KER­ALA PUB­LIC HEALTH

The Ni­pah out­break

FrontLine - - FRONT PAGE - BY R. KRISHNAKUMAR IN THIRUVANANTHAPURAM

Early de­tec­tion of the virus and prompt ac­tion by the gov­ern­ment con­tain the deadly out­break in Ker­ala, but health of­fi­cials stress the need for re­search and sound in­fec­tion con­trol poli­cies to han­dle fu­ture emer­gen­cies.

WITH the sud­den out­break of the deadly Ni­pah vi­ral in­fec­tion, whose ori­gin is still un­known, Ker­ala’s stressed health care sys­tem had to learn quite a few hard lessons be­fore it could de­clare that the “first wave” of the rare in­fec­tion in the State was more or less un­der con­trol.

It was on May 19 that the Ni­pah in­fec­tion was first re­ported from Kozhikode dis­trict. By May 28, 16 peo­ple in Kozhikode and Malap­pu­ram dis­tricts were con­firmed as hav­ing con­tracted the dis­ease, which causes se­vere res­pi­ra­tory in­fec­tion and fa­tal en­cephali­tis in hu­mans and an­i­mals. By May 30, 15 per­sons had died. Some 149 peo­ple sus­pected to have come in con­tact with those who had the in­fec­tion tested neg­a­tive in ex­am­i­na­tions con­ducted at the Na­tional Virol­ogy In­sti­tute, Pune.

Af­ter a high-level re­view meet­ing in Kozhikode, the epi­cen­tre of the Ni­pah oc­cur­rence, Health Min­is­ter K.K. Shaila­jah an­nounced on May 28 that the Ni­pah in­fec­tion was un­der con­trol. “It has been es­tab­lished that all Ni­pah cases re­ported so far are con­nected to a sin­gle source. But as a mat­ter of pre­cau­tion, we should be prepared to pre­vent chances of a sec­ond wave of in­fec­tion,” the Minis-

ter said. Ker­ala was praised for quickly iden­ti­fy­ing the virus and promptly ini­ti­at­ing con­tain­ment mea­sures. The virus was iden­ti­fied in the sec­ond per­son it was known to have in­fected in the State.

In con­trast, in the pre­vi­ous re­ported oc­cur­rence in In­dia 17 years ear­lier at Siliguri in West Ben­gal, 45 peo­ple died within weeks of the out­break, which went un­de­tected for a long time. The ma­jor­ity of the dead were hospi­tal work­ers or those who had come in con­tact with pa­tients in hos­pi­tals. Sim­i­larly, in Bangladesh in 2011, 40 of the 44 peo­ple who con­tracted the in­fec­tion died, ac­cord­ing to the World Health Or­gan­i­sa­tion (WHO).

EARLY DE­TEC­TION

It was thus a ma­jor achieve­ment for Ker­ala to have iden­ti­fied the virus early, thanks mainly to Dr A.S. Anoop Ku­mar and his fel­low doc­tors at the crit­i­cal care unit of the Baby Me­mo­rial Hospi­tal in Kozhikode. It was sheer skill and ded­i­ca­tion that made them look a bit more closely at a young man who came to the hospi­tal early in the morn­ing on May 17 with a lot of “breath­ing dif­fi­culty” and “al­tered con­scious­ness”.

The pa­tient was soon ad­mit­ted in the closed mul­ti­dis­ci­plinary in­ten­sive care unit (ICU), where doc­tors first con­sid­ered it a case of en­cephali­tis. “He was show­ing signs of en­cephali­tis, but un­likely fea­tures as well, such as very high blood pres­sure and heart rate and se­vere in­flam­ma­tion of the heart mus­cles, what we call my­ocardi­tis,” Dr Anoop Ku­mar told Front­line.

“Ir­re­spec­tive of all the or­gan sup­port mea­sures that were pro­vided, his con­di­tion kept de­te­ri­o­rat­ing. When we asked for his his­tory, the rel­a­tives told us that his brother too had died on May 5, at the Kozhikode Med­i­cal Col­lege Hospi­tal [MCH], re­port­edly of en­cephali­tis, and that there were two other mem­bers in the fam­ily who were sim­i­larly ill. We asked them to be brought to the hospi­tal and their con­di­tion, too, was bad and de­te­ri­o­rat­ing. We then thought it could be a case of ac­ci­den­tal poi­son­ing but soon veered around to the view that it was some kind of un­usual but se­vere vi­ral in­fec­tion.

“Sam­ples were sent to an ex­pert vi­rol­o­gist, Dr Arun Ku­mar of the Ma­ni­pal Virol­ogy In­sti­tute [about 300 kilo­me­tres away], the same day. The first pa­tient had be­come ex­tremely sick by then, and our neu­rol­ogy team led by Dr Jayakr­ish­nan sug­gested for the first time that it could be a case of Ni­pah virus en­cephali­tis. But by then the young man had died, and we con­vinced the rel­a­tives of the need for a patho­log­i­cal au­topsy, and or­gan sam­ples, too, were sent to Ma­ni­pal.”

Dr Anoop Ku­mar added: “We were soon in­formed that it was a deadly virus with high in­fec­tiv­ity and were asked to tighten in­fec­tion con­trol mea­sures at the hospi­tal. The gov­ern­ment was alerted and a meet­ing was or­gan­ised to dis­cuss pre­ven­tive mea­sures, even though it took two more days for the for­mal an­nounce­ment to be made based on con­for­ma­tion from the Na­tional Virol­ogy In­sti­tute, Pune. Within 36 hours of ad­mis­sion of the young man, we could find out the cause of the in­fec­tion.”

Ker­ala is known for its pre­pared­ness in deal­ing with out­breaks but in this case, the State’s early re­sponse was not ro­bust, health of­fi­cials said. For in­stance, al­though the sec­ond case was de­tected promptly in a pri­vate hospi­tal, the health au­thor­i­ties are wor­ried that a gov­ern­ment med­i­cal col­lege hospi­tal failed to de­tect the first case, that of the young man from the same fam­ily who died there as early as May 5.

Ra­jeev Sadanan­dan, Ad­di­tional Chief Sec­re­tary (Health), told Front­line: “Ni­pah in­fec­tion mim­ics the symp­toms of en­cephali­tis. So, those States that have preva­lence of other forms of en­cephali­tis could mis­take Ni­pah in­fec­tion for some other form of en­cephali­tis. In Siliguri they mis­took it for Ja­panese en­cephali­tis. That is why there was de­lay there and there were so many deaths. In the case of Ker­ala, these kinds of en­cephali­tis are very rare. Like malaria, for in­stance, which too is rare. So, when­ever such cases arise, we tend to in­ves­ti­gate it deeply. But we failed to do it this time.”

He added: “The first case of a 26-year-old man was re­ferred to the Kozhikode Med­i­cal Col­lege Hospi­tal, where we failed to iden­tify the real cause of death. Had they been able to iden­tify the virus cor­rectly, many lives could have been saved and we would have had a real good head start.”

But on May 17, the very next case at the Baby Me­mo­rial Hospi­tal was iden­ti­fied cor­rectly ow­ing to the di­ag­nos­tic skills and timely ef­forts of the team of doc­tors.

Once the in­fec­tion was iden­ti­fied, the State gov­ern­ment ma­chin­ery be­gan its emer­gency drill in right earnest. It started trac­ing all those who had come in con­tact with the pa­tients or oth­er­wise had any pos­si­bil­ity of ex­po­sure to the virus. On the ba­sis of the uni­ver­sally ac­cepted method of con­tact trac­ing, as on May 28, sam­ples from 149 peo­ple were sent for tests, but only 16 tested pos­i­tive for the virus.

“We went back to the ba­sics. Every case was re­viewed and their con­tacts were iden­ti­fied, put on ob­ser­va­tion, quar­an­tined and tracked and on the first sign of in­fec­tion shifted to hospi­tal care. That is how we be­lieve we were able to con­tain it,” a Health Depart­ment of­fi­cial said.

“Field staff were put on con­stant watch. Ded­i­cated am­bu­lances were kept ready to bring sus­pected cases di­rectly to the Kozhikode Med­i­cal Col­lege Hospi­tal. We sought out each per­son in the con­tacts list, metic­u­lously took their his­tory for the pre­vi­ous 25 days, took notes on where they went, who they met and the lat­ter be­came the next con­tact for us to trace. Thus, we prepared a list of 826 peo­ple, our tar­get list in what we de­scribe as the ‘first wave’. What we are most happy about is that all the cases that tested pos­i­tive were there on our list (ex­cept one, who later died in a pri­vate hospi­tal). So we are rea­son­ably con­fi­dent that our strat­egy has worked well, even al­low­ing for some gaps,” the of­fi­cial added.

The State au­thor­i­ties de­cided to ex­pand their in­quiries fur­ther af­ter

two deaths were re­ported on May 30 of peo­ple who were al­ready un­der treat­ment and who were ei­ther not on the orig­i­nal list or were from places where Ni­pah was orig­i­nally not re­ported.

Ac­cord­ing to the WHO’S sur­veil­lance and out­break alert of Ni­pah virus en­cephali­tis in Ker­ala, it is an emerg­ing in­fec­tious dis­ease spread by se­cre­tions of in­fected bats. It can spread to hu­mans through con­tam­i­nated fruit, in­fected an­i­mals or close con­tact with in­fected hu­mans.

The WHO Ni­pah fact sheet says that fruit bats of the Pteropo­di­dae fam­ily are the nat­u­ral host of the Ni­pah virus. It can be trans­mit­ted to hu­mans from an­i­mals such as bats or pigs or con­tam­i­nated foods and can also be trans­mit­ted di­rectly from hu­mans.

The virus in­fec­tion in hu­mans causes a range of clin­i­cal pre­sen­ta­tions, from asymp­to­matic in­fec­tion to acute res­pi­ra­tory in­fec­tion and fa­tal en­cephali­tis. The case fa­tal­ity rate is es­ti­mated at 40-75 per cent. This rate can vary de­pend­ing on lo­cal ca­pa­bil­i­ties for epi­demi­o­log­i­cal sur­veil­lance and clin­i­cal man­age­ment.

Over the years, the Ni­pah virus has shown a ten­dency to be in­creas­ingly fa­tal in hu­man be­ings. The fa­tal­ity rate in the first se­ries of out­breaks in Malaysia and Sin­ga­pore, where trans­mis­sion had oc­curred from bats to hu­mans through an in­ter­me­di­ary host, mainly pigs, was rel­a­tively low. But in the later out­breaks, in Bangladesh and In­dia from 2001, where trans­mis­sion was more from bats to hu­mans and be­tween hu­mans who had come in close con­tact with each other, es­pe­cially in hospi­tal set­tings, the fa­tal­ity rate was re­ported to be as high as 75 per cent or more.

In In­dia, ac­cord­ing to WHO fig­ures, the fa­tal­ity rate in Ker­ala was above 82.5 per cent as on May 28, while those re­ported in Siliguri in Fe­bru­ary 2001 and Na­dia, also in West Ben­gal, in April 2007 were 68 per cent and 100 per cent re­spec­tively.

In­creased hu­man-to-hu­man trans­mis­sion is a fea­ture of many re­cent Ni­pah out­breaks. The virus is highly vir­u­lent and lethal and there are no medicines or vac­cines. Hos­pi­tals can only pro­vide in­ten­sive sup­port­ive care, mostly to treat se­vere res­pi­ra­tory and neu­ro­log­i­cal com­pli­ca­tions.

The chances of in­fec­tion from fruit bats, the nat­u­ral reser­voirs of this virus found through­out South Asia, and for hu­man-to-hu­man trans­mis­sion have also in­creased in re­cent times. Ex­perts said that the former was be­cause of the wide­spread de­struc­tion of nat­u­ral habi­tats of the bats, while the lat­ter was be­cause of late de­tec­tion and in­ad­e­quate safety pre­cau­tions while deal­ing with in­fected per­sons, es­pe­cially in hos­pi­tals.

The virus is known to be present in the wild, in bat urine, and po­ten­tially bat faeces, saliva and birthing flu­ids.

The Ni­pah virus in­fec­tion is clas­si­fied un­der zoonoses, or dis­eases nat­u­rally trans­mit­ted be­tween hu­mans and ver­te­brate an­i­mals. Ac­cord­ing to one es­ti­mate, of the

ap­prox­i­mate 180 emerg­ing or reemerg­ing pathogens in the past 30 years, 130 are known to be zoonotic, with a dis­pro­por­tion­ate num­ber of the new zoonoses be­ing caused by RNA viruses, sim­i­lar to the Ni­pah virus, which have the po­ten­tial for high rates of mu­ta­tions.

Ni­pah and the closely re­lated Hen­dra virus are also sig­nif­i­cant in that they are listed as “Cat­e­gory C bio­threat agents” be­cause they can be iso­lated from their nat­u­ral reser­voir, eas­ily grown to large amounts in lab­o­ra­to­ries and trans­mit­ted through easy means.

IN­CU­BA­TION PE­RIOD

The virus does not be­come in­fec­tious im­me­di­ately af­ter it en­ters a host body. Its in­cu­ba­tion pe­riod is said to be be­tween four and 18 days. How­ever, ac­cord­ing to Health Depart­ment of­fi­cials, the mean in­cu­ba­tion pe­riod in the lat­est in­fec­tion was 9.6 days; the min­i­mum was eight days and the max­i­mum 17 days, the lat­ter an out­lier (the pa­tient died sub­se­quently on May 30).

Ex­cept for the fam­ily that first con­tracted the in­fec­tion, most of the oth­ers, in­clud­ing hospi­tal staff, got it from hos­pi­tals. The State man­aged to im­ple­ment proper screen­ing pro­ce­dure and fool­proof iso­la­tion care units only much later, when the “first wave” of in­fec­tion was ta­per­ing off.

Ra­jeev Sadanan­dan said: “Had we been a lit­tle more care­ful, we would have used the Ebola ex­pe­ri­ence to bet­ter de­sign the care cen­tre in Kozhikode. But that was a gap we plugged by May 28. We iden­ti­fied two sep­a­rate build­ings at the Kozhikode Med­i­cal Col­lege. All pa­tients sus­pected of hav­ing Ni­pah in­fec­tion would by­pass the rest of the Med­i­cal Col­lege wings and would be brought to this care cen­tre. They would first en­ter a pre­lim­i­nary screen­ing area. In­side, we have sep­a­rate ar­eas for hous­ing pa­tients with low prob­a­bil­ity of Ni­pah as well as high prob­a­bil­ity cases. Then [there is] an­other area for pa­tients with Ni­pah. We have a sep­a­rate en­try area for health care per­son­nel, where they put on their pro­tec­tive gear and an­other exit area where they re­move their gear. Both these are very im­por­tant when it comes to con­trol­ling Ni­pah in­fec­tion. We also learned that it was im­por­tant that we set up only one well-equipped hospi­tal cen­tre at each lo­ca­tion for han­dling such out­breaks.”

There was also a lot of con­fu­sion af­ter it be­came known that sam­ples taken from bats in­side a well be­long­ing to the fam­ily that first con­tracted the in­fec­tion and from other an­i­mals in the area proved neg­a­tive for the Ni­pah virus in tests done by the South­ern Re­gional Dis­ease Di­ag­nos­tic Lab­o­ra­tory in Ben­galuru.

The Health Sec­re­tary said that his depart­ment still be­lieved the source of the in­fec­tion was def­i­nitely a bat, ir­re­spec­tive of other opin­ions, “be­cause the virus is al­ways present in­side these bats.”

He added: “Most of the time they will be present in very low con­cen­tra­tions. When hor­monal changes oc­cur in bats, there is a prob­a­bil­ity for the virus to shoot up. Ex­perts call it a ‘spike’. Only then will the ex­cre­tions be­come in­fec­tious. That is the time when they in­fect other bats also. Be­cause bats live so close to each other and have sex with each other, a large num­ber of fruit bats may get in­fected. So, ir­re­spec­tive of the num­ber of bats you catch, un­less you catch the ones hav­ing the spike, the tests will show a neg­a­tive re­sult.”

He also said that the tests could have turned neg­a­tive be­cause there was a fail­ure to catch the right species of fruit bats—which are known to live on trees than in­side wells—or be­cause the bats had been caught when the virus con­cen­tra­tion in them was low, or be­cause ap­pro­pri­ate sero­log­i­cal tests were not used.

But if the virus is in cir­cu­la­tion, it can come back in later years. The State gov­ern­ment is there­fore un­der­tak­ing “a proper study of the bat pop­u­la­tion in Ker­ala” and the preva­lence of the virus among the bat pop­u­la­tion.

“We are try­ing to in­volve some of the best ex­perts in Asia to work with us. We are also ask­ing the ICMR [In­dian Coun­cil for Med­i­cal Re­search] to join us. Or we will do it our­selves,” Ra­jeev Sadanan­dan said.

Ker­ala was lucky in that it faced only one episode of Ni­pah out­break, un­like mul­ti­ple episodes as had hap­pened in Malaysia sev­eral years ear­lier. The cur­rent episode was con­fined to one lo­ca­tion where the pub­lic health fa­cil­i­ties were among the best in the State.

MI­GRANTS NOT THE SOURCE

The Ker­ala gov­ern­ment has scotched all ru­mours that the large pop­u­la­tion of mi­grant labour­ers could have been the source of the out­break. “We can rule out the mi­grant labour route be­cause had such a per­son been the source of in­fec­tion, oth­ers too would have got it by now be­cause they live in over­crowded quar­ters and we would have seen hordes of peo­ple in­fected and dy­ing of the dis­ease. But not one of them has been in­fected. So, by in­fer­ence the in­fec­tion has not been car­ried into Ker­ala by mi­grant labour­ers. The con­cern is whether some of them will get the in­fec­tion from here,” Ra­jeev Sadanan­dan said.

Sig­nif­i­cantly, he also said the gov­ern­ment be­lieved that there was a sin­gle source in­fec­tion. The per­son who died at the med­i­cal col­lege had come into con­tact with some sort of in­fected se­cre­tions from a bat. He added: “We can only con­clude that peo­ple have died even ear­lier be­cause of Ni­pah and we have failed to iden­tify it prop­erly. And the young man we know as the first ca­su­alty had got the in­fec­tion from such a per­son. But al­most all the cases that tested pos­i­tive are linked to the first case in one way or the other. One pa­tient alone is an ex­cep­tion. We have not been able to link it to the other cases; there is prob­a­bly some link that we have missed.”

Ac­cord­ing to him, one pos­i­tive fac­tor is that the Ni­pah virus is usu­ally found to be ac­tive be­tween De­cem­ber and May. “So far we have seen no sign of more in­fec­tions. So, the time for new in­fec­tions hope­fully is over.”

Doc­tors and other care­givers who spoke to Front­line said that fear was the dom­i­nant theme at the hos­pi­tals and iso­la­tion cen­tres and the crit­i­cal care units that han­dled sus­pected cases. The nor­mally crowded

Kozhikode Med­i­cal Col­lege premises have been largely de­serted ever since the first cases were ad­mit­ted. The hospi­tal it­self dis­charged sev­eral pa­tients [suf­fer­ing from other ail­ments] and ad­vised them to seek care else­where. Ni­pah was de­clared the top pri­or­ity. At Per­am­bra vil­lage in Kozhikode dis­trict, where the fam­ily of four first con­tracted the dis­ease, peo­ple were scared to come out and ru­mours spread more vi­ciously than the virus it­self. All pub­lic func­tions in Kozhikode and Malap­pu­ram dis­tricts were can­celled. Schools and col­leges re­mained closed. Peo­ple were re­luc­tant even to shake hands with each other and gen­er­ally pre­ferred to stay indoors.

There were in­stances of gov­ern­ment ini­ti­at­ing ac­tion against some el­e­ments spread­ing ru­mours that the out­break was the hand­i­work of pharma com­pa­nies and cir­cu­lat­ing videos with mis­chievous footage. There were also re­ports of at­tempts to stig­ma­tise pa­tients and their fam­i­lies and care­givers who had in­ter­acted with them in hos­pi­tals.

But in gen­eral, the pub­lic, the me­dia, the elected rep­re­sen­ta­tives and the State health per­son­nel were sup­port­ive in the fight against the out­break.

What did Ker­ala learn from its first tryst with the Ni­pah virus? The an­swer was quick: “The mes­sage is clear. We have to be prepared for out­breaks of this type any­time; it could be any­thing, MERS, SARS, any­thing. So, we need to put in place fa­cil­i­ties that can han­dle such emer­gen­cies. Two, we should have peo­ple work­ing on the sci­ence be­hind such dis­eases, sur­vey­ing our an­i­mal pop­u­la­tion, and so on, for which we need enor­mous funds. Three, it is es­sen­tial that we ob­serve sound in­fec­tion con­trol poli­cies and put in place all pre­cau­tion­ary mea­sures if we are to avoid tragedies such as the death of a young nurse on duty at a hospi­tal treat­ing Ni­pah pa­tients. We prob­a­bly got lucky this time, but we need to gain more ex­pe­ri­ence and ex­per­tise for man­ag­ing emer­gency sit­u­a­tions like this,” Ra­jeev Sadanan­dan said.

Ac­cord­ing to him, the State Health Depart­ment has al­ready con­tacted a net­work of in­ter­na­tional ex­perts and groups and is cur­rently con­sid­er­ing two mol­e­cules that have been found to be po­ten­tially ef­fec­tive against the Ni­pah virus. One is a hu­man mon­o­clonal an­ti­body called “m102.4”, which proved suc­cess­ful against Ni­pah and Hen­dra viruses in an­i­mal tests; the other is “GS5734”, an ex­per­i­men­tal anti-vi­ral drug be­ing de­vel­oped by the U.S. drug­maker Gilead Sciences.

The two mol­e­cules had al­ready been iden­ti­fied by the Ni­pah Clin­i­cal Trial Work­ing Group set up by the WHO Health Emer­gency Pro­gramme, which is cur­rently work­ing on the pro­to­cols for its use. Ker­ala has agreed to pro­vide sup­port if the ICMR de­cides to join hands with the Queens­land (Aus­tralia) gov­ern­ment in the re­search.

Among the key re­searchers the State gov­ern­ment au­thor­i­ties are in touch with are Prof. Lin-fa Wang, an in­ter­na­tional leader in the field of emerg­ing zoonotic viruses, and Prof. Christo­pher C. Broder, direc­tor of the Emerg­ing In­fec­tious Dis­eases Grad­u­ate Pro­gram of the U.S. Uni­formed Ser­vices Univer­sity of the Health Sciences (USU), who has been in­volved in vac­cines and an­ti­body ther­a­peu­tics de­vel­op­ment for the hu­man im­mun­od­e­fi­ciency virus (HIV) and emerg­ing zoonotic viruses, in­clud­ing the Ni­pah and Hen­dra viruses.

Prof. Wang, who is the direc­tor of the Emerg­ing In­fec­tious Dis­eases Pro­gramme at DUKE-NUS Med­i­cal School, Sin­ga­pore, has been study­ing bat-borne viruses for over two decades. He also co-led the de­vel­op­ment of a vac­cine for horses to pre­vent trans­mis­sion of the bat-borne Hen­dra virus to horses, which can pre­vent the in­fec­tion from spread­ing from horses to hu­mans.

Mean­while, a Reuters re­port on May 24 said that the Coali­tion for Epi­demic Pre­pared­ness In­no­va­tions (CEP), a global pub­lic-pri­vate body set up nearly a year ago with the aim of fi­nanc­ing and co­or­di­nat­ing the de­vel­op­ment of new vac­cines to pre­vent and con­tain in­fec­tious dis­ease epi­demics, had an­nounced that it had struck a $25 mil­lion deal with two U.S. biotech com­pa­nies to ac­cel­er­ate work on a vac­cine against the Ni­pah virus in the wake of the out­break in Ker­ala.

REL­A­TIVES and hospi­tal staff wear­ing safety gear at the fu­neral of V. Moosa, a vic­tim of the Ni­pah virus in­fec­tion, in Kozhikode on May 24.

GOV­ERN­MENT of­fi­cials in­spect­ing a well in Kozhikode dis­trict on May 21 to catch bats.

A FAM­ILY wear­ing pro­tec­tive masks at a hospi­tal in Kozhikode on May 25.

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