromycin, is the potential emergence of drug resistance both to the intended target pathogens for trachoma, yaws, and leprosy and to colonizing respiratory and gastrointestinal pathogenic bacteria. So far, mass azithromycin administration has been shown not to elicit drug resistance in Chlamydia trachomatis, but it may elicit azithromycin-resistant yaws.

Expanding the public health impact of preventive chemotherapy would significantly increase years of healthy life for people in affected regions and would be highly cost-effective. The mass drug administration platform is a successful manifestation of universal health coverage, and the broader range of NTD-control strategies contributes to progress toward the United Nations’ Sustainable Development Goals. Such assessments are key advocacy messages that encourage further investments in NTD programs, which deploy a proven strategy that reaches more than a billion of the world’s most vulnerable people each year.

 

 

Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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