Would dengue worsen Zika?

Prior dengue in­fec­tion does not in­crease Zika dis­ease sever­ity.

The Star Malaysia - Star2 - - Health - By RI­CARDO ZORZETTO

IN­DI­VID­U­ALS who are in­fected by the Zika virus af­ter hav­ing dengue fever do not ap­pear to be­come more se­verely ill than peo­ple with Zika who have never had dengue.

This is the con­clu­sion of a study pub­lished on June 20 in the jour­nal Clin­i­cal In­fec­tious Dis­eases. The study in­volved 65 peo­ple who live in and around São Paulo State, Brazil, where dengue is en­demic and there was a par­tic­u­larly rapid out­break of Zika dur­ing the 2016 epi­demic.

The study is the first to show that prior dengue in­fec­tion in hu­man be­ings in­fected by Zika does not nec­es­sar­ily lead to a worse ill­ness.

Pre­vi­ous re­search us­ing only cells and ro­dents sug­gested prior dengue in­fec­tion would in­ten­sify Zika dis­ease by fa­cil­i­tat­ing repli­ca­tion of the virus. Some physi­cians and vi­rol­o­gists sus­pected this pos­si­ble vi­ral am­pli­fi­ca­tion could ex­plain the con­cen­tra­tion of Zika-as­so­ci­ated mi­cro­cephaly cases in the North­east of Brazil, where dengue is more preva­lent than in other re­gions of the coun­try.

“Our re­sults show this ag­gra­va­tion doesn’t oc­cur, or oc­curs only very rarely and can’t be de­tected by a study such as this,” said vi­rol­o­gist Mau­rí­cio Lac­erda Nogueira, a pro­fes­sor at the São José do Rio Preto Med­i­cal School (FAMERP) and prin­ci­pal in­ves­ti­ga­tor for the study.

Dur­ing the pe­riod when the Zika epi­demic was at its most in­tense, be­tween Jan­uary and July 2016, Nogueira’s team col­lected blood sam­ples from 65 peo­ple who pre­sented with fever and symp­toms of dengue or Zika (sim­i­lar and eas­ily con­fused) at the emer­gency unit of the ref­er­ence hos­pi­tal in São José do Rio Preto, a health­care hub for north­ern and north­west­ern São Paulo.

Anal­y­sis of the vi­ral ge­netic ma­te­rial found in these blood sam­ples showed 45 pa­tients had been in­fected by Zika and 20 by dengue. The tests also showed 78% of those with Zika (35 peo­ple) and 70% of those with dengue had been in­fected pre­vi­ously by dengue virus.

Shortly af­ter the Zika epi­demic emerged, it be­gan to be sus­pected that prior in­fec­tion by dengue could lead to more se­vere clin­i­cal man­i­fes­ta­tions of Zika, sim­i­lar to those of dengue haem­or­rhagic fever, such as bleed­ing un­der the skin, a large de­crease in blood pres­sure, and even shock in par­tic­u­larly se­vere cases.

About 90% of pa­tients with dengue haem­or­rhagic fever have pre­vi­ously had dengue and are in­fected by a dif­fer­ent sub­type (there are four sub­types of dengue virus).

The prob­lem is that the an­ti­bod­ies pro­duced by the im­mune sys­tem against one sub­type do not al­ways ef­fec­tively neu­tralise the other sub­types, lead­ing to only par­tial im­mu­nity.

Ac­cord­ing to a hy­poth­e­sis called an­ti­body-de­pen­dent en­hance­ment (ADE), incomplete im­mu­ni­sa­tion ap­pears to help the virus en­ter de­fence sys­tem cells, where it re­pro­duces, in­creas­ing the num­ber of copies of it­self in the or­gan­ism and in­ten­si­fy­ing the sever­ity of the in­fec­tion.

Be­cause dengue and Zika are both fla­viviruses and ge­net­i­cally sim­i­lar, it was be­lieved that the par­tial im­mu­ni­sa­tion ob­served af­ter dengue in­fec­tion might also oc­cur in Zika-in­fected in­di­vid­u­als with prior dengue in­fec­tion.

This sus­pi­cion was strength­ened in mid2016, when re­search first showed that an­ti­bod­ies against dengue virus also pro­tect in­di­vid­u­als against Zika virus but do not neu­tralise it com­pletely.

In March 2017, US re­searchers found par­tial im­mu­ni­sa­tion to be the ex­pla­na­tion for mul­ti­pli­ca­tion of Zika in a study us­ing mice with weak­ened im­mune sys­tems.

The study just pub­lished in Clin­i­cal In­fec­tious Dis­eases now sug­gests what is true of cells cul­tured in vitro and lab­o­ra­tory mice does not nec­es­sar­ily apply to humans.

With the help of im­mu­nol­o­gist Jorge Kalil Filho, a pro­fes­sor at the Uni­ver­sity of São Paulo’s Med­i­cal School (FM-USP), Nogueira and his team mea­sured the num­bers of Zika virus copies in the blood of pa­tients pre­vi­ously in­fected by dengue and com­pared them with the num­bers found in the blood of pa­tients who had never been ex­posed to dengue.

If prior dengue in­fec­tion fa­cil­i­tated the mul­ti­pli­ca­tion of Zika, the num­ber should be much higher in the for­mer group, but the re­searchers found both groups had sim­i­lar vi­ral loads.

“Our study had suf­fi­cient sta­tis­ti­cal power to de­tect a very small dif­fer­ence in vi­ral load – a dif­fer­ence of only 10 times, in fact,” Nogueira said. If ADE had oc­curred in this sit­u­a­tion, vi­ral load should have been tens of thousands of times greater.

“These find­ings don’t en­tirely rule out the pos­si­bil­ity that ADE oc­curs, but they con­sti­tute im­por­tance ev­i­dence that hav­ing had dengue doesn’t in­crease the sever­ity of Zika dis­ease,” said Kalil, a co-author of the study.

“In fact, some peo­ple who have had dengue present with a milder form of in­fec­tion when they con­tract Zika, ac­cord­ing to un­pub­lished re­ports.”

“If ADE caused by dengue led to mi­cro­cephaly, we would have iden­ti­fied hun­dreds of cases in São José do Rio Preto and Ribeirão Preto, but we found none at all,” Nogueira said.

His team also mon­i­tored 55 women who had Zika dur­ing preg­nancy in São José do Rio Preto. They all gave birth to in­fants with­out mi­cro­cephaly; some had neu­ro­log­i­cal dam­age, but much milder than the cases re­ported in the North­east.

“This ar­ti­cle [in Clin­i­cal In­fec­tious Dis­eases] un­doubt­edly has far-reach­ing im­pli­ca­tions, both in epi­demi­o­log­i­cal terms and for the de­vel­op­ment of vac­cines. These find­ings sug­gest other fac­tors may be re­spon­si­ble for Zika con­gen­i­tal syn­drome,” said Nikos Vasi­lakis, a re­searcher at Uni­ver­sity of Texas Med­i­cal Branch and also a co-author of the study.

The early ev­i­dence that prior dengue in­fec­tion might lead to more se­vere Zika dis­ease raised con­cerns about the de­vel­op­ment of vac­cines, es­pe­cially against dengue.

A dengue vac­cine is cur­rently be­ing tested in Brazil. “There were fears that vac­ci­nat­ing peo­ple against dengue could lead to more se­vere cases of Zika,” Kalil said. “The re­sults we’ve ob­tained now sug­gest this prob­lem may not ex­ist.” — Pesquisa FAPESP

The lat­est re­search shows that prior dengue in­fec­tion does not lead to more se­vere Zika (pic) dis­ease. — TNS

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