Virulent outbreak

Chikungunya is spreading fast across the country in an epidemic form presenting a big challenge on the public health front.

R. RAMACHANDRAN in New Delhi

FOR India, 2006 is likely to go down as one of the worst years in terms of public health in recent times. The country is witnessing not just a high incidence of familiar diseases such as malaria, polio, Japanese encephalitis and dengue; chikungunya, practically unknown to a whole generation, has emerged after a gap of 32 years. The disease seems to have resurfaced in October 2005. It reached outbreak proportions by March 2006 in the States of Maharashtra, Karnataka and Andhra Pradesh and has spread since then across the southern States, coastal areas in particular, and to other parts of the country.

As of October 4, nearly 1.3 million suspected cases of the disease from 152 districts in 10 States have been reported (see table on page 118). Karnataka, Maharashtra and Andhra Pradesh, where the disease surfaced initially, are the worst affected States. What may, however, be of significance from a public health point of view is that all ages and both sexes have been affected. Unlike what has been observed in the past, the current outbreak seems to have affected the adult population (over 15 years of age) more. Also, in contrast to earlier chikungunya outbreaks, when only urban and semi-urban populations were affected, cases in the current outbreak have been predominantly reported from rural areas.

The Indian outbreak seems to have followed the chikungunya outbreak on the Indian Ocean islands of Madagascar, Mayotte, Mauritius, Reunion (territory of France) and the Seychelles, which began in 2005 and waned early this year. Whether the two outbreaks are in any way linked is a subject of ongoing epidemiological study in the country and elsewhere. It is pertinent to note that there is a great deal of tourist traffic between India and the Indian Ocean islands. Initial studies have, however, revealed that the causative viruses in the Indian Ocean and the Indian outbreaks are genetically linked and both belong to the African genotype of the virus.

Chikungunya, pronounced as chik-en-gun-yah, which incidentally has no relation to chicken or bird flu, is a debilitating but non-fatal, self-limiting illness caused by the bite of mosquitoes belonging to the Aedes species that infect humans with the chikungunya virus (CHIKV). CHIKV belongs to the virus family Togaviridae, genus Alphavirus. It is geographically distributed in Africa, India and South-East Asia. In India, the dominant carrier of the virus is Aedes aegypti, which breeds in stored fresh water in urban and semi-urban environments and bites during the day. The virus is maintained in the human population by a human-mosquito-human transmission cycle. This is somewhat different from the transmission cycle on the African continent where the virus is transmitted through a sylvatic transmission cycle between wild primates and mosquitoes of the types A. luteocephalus, A. furcifer and A. taylori.

The disease, in fact, was first reported in 1952 in Tanzania when the virus too was isolated. Since then, CHIKV outbreaks have occurred all over Africa, the most recent one being during 1999-2000 in Kinshasa in the Democratic Republic of the Congo, where an estimated 50,000 people were infected. The first Asian outbreak was in Thailand in 1958. Since then outbreaks have repeatedly occurred in various South-East and East Asian countries. Prior to the current outbreak, the most recent re-emergence in the Asian region was in Java in Indonesia in 2001-2003, which occurred after a 20-year gap.

According to a group of French scientists, led by Isabelle Schuffenecker of the Pasteur Institute, who investigated the genetic characteristics of the virus implicated in the current Indian Ocean outbreak, the reemergence of CHIKV in both Africa and Asia has been unpredictable, with intervals of seven to 20 years between epidemics. This observation has led them to study the microevolution of the virus, which has thrown up some interesting findings with regard to the changing virulence of the virus.

Chikungunya usually starts suddenly with fever, chills, headache, nausea, vomiting, joint pain and rashes. Many of the clinical symptoms resemble a non-severe form of dengue whose causative virus is also transmitted by A. aegypti. There is thus a likelihood of confusion between the two diseases at the level of initial clinical symptoms presented by a patient.

But there are distinct features of chikungunya, which are severely arthritic in nature, that serve to distinguish clinically the Chikungunya cases. In fact, the disease derives its name from the language of the tribes in the Makonde plateau of Tanzania. Literally meaning "that which contorts or bends up", the term is descriptive of the stooped posture of patients who are afflicted with severe pain and inflammation in the joints - referred to in medical parlance as poly-arthralgia - which is the typical clinical symptom of the disease. While the disease itself is self-limiting and lasts for 10-15 days, arthralgia or joint pains could persist for months or even years, requiring long-term pain medication. The infection itself has been found to confer long-term immunity.

The severe arthritis itself is considered sufficient diagnosis for official classification of "suspected chikungunya cases" and the guidelines apparently require that virological confirmation be done on only a fraction of suspected cases, according to P.L. Joshi, Director of the National Vector Borne Disease Control Programme (NVBDCP) of the Union Health Ministry (see table). However, from the figures it would seem that there is gross misdiagnosis at the State level, which is the primary source for the data. "Often dengue or even other infections like influenza that cause high fever get mistakenly classified as suspected chikungunya," points out P.K. Das, Director of the Vector Control Research Centre (VCRC), Puducheri (formerly Pondicherry). This is apparent from the fact that, of the samples sent by the States to the National Institute of Virology (NIV), Pune, or the National Institute for Communicable Diseases (NICD) for laboratory confirmation (which for some reason constitutes only about 1 per cent of the suspected cases), only about 10 per cent were found to be positive for the chikungunya virus (see table). How this translates into the actual incidence of the disease is not very clear.

As for patient care, this does not matter because clinical management for chikungunya and non-severe forms in the initial phase of dengue, which are basically self-limiting and do not have any curative medicine, is the same involving control of fever and pain through paracetemol and non-aspirin-based pain relievers. It is also possible that both infections are simultaneously present in a patient. Of course, if any case progresses into features that characterise severe forms of Dengue with Haemorrhagic Fever (DHF) or Shock Syndrome (DSS), the clinical management and the course of treatment are entirely different.

So, while the detailed data may not be important for the management of chikungunya patients, for epidemiological studies they are important. Even from a public health perspective, since the carrier of both the viruses is the same, namely the A. aegypti mosquito, prevention strategies in terms of vector control also would be the same. Unfortunately, given the weak district-level public health system and disease monitoring, the true burden of the disease may not be known at all. A nave extrapolation to the total number of cases would suggest that there would be about 0.13 million cases, which is not a small number.

In India, the first CHIKV outbreak was in 1963 in Kolkata. This was followed by epidemics in Chennai, Puducheri and Vellore in 1964. The next year it spread to Visakhapatnam, Rajamundry, Kakinada and Nagpur. The last outbreak was in Barsi in 1973. As mentioned earlier, the current Indian outbreak has followed the massive outbreaks reported since 2004-end in the islands of south-western Indian Ocean where A. albopictus is the vector of transmission. Based on virus isolates from mosquitoes, A. aegypti has been implicated as the primary carrier in the current outbreak, though A. albopictus was found in a negligible number of cases.

According to some French scientists, between January and March 2005, more than 5,000 cases were reported in the Comoros islands from where it appears to have spread to other islands of the south-western Indian Ocean region. Starting in December 2005, the rainy season resulted in renewed circulation of the virus leading to several thousands of cases of the disease, they pointed out. The most affected island is Reunion. Of its total population of 770,000, it is estimated that 244,000 have been affected. The obvious scientific question is whether the two outbreaks are related.

In a study published in the online journal Emerging Infectious Diseases of the Centres for Disease Control and Prevention (CDC), United States, scientists of the NIV have reported some interesting findings. According to them, while the genetic make-up of the earlier isolates from the outbreaks between 1963 and 1973 belonged to the distinct Asian genotype, the current isolates from the few localised cases belong to the African genotype. That is, the genotype to which the virus implicated in the current outbreak belongs has been in circulation in the country for more than five years. Whether there have been mutations in the past five years in the key genes of this particular strain that has made it more virulent is a subject for further analysis, pointed out Akhilesh C. Mishra, NIV Director. Earlier, with limited sequencing analysis, some scientists from Warangal University had speculated that the current strain may have even mutated from the 1965 Nagpur strain. But a complete sequencing that the NIV completed recently has ruled that out, Akhilesh Mishra told Frontline.

Equally significant is the finding that the recent Indian Ocean isolates too belong to the African genotype to which the current Indian strain and the 2000 strain have been linked. This raises the question whether the strain went from India to the islands where it mutated to a more virulent form and has been carried back to India or the Indian Ocean strain is the result of an independent evolutionary strand from the African genotype. This is again a matter for detailed molecular analysis, said Akhilesh Mishra.

In the NIV study, blood samples from 1,938 suspected patients from Maharashtra, Karnataka and Andhra Pradesh were collected and a pylogenic (evolutionary history) analysis based on the viral genes called NS4 and E1 was carried out. The analysis showed that the Indian isolates from 1963 through 1973 belonged to the Asian genotype, while the current isolates from the three States and the Yawat isolate of 2000 belonged to the Central/East African genotype. The sequence from Reunion Islands, as reported by the French group, was also found to group with the Indian isolates.

The grouping of the Yawat isolate with the current ones suggests that this genotype had been introduced into the country more than five years ago, argue the NIV scientists in their paper. "In this context," the paper says, "determining the genotype of currently circulating strains in South-East Asia and understanding the modes of transportation of this strain in India and conditions favouring such large outbreaks would be worthwhile." Viruses have only a small amount of genetic material and this keeps changing rapidly. The resulting mutations in virus' genetic sequencing over relatively short time-scales enable the study of the evolutionary history of various strains.

In the context of the high transmission and virulence observed in the Indian Ocean islands, the French study has arrived at an interesting conclusion. The study carried out a complete genome sequencing of six selected viral isolates along with partial sequences of the gene E1 from a total of 127 patients from Reunion, Seychelles, Mauritius, Madagascar and Mayotte islands. Their results showed that the virus had high evolutionary potential and that the outbreak in 2004 was owing to a strain that belonged to the East-African group, which had been confirmed by the NIV study as well. In fact, another French study has pointed out that movement of old tyres (in which mosquitoes thrive) from Africa to Indian Ocean islands by sea is an effective route for the migration of the virus.

But more interestingly, they found that this initial East-African strain subsequently evolved into several distinct variants. All the Indian Ocean sequences, right from the initial phase, were found to be different from the sequences determined earlier. But, according to their findings, some changes appeared midway after which infection rates were found to increase. One significant mutation relates to a specific change in the position 226 of E1 protein.

By comparing a similar change in a close relative of CHIKV, the scientists have argued that the virus no longer needed cholesterol in the host which viruses normally require to infect the cells of mosquitoes and humans. Usually mosquitoes do not have sufficient cholesterol for viruses to infect their cells efficiently. By circumventing this need through mutation, the virus may have developed the capacity to survive and multiply better in mosquitoes. This, in turn, could have contributed to the rapid spread of the disease, French scientists have speculated.

The NIV group, however, does not find this to be the case from their analysis. "We are, in fact, going to send in a rejoinder to the French paper," Akhilesh Mishra said. So the question of the reasons for the sudden spurt in the transmissibility and virulence of the virus remains an open one. "We are continuing our studies. Hopefully extensive analysis with more isolates will tell us something," he said.

"From a public health point of view, these deeply scientific issues, such as how the virus has mutated, whether it was transported from Africa or Indian Ocean or is an indigenous Asian strain, while important, tend to obfuscate the main issue," says P.K. Das.

"Whatever be the virus, the environment is allowing it to survive and circulate. There is poor sanitation, dirty environment, lack of water supply, changing lifestyles, increasing use, even in rural areas, of motorised vehicles whose old tyres provide an excellent breeding ground for A. aegypti. No one wants to pay attention to these issues of public health. You can endlessly argue about where the virus has come from. If you attack the main problem, all the rest become irrelevant," says P.K. Das.