India’s mysterious diseases: The ailments that remain undiagnosed

Unnamed and unidentified outbreaks kill hundreds of people each year in India.  But some diseases in India have perplexed the government and medical fraternity for decades now.

“If the expert is unable to identify the disease, it is classified as mysterious,” Prabir Chatterjee, former epidemiologist with Chhattisgarh State Health Resource Centre, said. 

In Gorakhpur, Uttar Pradesh, such a mysterious disease has been doing the rounds for 15 years now. When this fever was reported from the area in 2005, three decades after it was last heard of, it was believed to be Japanese encephalitis (JE). That year, more than 1,000 children succumbed to the disease.

As JE is transmitted by mosquitoes, vector control was the prime focus. A vaccine too was available and it was quickly deployed in the area. But patients continued to come to the hospital in subsequent years. JE, however, started featuring less among the encephalitis cases, most probably because of vaccination.

Researchers started looking for an alternate cause and turned up the possibility of enterovirus being the culprit. The symptoms of both the diseases are similar — high fever, vomiting, unconsciousness and seizure. The only symptomatic difference is that the fever caused by enterovirus stretches up to 15 days as against JE, which lasts about a week. Enterovirus attacks the brain and permanently destroys its cells, killing the patient through multiple organ failure or leaving him or her physically or mentally handicapped.

In 2007, the National Institute of Virology (NIV) in Pune identified two enteroviruses — EV 76 and EV 89. But it is not sure if these cause brain fever. NIV’s tests on cerebrospinal fluid (CSF) and rectal swabs for three consecutive years found only some indication of the virus in rectal swabs but very little evidence in the more reliable CSF tests.

In 2017, deaths were linked to scrub typhus, a disease caused by Orientia tsutsugamushi, a rickettsial group of bacteria. However, the symptoms were atypical and only around a quarter of the patients tested positive.

There are several reports of the disease affecting infants, which is unlikely as the mites that transmit this bacteria, live in scrub vegetation and babies would not be exposed to such areas.

Also, patients with scrub typhus seldom die but deaths are quite common in Gorakhpur.

George M Varghese, professor at the Department of Infectious Diseases, Christian Medical College, Vellore, says that although  this region has witnessed a mixed bag of diseases such as JE, scrub typhus and enteroviral disease in the past, 2019 documented a much lower number of encephalitis and fatalities. Hopefully, the trend will continue, he said. 

In Muzzaffarpur, Bihar, encephalitis has been doing the rounds since 1995 and has a propensity for killing children. Studies by the NIV show that there was no viral infection. Though exposure to pesticides used in the litchi plantations has been blamed but researchers say that symptoms that occur in children are very different from classical symptoms caused by pesticide consumption.

One group of researchers suggested that the children could be dying because of heat stroke.

Another theory is that this is due to consumption of litchi fruit by undernourished children. Litchi fruit contains a toxin called methylenecyclopropylglycine or MCPG, that can lead to hypoglycaemia (fall in blood sugar levels). 

When undernourished children consume litchi fruits, their sugar levels fall, sometimes even becoming zero and they go into a coma. Hence, if a child sleeps without food, this whole physiological process gets completed by the early hours of the day and then the kid gets fever with convulsions and loses consciousness. 

Toxins have also been implicated in the mysterious fever reported from Saharanpur, a town in western Uttar Pradesh in 2002. Nearly 100 children died within two weeks but the local authorities disregarded the disease as ‘normal’.

This was not the first time the disease had struck the area. For two decades before this, an average of 400 children were dying each year in the region. The Industrial Toxicology Research Centre, now called Indian Institute of Toxicological Research, Lucknow, claimed that a pesticide was killing the children. After a media furore, National Institute of Communicable Diseases, which is now called NCDC, zeroed in on JE on the basis of tests.

In 2007, a group of doctors came up with another explanation for the mystery disease: Toxic pods of the weed Cassia occidentalis (locally called kasondi or pamaad), which children — especially the ones from poor families — ingested accidentally. Many of the deceased children had reportedly eaten the pods, some while playing the ‘kitchen game’ as the pods look like commonly consumed vegetables.

The doctors defined the disease on the basis of symptoms and pathological tests and found that children aged between two and four, coming from poor families, were mostly at higher risk. All of them showed similar symptoms: vomiting, fever and abnormal behaviour.

The symptoms were different from those of JE. No microorganism could be isolated from serum and internal organs in pathological tests. The researchers thus suggested that the symptoms could be due to a phytotoxin (plant toxin) and called the disease hepatomyoencephalopathy: it affects the liver, the brain and muscles. 

“Due to the failure of government orgainsations like NCDC and the Indian Council of Medical Research (ICMR) to identify the pathogens, individual researchers and doctors often try to unravel the mystery outbreaks. However, in absence of support from the government, a consensus on the cause of a disease is rarely reached,” Vipin M Vashishtha, consultant paediatrician in Bijnor, who was part of the Saharanpur investigation, said.

The investigating authority should ensure diagnosis thorough clinical, biochemical, histopathological and microbiological investigations, says Vashishtha. The second stage of investigations should consist of proper epidemiological probes to identify the risk factors.

The team should include epidemiologists, pathologists, neurologists, toxicology experts, public health experts and paediatricians. Autopsies must be performed to reach at a correct diagnosis, he said. 

It has been a rare feat when the cause of encephalitis has been identified quickly in India.

One such instance is the case of the 2003 outbreak of acute encephalitis of unknown origin reported in children from Andhra Pradesh. The disease had a high case fatality (183 of 329 cases). Researchers from NIV looked into the outbreak and using electron microscopy, serological and molecular assay, identified the pathogen to be the ‘Chandipura virus’.

The researchers suggested that this virus should be considered as an important emerging pathogen in their paper published in The Lancet in 2004. The likely vector of the virus is the female phlebotomine sandfly, the same pathogen that transmits Kala Azar or visceral leishmaniasis.

Chandipura virus is a member of the family Rhabdoviridae and has been detected in sandflies in Senegal and Nigeria too. It was first isolated in 1965 in a village in Maharashtra and since then, sporadic cases have been reported from adjoining states.

The whole process of identification just took around 6-8 months but even here, another group of researchers, who were neurologists claimed the outbreak was caused by a neurovascular stroke called ‘epidemic brain attack’. 

The inability to figure out the cause for encephalitis is unfortunate considering the huge number of deaths it causes each year. According to the National Vector Borne Disease Control Programme, which also monitors Acute Encephalitis Syndrome / JE cases in India, there have been a total of 51,999 cases in India since 2014 out of which, 6,713 patients died. 

“The search for the cause of a disease often leads to wild goose chases and the researchers need patience,” Lalit Kant, former head of epidemiology and communicable diseases division at the ICMR, said. “Skilled and experienced people are especially important in recognising a re-emerging zoonotic disease,” Kant added. The problem is more with new and emerging diseases as there are no diagnostic tests and the doctors have to diagnose on the basis of symptoms. For  a new disease of suspected zoonotic origin, working in collaboration with a veterinarian would be ideal, he suggested.

This is the second article of a 3-part series. The first can be read here

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