Virus ap­pears to dam­age or­gans be­yond the lungs

The Washington Post - - FRONT PAGE - BY LENNY BERN­STEIN, CAROLYN Y. JOHN­SON, SARAH KA­PLAN AND LAURIE MCGINLEY

The new coro­n­avirus kills by in­flam­ing and clog­ging the tiny air sacs in the lungs, chok­ing off the body’s oxy­gen sup­ply un­til it shuts down the or­gans es­sen­tial for life.

But clin­i­cians around the world are see­ing ev­i­dence that sug­gests the virus also may be caus­ing heart in­flam­ma­tion, acute kid­ney dis­ease, neu­ro­log­i­cal mal­func­tion, blood clots, in­testi­nal dam­age and liver prob­lems. That de­vel­op­ment has com­pli­cated the treat­ment of the most se­vere cases of covid-19, the ill­ness caused by the virus, and makes the course of re­cov­ery less cer­tain, they said.

The preva­lence of these ef­fects is too great to at­tribute them solely to the “cy­tokine storm,” a pow­er­ful im­mune-sys­tem re­sponse that at­tacks the body, caus­ing se­vere dam­age, doc­tors and re­searchers said.

Al­most half the peo­ple hos­pi­tal­ized be­cause of covid-19 have blood or pro­tein in their urine, in­di­cat­ing early dam­age to their kid­neys, said Alan Kliger, a nephrol­o­gist at the Yale School of Medicine who co-chairs a task force as­sist­ing dial­y­sis pa­tients who have covid-19.

Even more alarm­ing, he added, is early data that shows 14 to

30 per­cent of in­ten­sive-care pa­tients in New York and Wuhan, China — birth­place of the pan­demic — los­ing kid­ney func­tion and re­quir­ing dial­y­sis, or its in­hos­pi­tal cousin, con­tin­u­ous re­nal re­place­ment ther­apy. New York in­ten­sive care units are treat­ing so much kid­ney fail­ure, he said, they need more per­son­nel who can per­form dial­y­sis and have is­sued an ur­gent call for vol­un­teers from other parts of the coun­try. They also are run­ning dan­ger­ously short of the ster­ile flu­ids used to de­liver con­tin­u­ous re­nal ther­apy, he said.

“That’s a huge num­ber of peo­ple who have this prob­lem. That’s new to me,” Kliger said. “I think it’s very pos­si­ble that the virus at­taches to the kid­ney cells and at­tacks them.”

But in medicine, log­i­cal in­fer­ences of­ten do not prove true when re­search is con­ducted. Ev­ery­one in­ter­viewed for this story stressed that with the pan­demic still rag­ing, they are spec­u­lat­ing with much less data than is nor­mally needed to reach solid clin­i­cal con­clu­sions.

Many other pos­si­ble causes for or­gan and tis­sue dam­age must be in­ves­ti­gated, they said, in­clud­ing res­pi­ra­tory distress, the med­i­ca­tions pa­tients re­ceived, high fever, the stress of hos­pi­tal­iza­tion in an ICU and the now well-de­scribed im­pact of cy­tokine storms.

Still, when re­searchers in Wuhan con­ducted au­top­sies on peo­ple who died of covid-19, they found that nine of 26 had acute kid­ney in­juries and that seven had par­ti­cles of the coro­n­avirus in their kid­neys, ac­cord­ing to a pa­per by the Wuhan sci­en­tists pub­lished April 9 in the med­i­cal jour­nal Kid­ney In­ter­na­tional.

“It does raise the very clear sus­pi­cion that at least a part of the acute kid­ney in­jury that we’re see­ing is re­sult­ing from di­rect viral in­volve­ment of the kid­ney, which is dis­tinct from what was seen in the SARS out­break in 2002,” said Paul M. Palevsky, a Univer­sity of Pitts­burgh School of Medicine nephrol­o­gist and pres­i­dent-elect of the Na­tional Kid­ney Foun­da­tion.

One New York hospi­tal re­cently had 51 ICU pa­tients who needed 24-hour kid­ney treat­ment but had just 39 ma­chines to do it, he said. The hospi­tal had to ra­tion the care, keep­ing each pa­tient on the ther­apy less than 24 hours a day, he said.

The virus also may be dam­ag­ing the heart. Clin­i­cians in China and New York have re­ported my­ocardi­tis, an in­flam­ma­tion of the heart mus­cle, and, more dan­ger­ous, ir­reg­u­lar heart rhythms that can lead to car­diac ar­rest in covid19 pa­tients.

“They seem to be do­ing re­ally well as far as res­pi­ra­tory sta­tus goes, and then sud­denly they develop a car­diac is­sue that seems out of pro­por­tion to their res­pi­ra­tory is­sues,” said Mitchell Elkind, a Columbia Univer­sity neu­rol­o­gist and pres­i­dent-elect of the Amer­i­can Heart As­so­ci­a­tion. “This seems to be out of pro­por­tion to their lung dis­ease, which makes peo­ple won­der about that di­rect ef­fect.”

One re­view of se­verely ill pa­tients in China found that about 40 per­cent suf­fered ar­rhyth­mias and 20 per­cent had some form of car­diac in­jury, Elkind said. “There is some con­cern that some of it may be due to di­rect in­flu­ence of the virus,” he said.

The new virus en­ters the cells of peo­ple who are in­fected by latch­ing onto the ACE2 re­cep­tor on cell sur­faces. It un­ques­tion­ably at­tacks the cells in the res­pi­ra­tory tract, but there is in­creas­ing sus­pi­cion that it is us­ing the same door­way to en­ter other cells. The gas­troin­testi­nal tract, for in­stance, con­tains 100 times more of these re­cep­tors than other parts of the body, and its sur­face area is enor­mous.

“If you un­furl it, it’s like a ten­nis court of sur­face area — this tremen­dous area for the virus to in­vade and repli­cate it­self,” said Bren­nan Spiegel, co-ed­i­tor in chief of the Amer­i­can Jour­nal of Gas­troen­terol­ogy.

In a sub­set of covid-19 cases, re­searchers have found, the im­mune sys­tem bat­tling the in­fec­tion goes into hy­per­drive. The un­con­trolled re­sponse leads to the re­lease of a flood of sub­stances called cy­tokines that, in ex­cess, can re­sult in dam­age to mul­ti­ple or­gans. In some se­verely ill covid19 pa­tients, doc­tors have found high lev­els of a pro-in­flam­ma­tory cy­tokine called in­ter­leukin-6, known by the med­i­cal short­hand IL-6.

The un­fet­tered re­sponse, also called “cy­tokine re­lease syn­drome,” has long been rec­og­nized in other pa­tients, in­clud­ing those with au­toim­mune diseases such as rheuma­toid arthri­tis or in can­cer pa­tients un­der­go­ing cer­tain im­munother­a­pies.

For covid-19 pa­tients, cy­tokine storms are a ma­jor rea­son that some re­quire in­ten­sive care and ven­ti­la­tion, said Jef­frey S. We­ber, deputy di­rec­tor of the Perl­mut­ter Can­cer Cen­ter at NYU Lan­gone Med­i­cal Cen­ter.

“When your cy­tokines are sys­tem­i­cally out of con­trol, bad stuff hap­pens,” he said. “It can be a com­plete disas­ter.” It isn’t clear why cy­tokine storms oc­cur in some pa­tients and not oth­ers, though ge­netic fac­tors may play a role, some doc­tors say.

To treat cy­tokine storms, some doc­tors are us­ing anti-il-6 drugs such as tocilizuma­b, which is ap­proved for can­cer pa­tients who develop cy­tokine storms as a re­sult of im­munother­apy.

An­other odd, and now well­known, symp­tom of covid-19 is loss of smell and taste. Claire Hop­kins, pres­i­dent of the Bri­tish Rhi­no­log­i­cal So­ci­ety, said stud­ies of pa­tients in Italy and else­where have shown that some lose their sense of smell be­fore they show signs of be­ing sick.

“The coro­n­avirus can ac­tu­ally at­tack and in­vade ol­fac­tory nerve end­ings,” Hop­kins said. When these aroma-de­tect­ing fibers are dis­rupted, they can’t send odors to the brain.

Anos­mia — the med­i­cal term for the in­abil­ity to smell — was not ini­tially rec­og­nized as a symp­tom of covid-19, Hop­kins said. Doc­tors were so over­whelmed by pa­tients with se­vere res­pi­ra­tory prob­lems, she said, that “they didn’t ask the ques­tion.”

But sub­se­quent data from a symp­tom-track­ing app has shown that 60 per­cent of peo­ple later di­ag­nosed with covid-19 re­ported los­ing their senses of smell and taste. About a quar­ter of par­tic­i­pants ex­pe­ri­enced anos­mia be­fore de­vel­op­ing other symp­toms, sug­gest­ing it can be an early warn­ing sign of in­fec­tion.

In­trigu­ingly, Hop­kins said, peo­ple who lose their sense of smell don’t seem to develop the same se­vere res­pi­ra­tory prob­lems that have made covid-19 so deadly. But a very small num­ber of pa­tients have ex­pe­ri­enced con­fu­sion, low blood oxy­gen lev­els and even lost con­scious­ness — a sign that the virus may have trav­eled along their ol­fac­tory nerve end­ings straight to the cen­tral ner­vous sys­tem.

“Why you get this dif­fer­ent ex­pres­sion in dif­fer­ent peo­ple, no­body knows,” she said.

There are also re­ports that covid-19 can turn peo­ple’s eyes red, caus­ing pink­eye, or con­junc­tivi­tis, in some pa­tients. One study of 38 hos­pi­tal­ized pa­tients in Hubei prov­ince, China, found that a third had pink­eye.

But like many of the non-res­pi­ra­tory ef­fects of the virus, this symp­tom may be rel­a­tively un­com­mon — and may develop only in peo­ple al­ready se­verely ill. The fact that the virus has been found in the mu­cus mem­brane that cov­ers the eye in a small num­ber of pa­tients, how­ever, does sug­gest that the eye could be an en­try­way for the virus — and is one rea­son that face shields and gog­gles are be­ing used to pro­tect health-care work­ers.

The virus also is hav­ing a clear im­pact on the gas­troin­testi­nal tract, caus­ing di­ar­rhea, vom­it­ing and other symp­toms. One study found that half of covid-19 pa­tients have gas­troin­testi­nal symp­toms, and spe­cial­ists have coined a the hash­tag #Notjust­cough for so­cial me­dia to raise aware­ness of them.

Stud­ies sug­gest that pa­tients with di­ges­tive symp­toms will also develop a cough, but one may oc­cur days be­fore the other.

“The ques­tion is, is it kind of be­hav­ing like a hy­brid of dif­fer­ent viruses?” Spiegel said. “What we’re learn­ing is, it seems any­way, that this virus homes in on more than one or­gan sys­tem.”

Re­ports also in­di­cate that the virus can at­tack the liver. A 59year-old woman in Long Is­land came to the hospi­tal with dark urine, which was ul­ti­mately found to be caused by acute hep­ati­tis. After she de­vel­oped a cough, physi­cians at­trib­uted the liver dam­age to a covid-19 in­fec­tion.

Spiegel said he has seen more such re­ports ev­ery day, in­clud­ing one from China on five pa­tients with acute viral hep­ati­tis.

A par­tic­u­lar dan­ger of the virus ap­pears to be its ten­dency to pro­duce blood clots in the veins of the legs and other ves­sels, which can break off, travel to the lung and cause death by a con­di­tion known as pul­monary em­bolism.

An ex­am­i­na­tion of 81 pa­tients hos­pi­tal­ized with pneu­mo­nia caused by covid-19 in Wuhan found that 20 had such events and that eight of them died. The peer­re­viewed data was pub­lished on­line April 9 in the Jour­nal of Throm­bo­sis and He­mosta­sis.

Across New York City, blood thin­ners are be­ing used with covid-19 pa­tients much more than ex­pected, said San­jum Sethi, an in­ter­ven­tional car­di­ol­o­gist and as­sis­tant pro­fes­sor of medicine at Columbia Univer­sity’s Irv­ing Med­i­cal Cen­ter.

“We’re just see­ing so many of these events that we have to in­ves­ti­gate fur­ther,” he said.

JON GERBERG/THE WASH­ING­TON POST

A scene at Mai­monides Med­i­cal Cen­ter in Brook­lyn on April 1. Some stud­ies of coro­n­avirus pa­tients have found that some lose their sense of smell be­fore they show signs of get­ting sick.

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