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A Social Issue Neglected Tropical Diseases and Three Major Infectious Diseases

Chagas’ disease

<Appearance of a patient with Romana’s sign> CDC

Chagas’ disease is caused by the parasite Trypanosoma cruzi, a species of flagellate trypanosomes that are transmitted to people via insects formally referred to as Reduviidae common to Latin American and Caribbean countries. Since Chagas’ disease sometimes does not develop even after an infection, it is also known as the “silent disease.” Nevertheless, this disease can kill suddenly if left untreated. Chagas’ disease is endemic to Latin America, where some 6–7 million people are estimated to be infected.

Causes of Infection

Disease Agent

T. cruzi, a species of parasitic flagellate, trypanosomes, also known as American trypanosomes

< Microscopic view of Trypanosomes of cruzi > CDC

Vector

Reduviidae

< Reduviidae > CDC

Chagas’ disease is caused by metacyclic trypanosomes of T. cruzi transmitted to people and animals via Reduviidae. T. cruzi live in the feces of infected Reduviidae, which suck blood from people’s faces when they are sleeping and excretes the feces with T. cruzi.(For this peculiar behavior, Reduviidae are also called “kissing bugs.”)When the sleeper inadvertently touches the wound and then touches their eye or mouth with the same finger, the infection thus spreads with T. cruzi through membrane mucosa as well as the bite wound.

Reduviidae live indoors in soil or sun-dried bricks. Hiding itself in cracks in walls or ceilings during daytime, it comes out at night after people go to bed. Its outdoor habitat is relatively inconspicuous areas, such as underneath verandahs, under concrete, as well as in piles of rocks or logs.

感染経路

U.S. Centers for Disease Control and Prevention,
"Parasites - American Trypanosomiasis (also known as Chagas Disease)." Accessed March 19, 2014,
http://www.cdc.gov/parasites/chagas/biology.html

Symptoms

Symptoms of Chagas’ disease have acute and chronic stages. In either one, symptoms may not be conspicuous. Nevertheless, it can develop into a fatal disease.

< Appearance of a patient with Romana’s sign > CDC

Acute Stage

From several weeks to several months after infection, only nonspecific symptoms that can be attributed to other diseases are observed, e.g., fever, fatigue, itchiness, headache, and diarrhea. However, closer examination discloses a swollen liver and spleen as well as skin lesions, such as red swelling or stiffness around the wound, called a chagoma. This stage is also characterized by swollen eyelids (Romana’s sign) caused by reduviidae bites or contact with its feces. Although these symptoms disappear in a few weeks, it does not mean that Chagas’ disease is cured.

 
Chronic Stage

No symptoms may appear for a few decades after the acute stage. In some cases, they never appear. Nevertheless, about 20 to 30% of the infected show the following symptoms:

Heart complications (maximum of 30% of the infected)

Cardiac hypertrophy, heart failure, an irregular pulse, unstable heart rate, apex aneurysm and thrombus formation, cardiopulmonary arrest (sudden death)

Gastro-intestinal complications (maximum of 10% of the infected)

Megaesophagus and megacolon with resultant difficulty in swallowing and an excretory disorder. When these symptoms appear, they cannot be treated with anti-Chagas’ disease therapeutics, calling for specialized treatment.

 

Diagnosis and Treatment

Diagnostic Methods

Infection is discovered by microscopic examination of blood. When infection is confirmed, electrocardiography is conducted to look for heart problems.
  Blood examination is effective only during the acute stage when parasites are active in peripheral blood. Immediately after infection, Chagas’ disease can be diagnosed and treated with a high degree of success.
  Once the disease enters the chronic stage, parasites disappear from the peripheral blood, making it difficult to diagnose its presence using an ordinary blood test. For this reason, when there is a high probability of infection, it is necessary to conduct at least two kinds of serologic tests (enzyme linked immunosorbent assay: ELISA, and immunofluorescence:IFA, etc.) to verify the presence of an antibody.

 
Treatment

Treatment for this disease include administering a chemotherapeutic agent anthelmintic to eliminate the agent and symptomatic treatment to deal with emerging symptoms.

Chemotherapeutic agent

Chemotherapeutic agent can be administered not only during the acute stage but also during the early chronic stage, when disease has not appeared in the heart or digestive systems.
Chemotherapeutic agent for T. cruzi include benznidazole and nifurtimox. In either case, the amount to be administered is determined by the age of the patient. At a maximum, benznidazole is given consecutively for 60 days and nifurtimox for 90 days.
On the other hand, these drugs have a high side effect incidence rate (40%), requiring care when they are administered. (The side effects of benznidazole include allergic dermatitis, peripheral nerve disorder, anorexia, weight loss, and insomnia; the side effects of nifurtimox include anorexia, weight loss, polyneuropathy, nausea, headaches, and dizziness.)Neither can be administered to pregnant women or patients with kidney or liver problems, and nifurtimox cannot be administered to patients with nervous or mental diseases. For these reasons, development of new drugs for treating Chagas’ disease is strongly hoped for.

Symptomatic Treatment

When disease appears in the heart or digestive system, it is necessary for the patient to wear a heart pacemaker and to take medicine that suppresses arrhythmia.

 

Prevention

Currently, no vaccine can prevent infection. Therefore, it is important to block entry of reduviidae from outdoors and to avoid bites of reduviidae that live indoors.
For this reason, it is necessary to use an indoor insecticide and a mosquito net sprayed with a long-lasting insecticide, to wear long-sleeved shirts and long pants, and to apply insect repellent to exposed skin.
From the viewpoint of public hygiene, it is imperative to screen blood and internal organs before blood transfusions and organ transplants. Also, to prevent mother-to-child transmission, it is important to conduct an examination of expectant women and a post-eight month examination of the newborn.

Regions at High Risk of Infection

Chagas disease occurs mainly in Latin America, with the exception of the Caribbean isles. It is particularly rampant in rural villages, where houses have earthen walls and straw roofs. In the past few decades, however, it has been increasingly detected in the United States of America, Canada, and many European and some Western Pacific countries. This is due mainly to population mobility between Latin America and the rest of the world. Also since the disease can be transmitted by blood transfusions from migrants or tourists, infectious regions are not confined to specific areas of the world. In Japan, the antibody for Chagas’ disease was found for the first time in 2013 in blood donated by a Latin American male.

感染リスクのある地域

Estimated Number of Infected People

Some 6 to 7 million people are infected with this disease and the majority live in Latin America.

Estimated Number of the Deaths

During the acute stage, there have been rare cases of infants dying from serious inflammation like, myocarditis, or meningoencephalitis. Also, when those infected have compromised immunity or when there are a large number of infected protozoa, mortality rates tend to be high among children under five years and the elderly.
Chagas’ disease is the number one killer among infectious diseases (including malaria) in Latin America, where it is estimated that more than 12,000 people die of Chagas’ disease every year.

Initiatives by Pharmaceutical Companies and NGOs

In 2007, it was agreed that WHO (World Health Organization) would receive financial support from the pharmaceutical industry, including free drugs, to eliminate Chagas’ disease by 2010. In the three years up to 2010, WHO distributed 2.5 million nifurtimox tablets as a secondary therapy measure and, as primary therapy, benznidazole tablets for 30,000 patients in epidemic regions.
However, since these two types of drugs were found to be ineffective for adults already in the chronic stage, Eisai and the Drugs for Neglected Diseases initiative (DNDi) concluded a partnership and a license contract agreement in September 2009 for developing new drugs to cure Chagas’ disease.
WHO aims to eliminate indoor vector insects from Latin America by 2015 and to prevent infections from blood transfusions in Latin America, Europe, and the western Pacific. If WHO succeeds in eradicating vector insects around homes by 2020, anti-Chagas’ measures will have reached a major milestone.

Eisai

In partnership with DNDi, Eisai is developing a new drug to cure Chagas’ disease. DNDi uses a chemical compound that Eisai developed (development code: E1224) for clinical development and to verify its effectiveness and safety. Eisai, for its part, provides DNDi with scientific expertise on clinical development of E1224 as well as drug products that are required for clinical development.
To develop vaccines for the Chagas’ disease and the the leishmaniases, Eisai provides Sabin Vaccine Institute with a vaccine adjuvant that Eisai developed(E6020)and related information on the chemical compound.

Eisai, AstraZeneca, Celegene, Shionogi and Takeda

The above pharmaceutical companies launched a partnership (NTD Drug Discovery Booster) with DNDi, an independent nonprofit organization. This partnership aims to jointly discover lead compounds to develop new drugs for chagas disease and visceral leishmaniasis.

Bayer

While Bayer had provided 500,000 free nifurtimox tablets a year until 2011, it started to provide 1 million free tablets every year since 2012 under the banner of the London Declaration, which aims to eliminate neglected tropical diseases.

References
WHO- Neglected Tropical Diseases, accessed April 2, 2015,
http://www.who.int/neglected_diseases/mediacentre/factsheet/en/
CDC- Neglected Tropical Diseases, accessed April 2, 2015,
http://www.cdc.gov/globalhealth/ntd/diseases/