Introduction to Diarrheal Diseases

Diarrhea is a leading killer of children around the world. Responsible for 4 to 6 million deaths per year according to the World Health Organization (WHO), diarrhea is especially dangerous for infants and young children. Globally, it is estimated that 1.4 billion episodes of diarrhea occur in children less than five years of age annually. [12]

There are many different diarrheal agents, including bacteria, parasites and viruses. Determining the causes for diarrhea can be difficult with such a variety of infectious agents, and determination of disease burden for individual diarrheal agents is complicated by the lack of access to laboratory tests in many developing countries.

Causes of Diarrhea

Bacterial agents are responsible for many dangerous diarrheal diseases. Cholera caused by Vibro cholerae, Shigella caused by Shiga bacillus and Typhoid Fever cause by Salmonella typhi are some of the most common types of bacterial gastroenteritis. Other examples of bacteria that cause diarrhea include Campylobacter, Clostridium difficile [11], Escherichia coli, Listeria monocytogenes, and Salmonella enteritidis.

Protozoan parasites can also cause dangerous episodes of diarrhea. Cryptosporidiosis caused by Cryptosporidium parvum and Giardiasis caused by Giardia lamblia are two of the most common protozoan diarrheal agents.

Electron micrograph images of Cryptosporidium parvum oocytes

Viral Gastroenteritis is caused by a variety of agents. Noroviruses, adnenoviruses, astroviruses and many others may be responsible for diarrhea. Our website focuses on rotavirus, which is a primary cause of diarrhea among infants worldwide.

The burden of diarrheal disease can and must be reduced by improving sanitation and educating parents on rehydration therapy to prevent child deaths from dehydration and developing vaccines to prevent disease. Since improving sanitation is complicated by lack of infrastructure and funding in many countries where diarrhea is particularly devastating, and is insufficient in combating some pathogens, vaccines offer hope for reducing the toll that diarrhea takes on the world's children.

Introduction to Rotavirus

Rotavirus is a non-enveloped virus of the family Reoviridae. It derives its name from its wheel like appearance when viewed under an electron microscope, from the latin rota, meaning wheel. Rotavirus can infect people of all ages, as well as many other animals, however, in humans its primary targets are infants, the elderly, and people with compromised immune systems, as is seen in AIDS. By the age of three, most children have been infected at least once by rotavirus, with a significant number infected 2 or more times. Although no natural immune state exists for rotavirus, secondary infections are usually less severe than primary infection. The primary symptoms of rotaviral infection are fever and vomiting for several days, followed by non-bloody diarrhea. Though not normally fatal, the diarrhea caused by the virus can be quite severe, leading to potentially life-threating dehydration. Though easily treated with intravenous fluids in developed nations, these supplies are often unavailable in the developing world, and the dehydration caused by rotavirus is a significant cause of mortality. By developing a vaccine to rotavirus that could prevent or reduce the severity of rotavirus infection many of these deaths could be prevented.

Transmission

Rotaviruses are transmitted by the fecal-oral route. Only 10 to 100 infectious virus particles are needed to cause infection. This amount can readily be acquired through contact with contaminated hands and objects. Large numbers of viruses are shed in fecal matter, from 100 to 1000 particles per milliliter, so contamination of objects is relatively easy. Such routes of infection are common in day care centers, homes for the elderly, and family homes. Food handlers can contaminate foods that will not be subsequently cooked. Additionally, virus excretion occurs in asymptomatic individuals. Notably, standard sanitary measures that kill most bacteria and parasites are ineffective in controlling rotavirus, as demonstrated by the fact that rotavirus incidence is similar in countries with both high and low sanitation standards. [1]

The Need for a Vaccine

Rotavirus Primarily Affects Children

People of all ages are susceptible to rotavirus infection, but children 6 months to 2 years of age, premature infants, the elderly, and immunocompromised individuals are particularly prone to more severe symptoms. [1] The peak incidence occurs between 7 and 15 months of age, with approximately 0.8 episodes per child per year. [2] Children become most susceptible after 6 months of age when the protection afforded by maternal antibodies wanes. By 15 months of age many have developed some protection after primary infection [3] Almost all children get rotavirus at least once before they are three years old. [4]

Characteristic peaking of the skin in a dehydrated child.

Morbidity and Mortality

In the United States alone, rotavirus is responsible for more than 3 million cases of diarrhea each year, 500,000 doctor visits, and 55,000 hospitalizations for children under 5 years of age. [4] While the disease causes only about 100 deaths in the United States per year, in less developed parts of the world it is a major cause of mortality, with approximately one million deaths annually. [5] About 85% of fatal cases of rotavirus occur in nations defined as “low-income” by the World Bank. Various studies have found that in developing countries rotavirus accounts for approximately of 8% of all diarrheal episodes, 28% of clinic visits for diarrhea, and 34% of hospitalizations of young children for diarrhea. [6] Hospitalization worldwide for rotavirus varies from 1 in 16 children in Venezuela to 1 in 77 in the US. [7]

Estimated global distribution of the 800,000 annual deaths due to rotavirus diarrhea. Each point signifies five hundred deaths.

Sanitation Does Not Affect Transmission

Standard methods of sanitation such as antibiotic soaps are not 100% effective in killing the virus, and because low numbers of viruses can cause infection, transmission is common even with good hygiene practices. [5] The most effective antiseptics against rotavirus are alcohols, which have been found to reduce the number of viruses on the hands by greater than 99%. However, tap water alone, or tap water with regular soap reduces the titer by only 72-84%. [8] Handwashing can reduce the spread of the virus, but is an ineffective means of eliminating it. For that, a vaccine is needed. [5]

Treatments Are Difficult to Distribute in Developing Nations

In the United States, intravenous treatments are widely used to treat severe dehydration. These treatments are largely unavailable to the developing world’s 575 million children under age five. [9] While the alternative treatment of oral rehydration therapy (ORT) is more available, there are still significant setbacks in distributing ORT or instructions for its production. Due to all of these issues, a vaccine would be a much more cost-effective solution. [9]

A Vaccine is the Best Solution

We know that there are correlates of protection. Older children are not significantly at risk for disease because they have acquired immunity from past infections. A vaccine could induce this immunity without the children needing to go through multiple infections, and the risks associated with infections. [10] By preventing children from acquiring infection, a vaccine could greatly reduce the number of deaths due to diarrheal diseases, and greatly reduce the burden on the health system.