Bihar Puzzle: What is the unexplained illness killing so many children?

There is an urgent need for a structured research plan and epidemiological surveys to understand the underlying cause of the outbreak that has killed at least 132 children in Bihar.

Megha PrakashMegha Prakash   22 Jun 2019 1:04 PM GMT

Bihar Puzzle: What is the unexplained illness killing so many children?

Till June 20, one-hundred-thirty-two children have 'officially' died in Muzaffarpur, Bihar due to a suspected outbreak of acute encephalitis syndrome in the state. Suspected because a well-established cause that explains death of so many children within a period of three weeks is missing.

The response of the government -- both Centre and the state -- towards the public health disaster in Bihar is anything but satisfactory.

Whereas the state government failed to pick up early signs of an impending outbreak in Muzaffarpur district, the Union minister, Harsh Vardhan has made what seem like customary announcements. These include increasing the number of hospital beds at Shri Krishna Medical College (SKMC) Hospital in Muzaffarpur from the present 40 to 100 in the paediatric ICU ward; adding eight advanced life-support (ALS) ambulances in the affected districts of the state; setting up well-equipped virology laboratories in the five worst affected districts of the state to ensure detection and prevention of the disease. One such laboratory is expected to start functioning in Muzaffarpur within a year, said Vardhan.

Coincidentally, the health minister had made similar announcements five years ago on June 24, 2014 on his Facebook page when Muzaffarpur was in the grip of a similar outbreak.

None of these promises were kept. And, similar announcements have again been made.

A team of paediatricians has been sent to Muzaffarpur to deal with the growing disaster. Also, an expert committee has been set up to find the underlying cause of the recent outbreak in Bihar.

What's the outbreak?

This isn't the first time such an outbreak has hit Bihar. Since 1995, various teams have been studying the almost annual outbreak of the 'disease' in Bihar.

"We are dealing in the dark. Investigation in India is in dismal state. So far, not even a single autopsy has been conducted, no histopathology of major organ like liver performed by any agency," Vipin M Vashishtha, a Bijnor-based pediatrician and neonatologist told Gaon Connection. Vashishtha was part of an expert team, headed by T Jacob John, former president of the Indian Academy of Pediatrics, which investigated a similar outbreak in Uttar Pradesh's Saharanpur district in 2007.

For a long time, it was believed that the disease outbreak in Bihar was Japanese encephalitis (JE), a viral infection of the brain widely prevalent in India.

For instance, in June 2011, an outbreak, suspected to be Japanese encephalitis, occurred in Muzaffarpur. In June month alone, 125 children were brought to the SKMC Hospital, and the Kejriwal Hospital, of which 43 died.

The next month, in July 2011, Madurai-based Centre for Research in Medical Entomology, under the ICMR (Indian Council of Medical Research), undertook an investigation.

Since Japanese encephalitis is known as a vector-borne disease caused by mosquito, the researchers of the Centre for Research in Medical Entomology investigated if the mosquitoes were infected with the same virus. The findings of their study, published in May 2013 issue of the Indian Journal of Medical Research, ruled out Japanese Encephalitis Virus (JEV), as infection was not found in mosquito samples collected from the affected areas.

In their 2013 study, which was based on the analysis of human serum samples collected in July 2011 in Muzaffarpur, the researchers concluded that although all the afflicted children uniformly suffered from high fever, which gave way to convulsions and seizures, and brought in a semi-consciousness state for treatment, the disease was not Japanese encephalitis.

The researchers went on to note that since no confirmed reports were available on the etiology of the 2011 outbreak, the available secondary data confirmed the 'mysterious fever' was not Japanese encephalitis. Patients were also found to be negative for other viruses of Chandipura (virus known to be spread by sandflies) and Nipah (virus spread by fruit bats).

Acute encephalitis syndrome, or chamki bukhaar

Acute encephalitis syndrome (AES), locally known as chamki bukhaar, is defined as the acute-onset of fever with change in mental status (including symptoms such as confusion, disorientation, coma, or inability to talk) and often with new onset of seizures.

This syndrome is a major health problem in Asia. It includes illness caused by a wide variety of viruses, bacteria, protozoa, fungi. But, mostly considered as viral encephalitis. Cases of acute encephalitis syndrome are reported throughout the year, but there is an increase in these cases in June, which peak during July and August, and then decline in September-October.

Between 2008 and 2013, acute encephalitis syndrome cases have recorded an increase in the country, from 3,855 to 7,485. As per news reports, last year 10,485 such cases were diagnosed and 632 deaths recorded across 17 states.

India's fatality rate in acute encephalitis syndrome is 6 per cent, but in the case of children it is as high as 25 per cent.

Standard Operating Procedure

In 2012, the Department of Health of the Bihar government prepared a standard operating procedure (SOP) to deal with cases of acute encephalitis syndrome (AES). This SOP document was updated last year with an opening message from the chief minister Nitish Kumar.

The SOP not only defines AES, but also classifies AES cases into Japanese encephalitis (JE), known AES, and unknown AES.

Whereas the vector of Japanese encephalitis is mosquito, in case of known acute encephalitis syndrome, it can be viral encephalitis or non-viral encephalitis (see chart).

In 2016, of the total 424 acute encephalitis syndrome cases in the state, 52.8 per cent were unknown AES, 23.6 percent known AES, and 23.6 per cent Japanese encephalitis.

The next year, in 2017, 50 per cent of the cases were classified as unknown AES, 32 per cent as Japanese encephalitis, and the rest known acute encephalitis syndrome cases.

The etiology of 2017 cases showed 49 per cent were due to herpes encephalitis (encephalitis due to herpes simplex virus), 23 per cent due to hypoglycemia (a condition caused by a very low level of blood sugar), 13 per cent by dyselectrolytemia (acute muscle weakness), 10 per cent pyogenic meningitis (bacterial meningitis affecting brain or spinal cord), and others. Thus, there are a hoard of viruses and conditions that can cause encephalitis.

The 2018 SOP document has details on how acute encephalitis syndrome patients have to be managed by the ASHA (accredited social health activist) workers, the primary health centres (PHCs), controlling convulsions in children, the danger signs that should lead to referral to bigger hospitals, etc.

The doctors in Bihar follow the Standard Operating Procedure (SOP) of the state health department and treat children showing symptoms of high fever, unconsciousness, convulsions and hypoglycaemia. The 2018 version of the SOP document also carries a verbal autopsy form to help determine probable cause of death.

To some extent the SOP has worked. After a death toll of 117 due to suspected acute encephalitis syndrome in 2014 in Muzaffarpur, the cases dwindled (see graph). But, this year the disease, it seems, is back with a vengeance and has 'officially' already killed 132 children in the state.

News reports allege the ASHA workers in the state were busy in the last few months due to election duties and were unable to do their job as frontline health workers.

Blaming the litchis

In the last few years, a couple of research studies have tried pinpointing the reasons behind such 'mystery fever' outbreaks in Bihar. Litchis (Litchi chinensis) are at the centre-stage of this debate.

In 2013, a two-member team including the then professor of virology at Vellore-based Christian Medical College and a paediatrician, T Jacob John, and Mukul Das, studied the 'unknown disease'.

A year later, in a series of publications, John and Das suggested that when hungry malnourished children with poor glycogen (type of glucose) reserves consume litchi fruit or seed, they may slip into a hypoglycemic (low blood sugar level) state and develop encephalitis.

In their May 2014 'scientific correspondence' published in Current Science, John and Das wrote: "We found that the disease broke out during the months when litchi was harvested, i.e. April, May and June. Muzaffarpur is full of litchi orchards. The illness started suddenly — children were found vomiting, displayed abnormal movements, were semi-conscious, and were convulsing between 4 a.m. and 7 a.m. The disease progressed fast — children went into coma and died within a few days. When sick children were tested, the blood glucose level was always below normal."

In another 'scientific correspondence', published in August 2014 issue of Current Science, John and Das not only established a link between litchi consumption and how the metabolic pathway is affected in malnourished children, but also described it as acute encephalopathy and not acute encephalitis syndrome .

Encephalopathy is a biochemical disease whose primary pathology is not in the brain. Specific treatment is scanty for viral encephalitis, but encephalopathy is eminently treatable.

Another 2014 research study, authored by the scientists of National Vector Borne Disease Control Programme of the Directorate General of Health Services, reads: "The AES cases in Muzaffarpur and adjoining litchi producing districts have been observed mostly during April to June particularly in children who are undernourished with a history of visiting litchi orchards; many of the cases are hypoglycaemic." Hypoglycemia occurs when blood glucose levels fall below normal levels. But, what causes this health condition isn't still clear.

Three years later, in April 2017, a study published in The Lancet, and funded by the US Centers for Disease Control and Prevention, concluded: "... an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness." Methylenecyclopropylglycine (MCPG) toxin is known to be present in litchi fruit.

There are some other studies that point towards the litchi link. For instance, a 2014 study, 'Possible factors causing Acute Encephalitis Syndrome outbreak in Bihar, India', published in International Journal of Current Microbiology and Applied Sciences noted that the first epidemic outbreak of acute encephalitis syndrome appeared in North Bihar districts during 2011, particularly among the poor community in the paediatric age group. The disease appeared in paediatric age group coinciding with the litchi fruit season.

But, the authors of this 2014 study noted that "heat stroke was suspected as major possible factor". They also said that "social and economic factors play an essential role in occurrence of AES… AES in Muzaffarpur has mostly been observed amongst the children with low socio- economic background".

To add to the mystery around the disease, in 2016, researchers from UNICEF and AIIMS Patna published their findings of a socio-demographic and behavioral study that included all the 135 cases of acute encephalitis syndrome registered at the two hospitals in Muzaffarpur in the last week of May to the third week of June 2013.

Based on the collected data, these researchers found that children who were later suspected of suffering from acute encephalitis syndrome, belonged to low-income families, lived in cluttered houses in poor hygienic conditions and followed poor sanitation practices. Most of these children did not wash their hands properly after defecation.

In their 2016 study published in Clinical Epidemiology and Global Health, these researchers proposed the hypothesis of oral-fecal transmission. Many of these children accompanied their parents, who worked in litchi orchards and might have picked up ripe fruits off the ground and eaten them. These fruits lying on the ground might be contaminated with faecal matter, the researchers suggested.

Meanwhile, in a commentary published in The Lancet in 2017, Valerie S Palmer and Peter S Spencer, proposed the researchers work with the litchi industry to determine how levels of hypoglycemic acids vary across cultivars, soil, climate and harvest conditions in the region.

Beyond litchis

But, there are researchers and doctors who refuse to accept any linkages between litchi and the suspected acute encephalitis syndrome that has gripped Bihar right now.

In a telephonic interview, Vishal Nath, head of Muzaffarpur-based National Research Centre on Litchi, an ICAR - NRCL premier national institute for conducting research and developments on litchi, also told Gaon Connection there was no connection between the disease outbreak and litchi consumption.

Chander Shekhar, additional director-general of the Indian Council of Medical Research (ICMR) also recently said: It is premature to blame litchi consumption as a reason for this season's outbreak. While we have not been able to ascertain the causes of deaths as of now, we should be able to get a better understanding of the causes in two to three days."

"Each time there is an outbreak, individual teams visit hospitals, collect blood and tissue samples and test them. But, the outcome remains the same — no substantial evidence of what is causing the disease," Gopal Shankar Sahni, head of the Department of Paediatrics at the SKMC Hospital told Gaon Connection. "Some blame litchi consumption, others malnutrition and lack of hygiene. But, it is imperative to explore other clinical observations, such as heat encephalopathy caused by high temperature and humidity," he added.

In 2014, John and Das linked chamki bukhar to litchi consumption and poor nutrition. "But, in 2015 there was record litchi production, and no such disease outbreak in Muzaffarpur. Then why no attempt beyond litchi link to properly investigate the underlying cause of this disease, which raises its head almost every year in Muzaffarpur and neighbouring districts," questions Sahni.

Vashishtha stresses on the need for autopsy and histopathology of major organs to find out the exact nature of the disease.

"But, without parental consent autopsies cannot be performed," said Brij Mohan, former head, pediatrics SKMC Hospital, Muzaffarpur. Since 1994, Mohan has seen several such disease outbreaks in the district.

Sahni, who has witnessed similar outbreaks in the past, points at the extreme climatic conditions in Muzaffarpur.

"The climate in the district during the months of April to June is extremely hot and humid. It could be one of the risk factors that favour the epidemic of heat encephalopathy [Brain disease, damage, or malfunction caused due to heat stroke] in children in the area of Muzaffarpur," said Sahni. "With the arrival of the monsoon rains, there is a drop in temperature and the number of cases also decrease. "The symptoms I observed during examination of these children match that of heat encephalopathy", he added.

According to Vashishtha, "What India needs is a well-coordinated, thorough systematic outbreak investigation approach with correct methodology to investigate all these recurring outbreaks of unknown etiology or cause. These should not be clubbed under one head of viral encephalitis." A thorough approach would entail first defining the clinical entity, histopathological investigations including autopsies, if required, and detailed epidemiological and toxicological investigations in a coordinated manner, he added.

Meanwhile, some diagnostic kits are available that can provide some succor. For instance, in 2011, a diagnostic chip was jointly developed by Bengaluru-based National Institute of Mental Health and Neurosciences (NIMHANS) and Xycton Diagnostic Limited. This kit can detect 22 pathogens that cause acute encephalitis syndrome by using just a single drop of blood. But, its availability is limited to private pathology laboratories and this 22-panel kit costs up to Rs 14,000 each.

J Ravi, professor of neurovirology at NIMHANS and an expert on Japanese encephalitis , who developed the kit, told Gaon Connection that the diagnostic technology is expensive and needs infrastructure before such a facility is installed at hospitals. "This kit is not a lab tool, which can be carried to the field, or can be handled by frontline healthcare professionals. At present, the samples drawn from infected areas are tested in laboratories," said Ravi. But, in future, if there is willingness then the states can adopt the technology to test for acute encephalitis syndrome, says Ravi.

Now all eyes are set on the expert committee -- a mix of virologist, nutritionist, paediatrician and scientists -- set up by the Union health minister Vardhan, which is expected to unravel the mystery around the mysterious disease that kills several children every year in Bihar.

(With inputs from Nidhi Jamwal)

Prakash is an independent science journalist based in Bengaluru.

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