Combining forces to alleviate the burden of Cryptosporidium

But while diarrheal disease is the second leading infectious killer of children under five worldwide, its causes and the extent of its impact on children haven’t always been well understood.

In 2013, a major clinical and epidemiological survey conducted across Africa and Asia made a surprising discovery[RL1] . The Global Enteric Multicenter Study (GEMS) found that a parasite that had received scant attention—Cryptosporidium—was actually among leading causes of illness and death.

First identified as a human pathogen as recently as 1976, Cryptosporidium (or Crypto) became recognized as a public health threat in the mid-1990s. By then, it had been linked to waterborne diarrhea outbreaks in high-income countries, chronic life-threatening diarrhea in AIDS patients, and diarrhea in malnourished children in low-income countries. In the United States, the most common route of exposure is swimming pools, as chlorine is ineffective at controlling “Crypto.” However, the most deadly cases occur in rural, impoverished areas, largely in sub-Saharan Africa and South Asia. Yet the magnitude of the little-studied protozoan parasite’s effects wasn’t understood.

While it was known that most children are exposed to Crypto within the first two years of life (without always showing symptoms of diarrhea), GEMS revealed two key new pieces of information: (1) Crypto is the second leading pathogen associated with moderate to severe diarrhea in children under two years and (2) it is the leading pathogen associated with death in toddlers (ages 12 to 23 months).

In 2015, another major international study—The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED)—corroborated and extended the surprising findings of GEMS. MAL-ED demonstrated that Crypto is also a key pathogen in community-level (i.e., mild) cases of diarrhea in children under two years old.

In addition to causing illness and death, Crypto’s damaging effects to the GI system can leave survivors suffering from chronic malnutrition, stunted growth, and delayed mental development, symptoms that may be part of a larger syndrome known as environmental enteric dysfunction. These effects also make survivors more vulnerable to other illnesses, in part due to the subsequent failure of oral vaccines for diseases such as rotavirus—an even deadlier form of diarrhea—in patients who have been sickened by Crypto.

At PATH, we realized there was a deadly gap in diagnosis and treatment for Crypto. None of the available diagnostic tests met all of the requirements—rapid, low-tech, sensitive, specific, and affordable—for the low-resource settings in which they are needed.

As a parasitic disease, Crypto is also more difficult to treat than other bacterial or viral infections. While other diarrheal diseases can be prevented with vaccines or treated with antibiotics, there is no Crypto vaccine or effective treatment for all patients.

In 2002, the drug nitazoxanide (NTZ) was approved by the US Food and Drug Administration for the treatment of Crypto and Giardia lamblia infections. While NTZ benefits users who are otherwise healthy, it is largely ineffective in children who are undernourished and in individuals with compromised immune systems, such as HIV/AIDS patients—in other words, the people most at risk for severe health impact or death. NTZ is commercially available in many countries, but actual use of the drug is limited, even in areas where the infection may account for 15 to 25 percent of all cases of diarrhea in children.

Due to these factors and others, including material and personnel costs, and lack of infrastructure or training, the standard of care for Crypto and other diarrheal diseases remains treatment with oral rehydration solution (ORS). While ORS is effective at alleviating the symptoms of dehydration, it does not cure the infection or reduce stool output. It also does not reverse damage caused to the GI system by diarrheal illnesses. Chronic malnutrition and decreased nutrient absorption continue to plague survivors, even if ORS has helped them survive.

We recognized that we need new and improved therapies that can reduce the burden of diarrhea and more quickly reduce symptoms, alleviating the length and severity of illness. To better deploy treatment, we also need new and better diagnostic tools to identify the disease in the areas where it is taking the largest toll. As part of our multifaceted approach to fighting diarrheal disease, we’ve combined forces with partners to advance Crypto research and development and identify a promising portfolio of lead optimization stage drug candidates.

• Calcium-dependent protein kinase 1 (CDPK1) “bumped kinase inhibitors” project to refine computer simulations of drug action in the intestine in order to better understand the properties necessary for a drug to be active against Crypto. Partner: University of Washington (UW).
• Methionyl-tRNA synthetase (MetRS inhibitors) project to advance a Crypto drug candidate to preclinical development. Partners: UW, the University of Vermont, and Takeda Pharmaceutical Company Limited.
• Celgene phenotypic screen project to identify promising drug candidates for treating Crypto from Celgene’s compound library. Partners: Celgene Global Health, UW, UVM.
• We also convene a bi-annual Symposium on Innovative Therapeutics for Cryptosporidium where global experts discuss opportunities for development of new treatments and coordinate research.

Crypto may currently be a virulent and largely unopposed threat, but with focused attention on developing safe and effective new treatments, we can alleviate both its near-term and long-term effects, including growth stunting and cognitive development deficits. These strategies present a real opportunity to improve health and save millions of lives, giving children around the world the best chance to thrive—something everyone deserves.