A COVID-19 outbreak in a rheumatology department upon the early days of the pandemic

ORIGINAL RESEARCH published: 25 Sep embe 2020 doi: 10.3389/ med.2020.576162 F on ie s in Medicine | www. on ie sin.o g 1Sep embe 2020 | Volume 7 | A icle 576162 Edi ed by: Geo ge Be sias, Uni e si y o C e e, G eece Re iewed by: Ma ia Del Pila Es e ez Diz, Uni e sidad de São Paulo, B azil Gecilma a Sal ia o Pileggi, Facul y o Heal h Sciences o Ba e os D . Paulo P a a (FACISB), B azil *Co espondence: João Eu ico Fonseca [email p o ec ed] †ORCID: João Eu ico Fonseca o cid.o g/0000-0003-1432-3671 ‡As lis ed in Collabo a i e G oup Au ho ship Sec ion Special y sec ion: This a icle was submi ed o Rheuma ology, a sec ion o he jou nal F on ie s in Medicine Recei ed: 25 June 2020 Accep ed: 14 Augus 2020 Published: 25 Sep embe 2020 Ci a ion: Romão VC, Oli ei a-Ramos F, C uz-Machado AR, Ma ins P, Ba ei a S, Sil a-Dinis J, Mendonça-Galaio L, P oença H, Melo C is ino J, Sacadu a-Lei e E, Khmelinskii N, Romeu JC, Fonseca JE and he CHULN Rheuma ology Depa men (2020) A COVID-19 Ou b eak in a Rheuma ology Depa men Upon he Ea ly Days o he Pandemic. F on . Med. 7:576162. doi: 10.3389/ med.2020.576162 A COVID-19 Ou b eak in a Rheuma ology Depa men Upon he Ea ly Days o he Pandemic Vasco C. Romão1,2, Filipa Oli ei a-Ramos1,2, Ana Ri a C uz-Machado1,2, Pa ícia Ma ins1,2, So ia Ba ei a1,2, Joana Sil a-Dinis1,2, Luís Mendonça-Galaio3, Helena P oença4, José Melo C is ino4, Ema Sacadu a-Lei e3, Niki a Khmelinskii1,2, José Ca los Romeu1, João Eu ico Fonseca1,2*†and he CHULN Rheuma ology Depa men 1‡ 1Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal, 2Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal, 3Occupa ional Heal h Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal, 4Clinical Pa hology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal Objec i es: To desc ibe ou expe ience wi h a co ona i us disease 2019 (COVID-19) ou b eak wi hin a la ge heuma ology depa men ea ly in he pandemic. Me hods: Symp oma ic and asymp oma ic heal hca e wo ke s (HCWs) had a naso-o opha yngeal swab o de ec ion o se e e acu e espi a o y synd ome co ona i us 2 (SARS-CoV-2) and we e ollowed clinically. Re e se ansc ip ion polyme ase-chain eac ion (RT-PCR) was epea ed o documen cu e, and se ological esponse was assessed. Pa ien s wi h isk con ac s wi hin he depa men in he 14 days p eceding he ou b eak we e sc eened o COVID-19 symp oms. Resul s: 14/34 HCWs (41%; 40 ±14 yea s, 71% emale) es ed posi i e o SARS-CoV-2, and 11/34 (32%) de eloped symp oms bu we e RT-PCR-nega i e. Hal o RT-PCR-posi i e HCWs did no epo e e , cough, o dyspnea be o e es ing, which we e absen in 3/14 cases (21%). Mild disease p e ailed (79%), bu 3 HCWs had mode a e disease equi ing u he assessmen , which excluded se e e complica ions. Ne e heless, symp om du a ion (28 ±18 days), i al shedding (31 ±10 days pos -symp om onse , ange 15–51), and wo k absence (29 ±28 days) we e p olonged. 13/14 (93%) o RT-PCR-posi i e and none o he RT-PCR-nega i e HCWs had a posi i e humo al esponse Highe IgG indexes we e obse ed in indi iduals o e 50 yea s o age (14.5 ±7.7 s. 5.0 ±4.4, p=0.012). O 617 heuma ic pa ien s, 8 (1.3%) de eloped COVID-19 symp oms (1/8 hospi aliza ion, 8/8 comple e eco e y), ollowing a consul a ion/p ocedu e wi h an asymp oma ic (7/8) o mildly symp oma ic (1/8) HCW. Conclusions: A COVID-19 ou b eak can occu among HCWs and heuma ic pa ien s, swi ly sp eading o e he p esymp oma ic s age. Mild disease wi hou ypical symp oms should be ecognized and may e ol e wi h delayed i al shedding, p olonged eco e y, and adequa e immune esponse in mos indi iduals. Keywo ds: COVID-19, heuma ology p ac ice, heuma ic pa ien s, heal hca e wo ke s (HCW), p esymp oma ic ansmission Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men INTRODUCTION Following he ini ial desc ip ions in ea ly Janua y 2020 o a no el o m o se e e pneumonia in pa ien s om Wuhan, China (1– 4), he co ona i us disease 2019 (COVID-19) quickly sp ead a a global le el. On Janua y 30, he Wo ld Heal h O ganiza ion decla ed i a public heal h eme gency o in e na ional conce n (5), and i was subsequen ly upda ed o a pandemic on Ma ch 11 (6). A e he i s epo ed case in Po ugal (Ma ch 2), exponen ial g ow h led o he ins i u ion o majo es ic i e measu es (7). Consis en ly high in ec ion a es among heal hca e wo ke s (HCWs) ha e been epo ed in se e al ha d-hi coun ies, such as China (8,9), I aly (10), Spain (11), and he Uni ed S a es (12), despi e adequa e sa e y measu es (13). One possibili y is ha in-hospi al ansmission among pa ien s and HCWs migh be a key o m o con agion (9,14,15). This is pa icula ly ele an gi en he ansmission dynamics o se e e acu e espi a o y synd ome co ona i us 2 (SARS-CoV-2), whe eby p esymp oma ic/asymp oma ic con amina ion is likely o play a majo ole in disease sp eading (14–19). In he ea ly days o he pandemic, mos ocus was gi en o se e e clinical pic u es (2,8,9,20), and epo s on mild o asymp oma ic disease we e sca ce (21,22). This may ha e con ibu ed o an ini ial o e sigh o mo e gene al, less se e e mani es a ions, such as uppe espi a o y and diges i e symp oms (23). These milde disease o ms migh be easily unde alued, including by HCWs esponding o he pandemic. In heal hca e acili ies, his may acili a e he gene alized sp ead among HCWs, who can se e as disease- ansmission agen s (9,14–16). This ac may be pa icula ly ele an in ou pa ien -o ien ed depa men s wi h a high olume o clinical ac i i y (e.g., heuma ology). In addi ion, heuma ology p ac ice equi es daily close physical con ac wi h pa ien s wi h heuma ic and musculoskele al diseases (RMDs), who a e o en immunosupp essed and ha e an inc eased o e all in ec ious isk. In he p esen epo , we aim o desc ibe ou expe ience wi h a COVID-19 ou b eak wi hin ou depa men , upon he ini ial weeks o he pandemic, highligh ing clinical, i ological, and immunological ou comes o HCWs and RMD pa ien s. MATERIALS AND METHODS Ou b eak Cha ac e iza ion O e he week o Ma ch 9–15, 2020, se e al HCWs o he heuma ology depa men o Cen o Hospi ala Uni e si á io Lisboa No e (CHULN) de eloped mild symp oms compa ible wi h COVID-19. All s a (symp oma ic/asymp oma ic) unde wen sc eening o SARS-CoV-2 on Ma ch 15–16. Double naso-o opha yngeal swabs we e ob ained, and samples we e es ed o SARS-CoV-2 by e e se ansc ip ion-polyme ase chain eac ion (RT-PCR; cobas R SARS-CoV-2 ki , cobas R 6800 Sys em, Roche Diagnos ics, USA). All he con i med and suspec ed cases we e qua an ined and e e ed o public heal h au ho i ies. Daily emo e clinical moni o ing o HCWs was conduc ed by 2 asymp oma ic heuma ologis s in conjunc ion wi h public heal h and occupa ional medicine specialis s. Tes ing o HCWs was epea ed (i) 7–14 days a e he i s nega i e es in subjec s wi h pe sis ing symp oms and (ii) 5–7 days ollowing he esolu ion o e e and imp o emen in espi a o y symp oms in con i med cases (24). Two consecu i e nega i e es s we e equi ed o con i m i al shedding cessa ion and allow e u n o wo k (25). Immunological esponse o SARS-CoV-2 was e alua ed by chemiluminescen immunoassay (MAGLUMI R 800 CLIA Sys em, MAGLUMI R 2019-nCoV (SARS-CoV-2) IgM/IgG-ki s, Snibe Co., L d., China) in all HCWs, ollowing symp om esolu ion and double-nega i e RT-PCR in con i med cases. We con ac ed pa ien s obse ed du ing he p e ious 2 weeks in he day-ca e uni , ou pa ien clinic, and p ocedu es oom who had possible con ac s wi h con i med RT-PCR-posi i e HCWs. Each pa ien was sc eened o sugges i e symp oms and eques ed o emain in isola ion o 14 days pos -con ac wi h he depa men . Pa ien s wi h symp oms compa ible wi h COVID-19 we e e e ed o he na ional heal h sys em ho line and signaled o heal h au ho i ies, who had also ecei ed he lis o sc eened pa ien s. S udy P ocedu es All HCWs o he heuma ology depa men who we e wo king du ing Ma ch 2–13, 2020, including isi ing ellows, we e in i ed o pa icipa e in his s udy. A s anda dized ques ionnai e was adminis e ed o collec demog aphic da a, symp om cha ac e iza ion, disease cou se and ou come, ea men , como bidi ies, and concomi an he apy. Resul s o labo a o y and imaging s udies pe o med, including RT- PCR and IgG/IgM o SARS-CoV-2 we e e iewed. Disease cou se was classi ied as mild, mode a e ( equi ing physical examina ion and labo a o y/imaging s udies), o se e e ( equi ing hospi aliza ion). Mo eo e , pa ien s obse ed in he depa men be ween Ma ch 2–13 who de eloped symp oms sugges i e o COVID-19 had an appoin men scheduled, upon de ini e esolu ion, o clinical obse a ion. The same da a we e collec ed as o HCWs, in addi ion o a iables ela ed o he RMD and associa ed ea men . Pa ien s obse ed in he pe iod o in e es who did no de elop COVID-19 symp oms o did so ou side he 14-day window a e he las con ac wi h he depa men , we e excluded. All s udy pa icipan s signed a s udy-speci ic in o med consen . This s udy was app o ed by he Lisbon Academic Medical Cen e E hics Commi ee ( e e ence 171/20). S a is ical Analysis Demog aphic and clinical cha ac e is ics we e p esen ed as equency, mean ±s anda d de ia ion, o median [in e qua ile ange (IQR)] as applicable. Compa ison o con inuous a iables be ween HCW g oups was pe o med using K uskal–Wallis (3 g oups) o Mann–Whi ney U- es (2 g oups). Ca ego ical a iables we e compa ed using Chi-squa e o Fishe ’s exac es . Ag eemen be ween RT-PCR and se ological es s was done using Kappa s a is ic. Pea son co ela ion was applied o s udy he ela ion o IgG humo al esponse and clinical a iables. S a is ical analyses we e pe o med using S a a-12.1 o Mac (S a aCo p, College S a ion, USA) and G aphPad-P ism-7 o MacOS (G aphPad So wa e, USA). P- alue was conside ed signi ican a p<0.05. F on ie s in Medicine | www. on ie sin.o g 2Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men RESULTS Clinical and Vi ological Cou se o HCWs A o al o 25/34 HCWs (17 heuma ologis s, 8 esiden s, 4 isi ing ellows, 1 nu se, 1 heal h aid, 2 sec e a ies, and 1 cleaning aid) de eloped symp oms sugges i e o a i al in ec ion, 14 o whom had a posi i e RT-PCR o SARS-CoV-2 (Table 1,Figu e 1, Supplemen a y Figu e 1). Ten ou o 14 (71%) posi i e cases we e emale o younge han 50 yea s old. Only 4/14 (29%) subjec s had a p e ious his o y o ca dio ascula disease and/o me abolic synd ome, whe eas 3/14 (21%) had a diagnosis o immune-media ed in lamma o y disease (one o whom ea ed wi h me ho exa e 15 mg/week). Impo an ly, 5/14 (36%) HCWs did no de elop e e , which las ed ≤3 days in 4/9 (44%) emaining cases. Cough was also absen in he same p opo ion (36%). O no e, 7/14 (50%) subjec s did no de elop any o he mani es a ions o he ypical COVID-19 iad p io o he posi i e RT-PCR es , which we e comple ely missing in 3 cases (21%) h oughou he disease. In u n, milde symp oms we e al eady p esen du ing he week p io o he ou b eak iden i ica ion in se e al ins ances. Anosmia and dysgeusia we e p esen in o e hal he cases, including 1 subjec (HCW6) who did no de elop e e , cough, o dyspnea. The majo i y o cases (11/14, 79%) had a benign cou se. The e we e no hospi aliza ions, bu 3/14 HCWs (aged 45–61 wi h ele an como bidi ies) unde wen clinical, labo a o y, and adiog aphic e alua ion 7–12 days a e symp om onse due o pe sis en e e , cough, ches pain, and/o sho ness o b ea h (Supplemen a y Table 1). Lymphopenia (1/3), h ombocy openia (1/3), aised lac a e dehyd ogenase (1/3), D-dime s (2/3), ib inogen (2/3), and C- eac i e p o ein (CRP; 2/3) we e iden i ied, bu hypoxemia and adiog aphic signs o COVID-19 pneumonia we e absen . Se en subjec s (50%) we e ea ed wi h hyd oxychlo oquine (400 mg/day, median 9 days, ange 7–14 days), and 4 ecei ed concomi an azi h omycin (500 mg/day, 5 days). One HCW de eloped a bac e ial sinus in ec ion, ea ed wi h amoxicillin/cla ulana e. Seconda y ansmission o household membe s was con i med in 7/14 (50%) cases, one o 2 close ela i es, all wi h mild disease. Despi e he a o able cou se o mos cases, symp om du a ion was p olonged (median 24.5 days, IQR 15–39, ange 2– 58; Table 1,Figu e 1,Supplemen a y Figu e 1). A he end o ollow-up, 2 subjec s had pe sis en symp oms (Figu e 1, Supplemen a y Figu e 1). Likewise, naso-o opha yngeal RT- PCR emained posi i e on a e age o 31 ±10 days om symp om onse (median 29.5 days, IQR 25–35, ange 15–51; Figu e 1). This esul ed in he need o epea RT-PCR es s equen ly, wi h a median numbe o es s pe posi i e subjec o 5 (IQR 4–6, ange 4–9). O no e, 8/34 (24%) o epe i ion es s in comple ely asymp oma ic subjec s we e posi i e. Ye , his was less han in indi iduals who epea ed es ing while s ill showing some symp oms (13/25, 52%, p=0.024; Figu e 1). On a e age, HCWs we e away om wo k o 29.2 ±9.8 days (median 24.5, IQR 23–36, ange 16–51). Ele en subjec s de eloped a ious symp oms bu es ed nega i e e en upon e es ing (Table 1,Figu e 1). These HCWs epo ed complain s o cough (55%), hino hea (45%), so e h oa (82%), and o he symp oms in simila equency and du a ion o con i med cases o e he same ime ame. Howe e , e e , a igue, malaise, headache, myalgia, anosmia, and dysgeusia we e signi ican ly less common. No ably, hese HCWs had a compa able demog aphic and como bidi y p o ile o hose wi h posi i e RT-PCR and he 9 asymp oma ic subjec s wi h nega i e RT-PCR (Table 1). No HCWs epo ed a el om a eas wi h ac i e communi y ansmission. A esiden (HCW6) wea ing a su gical mask obse ed a sugges i e case in he eme gency depa men 3 days be o e symp om onse (Ma ch 8), who did no ul ill es ing c i e ia a he ime ( a el om endemic a ea). A consul an (HCW4) had a sho , unp o ec ed con ac in he week p eceding he ou b eak wi h an inpa ien om ano he depa men who was la e ound o ha e COVID-19. O no e, 7/14 o in ec ed HCWs had a common link o ou heuma ological p ocedu es uni , ha ing spen he mos hou s he e o e he p e ious 2 weeks. None heless, he emaining RT-PCR-posi i e HCWs had minimal exposu e o his acili y, and 2 heuma ologis s (HCW18/21), who spen mo e han 10 h/week in he uni , es ed nega i e. Finally, all bu 10 HCWs (5 RT-PCR-posi i e, 5 RT-PCR-nega i e) we e p esen , unp o ec ed, in a 2.5-h depa men al mee ing (Ma ch 10) add essing he local esponse o he pandemic. A he ime, only 1 HCW (HCW7) had symp oms (mild hino hea). Immunological Response A e a median (IQR) o 45 (40.5–48.5) days ollowing symp om onse (o he i s RT-PCR es o asymp oma ic subjec s), 32 HCWs had an assessmen o he se ological esponse (Figu e 2). A posi i e IgM and IgG index (>1.0 AU/mL) was seen in, espec i ely, 2/14 (14.3%) and 13/14 (92.9%) o he con i med RT-PCR-posi i e cases and none o he symp oma ic/asymp oma ic RT-PCR-nega i e subjec s (Figu es 2A,B). Bo h es s had a 96.9% ag eemen in case classi ica ion (Kappa coe icien 0.936). Assessmen iming was simila o he HCWs wi h bo de line posi i e IgM (HCW 11/12, 1.10–1.18 AU/mL) o IgG (HCW 12/14, 1.10 AU/mL) compa ed o o he RT-PCR-posi i e subjec s. In addi ion, HCW10 had an IgG index below he posi i e h eshold, despi e 2 posi i e RT- PCR es s, no immunosupp ession, and compa able e alua ion iming and clinical cou se. Wi hin he RT-PCR-posi i e g oup, conside able a ia ion was seen in he an ibody esponse (Figu e 2B). No ably, subjec s o e 50 yea s old had a highe mean IgG index (14.5 ±7.7 AU/mL) han younge indi iduals (5.0 ±4.4 AU/mL, p= 0.012; Figu e 2C). Al hough he numbe s a e small, he 3 olde HCWs (HCW 8/11/13) who had an IgG index abo e 10 AU/mL expe ienced a mo e se e e disease cou se wi h high e e and cough, and 2 o hem had aised D-dime s, ib inogen, and CRP. In con as , he emaining olde HCW (HCW 7) had a mild cou se wi h limi ed hino hea and gas oin es inal symp oms and de eloped a lowe IgG index (4.99 AU/mL). Ne e heless, a posi i e end was obse ed in he co ela ion be ween age and IgG index (Pea son =0.53, p=0.051; Figu e 2D). No o he F on ie s in Medicine | www. on ie sin.o g 3Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men TABLE 1 | Demog aphic and clinical cha ac e is ics o s udy pa icipan s. O e all (n=34) SARS-CoV-2 RT-PCR es esul s and symp oms p- alue Posi i e (n=14) Nega i e, symp oms Nega i e, no symp oms (n=11) (n=9) Age, yea s ( ange) 41 ±12 (26–66) 40 ±14 (26–62) 40 ±8 (28–52) 44 ±15 (27–66) 0.759 Age ≥60 yea s, n(%) 4 (11.8) 2 (14.3) 0 2 (22.2) 0.286 Female, n(%) 23 (67.7) 10 (71.4) 8 (72.7) 5 (55.6) 0.723 Como bidi ies, n(%) 20 (58.8) 8 (57.1) 6 (54.6) 6 (66.7) 0.849 A e ial hype ension 5 (14.7) 3 (21.4) 0 2 (22.2) 0.279 Ca diac disease 3 (8.8) 2 (14.3) 0 1 (11.1) 0.601 Diabe es melli us 2 (5.9) 2 (14.3) 0 0 0.324 Obesi y 3 (8.8) 2 (14.3) 1 (9.1) 0 0.768 COPD/as hma 3 (8.8) 1 (7.1) 2 (18.2) 0 0.464 Ch onic hinosinusi is 4 (11.8) 1 (7.1) 2 (18.2) 1 (11.1) 0.806 IMID 6 (17.7) 3 (21.4) 1 (9.1) 2 (22.2) 0.732 Cance his o y 2 (5.9) 0 1 (9.1) 1 (11.1) 0.241 Smoking his o y (e e ) 9 (26.5) 4 (28.6) 2 (18.2) 3 (33.3) 0.790 Concomi an he apy, n(%) 5 (14.7) 3 (21.4) 0 2 (22.2) 0.279 ACEi/ARB 5 (14.7) 3 (21.4) 0 2 (22.2) 0.279 NSAIDs 1 (2.9) 0 1 (9.1) 0 0.588 DMARDs 3 (8.8) 1 (7.1) 1 (9.1) 1 (12.5) 1.000 COVID-19 symp oms, n(%)/du a ion, days 25 (73.5)/24 ±19 14 (100)/28 ±18 11 (100)/20 ±20 0 – Fe e 11 (32.4)/6 ±8 9 (64.3)/7 ±9 2 (18.2)/2 ±1 – 0.042 Cough 15 (44.1)/25 ±19 9 (64.3)/25 ±14 6 (54.6)/26 ±26 – 0.622 Dyspnea 3 (8.8)/3 ±31 2 (14.3)/14 ±10 1 (9.1)/66 1.000 Ches igh ness 4 (11.8)/17 ±16 3 (21.4)/22 ±16 1 (9.1)/4 – 0.603 Malaise 10 (29.4)/15 ±14 9 (64.3)/16 ±15 1 (9.1)/6 – 0.012 Fa igue 12 (35.3)/25 ±21 10 (71.4)/24 ±21 2 (18.2)/27 ±25 – 0.015 Headache 11 (32.4)/16 ±18 10 (71.4)/17 ±19 1 (9.1)/5 – 0.004 Rhino hea 14 (41.2)/18 ±16 9 (64.3)/24 ±17 5 (45.5)/7 ±3 – 0.435 So e h oa 16 (47.1)/7 ±7 7 (50.0)/9 ±9 9 (81.8) 5 ±3 – 0.208 Anosmia 9 (26.5)/15 ±13 8 (57.1)/16 ±13 1 (9.1)/6 – 0.033 Dysgeusia 8 (23.5)/12 ±7 8 (57.1)/12 ±7 0 – 0.003 A h algia 1 (2.9)/25 1 (7.4)/25 0 – 1.000 Myalgia 11 (32.4)/14 ±17 8 (57.1)/16 ±20 3 (27.3)/8 ±9 – 0.004 Abdominal pain 2 (5.9)/3 ±1 0 2 (18.2)/3 ±1 – 0.183 Nausea/ omi ing/dia hea 7 (20.6)/11 ±11 5 (35.7)/13 ±12 2 (18.2)/5 ±0 – 0.407 Dizziness 3 (8.8)/9 ±6 2 (14.3)/10 ±8 1 (9.1)/8 – 1.000 Disease se e i y, n(%) Mild 22 (64.7) 11 (78.6) 11 (100) – 0.230 Mode a e 3 (8.8) 3 (21.4) 0 Se e e 0 0 0 Hospi aliza ion 0 0 0 – – T ea men , n(%)/du a ion, days None/suppo i e 27 (79.4) 7 (50) 11 (100) 9 (100) – Hyd oxychlo oquine 7 (20.6)/9 ±3 7 (50)/9 ±3 0 0 Azi h omycin 4 (11.8)/5 ±0 4 (28.6)/5 ±0 0 0 Complica ions, n(%) 1 (2.9) 1 (7.4) 0 0 – Symp om esolu ion, n(%) 23 (92) 12 (85.7) 11 (100) – – Seconda y ansmission, n(%) 7 (20.6) 7 (50) – – – Days o 2 nega i e es s ( ange) 31 ±10 (15–51) 31 ±10 (15–51) – – – ACEi, angio ensin-con e ing enzyme inhibi o s; ARB, angio ensin-II ecep o blocke s; ch onic obs uc i e pulmona y disease; DMARDs, disease-modi ying an i- heuma ic d ugs; IMID, immune-media ed in lamma o y disease; NSAIDs, non-s e oidal an i-in lamma o y d ugs. Con inuous alues ep esen ed as mean ±SD. F on ie s in Medicine | www. on ie sin.o g 4Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men FIGURE 1 | E olu ion o symp oms and RT-PCR es esul s o heal hca e wo ke s wi h con i med o suspec ed COVID-19. Each ow ep esen s a heal hca e wo ke (HCW) ollowed o e ime (columns). Resul s o e e se ansc ip ion polyme ase-chain eac ion (RT-PCR) a e indica ed as posi i e (L), nega i e (—) o inde e mina e (±). Mild symp oms include symp oms o he han e e , cough, and dyspnea as e e ed o in he ex and Table 1. clinical ac o was associa ed wi h an ibody esponse, including sex; ea men ; o p esence/du a ion o e e , cough, o dyspnea. Seconda y T ansmission o Pa ien s Wi h RMDs A o al o 617 pa ien s we e iden i ied as ha ing had a po en ial isky con ac , 561 (91%) o whom we e con ac ed by elephone and sc eened o COVID-19 symp oms s a ing wi hin he 14-day window (Figu e 3). We iden i ied 8 (1.3% o o al) emale pa ien s (mean age 66.8 ±14.9 yea s) who de eloped symp oms compa ible wi h COVID-19 (Table 2). Six pa ien s had a diagnosis o an in lamma o y RMD; 3 we e ea ed wi h con en ional syn he ic disease-modi ying an i heuma ic d ugs (csDMARDs) and glucoco icoids and 2 wi h biologic DMARDs (bDMARDs). All con ac s ook place wi hin he same 2 days (Ma ch 9 and 11), all bu one we e wi h a con i med in ec ed HCW, and pa ien s denied addi ional suspicious con ac s. Con ac acing o Pa ien 1 wi hin he depa men con i med i o be limi ed o a symp oma ic physician wi h nega i e RT-PCR and se ology (HCW24). Impo an ly, in 7/8 cases, he HCW was asymp oma ic a he ime o con ac , and 1 pa ien (Pa ien 6) had a consul a ion wi h a physician (HCW7) p esen ing only mild se ous hino hea. O no e, 5/8 con ac s we e in he con ex o diagnos ic (ul asound) o he apeu ic p ocedu es (meso he apy), which in ol ed p olonged close physician–pa ien con ac . Pa ien s de eloped symp oms on a e age 4.3 ±2.1 days ( ange 2–9) a e he con ac . Hal epo ed e e , 88% had cough, and only 1 pa ien epo ed dyspnea. Gene al and uppe ai way symp oms we e common, including anosmia (50%) and dysgeusia (63%). Nasopha yngeal swabs we e pe o med in 6/8 cases (8.8 ±3.1 days pos -symp om onse ), 2 o which we e posi i e o SARS-CoV-2, and 1 was inconclusi e. Two pa ien s we e no es ed due o di icul y in eaching heal h au ho i ies o pe sonal choice (sel -isola ion). Pa ien s wi h nega i e/una ailable es s s ill had sugges i e COVID- 19 symp oms. All bu one pa ien had a mild- o-mode a e cou se and we e clinically eco e ed a e an a e age o 24.8 ±5.9 days. A 90-yea - old woman wi h gian cell a e i is and ele an ca dio ascula como bidi ies, exposed o long- e m me ho exa e and low- dose glucoco icoids, was hospi alized a e 6 days o e e and 3 days o wo sening ches pain and dyspnea. She equi ed oxygen he apy, ecei ed a combina ion o hyd oxychlo oquine (400 mg/day) and lopina i / i ona i (800/200 mg/day), and was discha ged a e 10 days. Impo an ly, none o he pa ien s expe ienced a la e o he baseline RMD. DISCUSSION Ou s udy p o ides impo an lessons on he ulne abili y and impac o a COVID-19 ou b eak wi hin a la ge heuma ology depa men a a ime when uni e sal su gical mask use was no ecommended. O e a single week, 41% o HCWs we e con i med o be in ec ed by SARS-CoV-2, and an addi ional 32% de eloped mos ly o e lapping symp oms. Al hough we could no de ec he index case, he sp ead o he con agion was as and occu ed when almos all HCWs we e asymp oma ic o exhibi ed only mino symp oms, easily dismissed o a ibu ed o ano he concu en i al disease. These indings a e in acco dance wi h F on ie s in Medicine | www. on ie sin.o g 5Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men FIGURE 2 | Immunological esponse o SARS-CoV-2 in ec ion among heal hca e wo ke s. (A) Pe cen age o heal hca e wo ke s (HCWs) wi h a posi i e immunological esponse o se e e acu e espi a o y synd ome co ona i us 2 (SARS-CoV-2) in ec ion, de ined as an IgM o IgG index equal o abo e 1.0 AU/mL. Analysis di e en ia ed by HCW g oup, depending on he p esence o COVID-19 symp oms and he esul o e e se ansc ip ion-polyme ase chain eac ion (RT-PCR). N=32 (RT-PCR+,N=14; RT-PCR– symp oms, n=10; RT-PCR– no symp oms, n=8). *None o he HCWs in his g oup de eloped an i-SARS-CoV-2 an ibodies (i.e., equency =0%) (B) Index o an i-SARS-CoV-2 an ibodies (IgG and IgM) acco ding o RT-PCR esul and COVID-19 symp oms. Dashed line ep esen s posi i e h eshold (1.0 AU/mL). E o ba s ep esen mean wi h s anda d de ia ion. (C) Dis ibu ion o an i-SARS-CoV-2 IgG an ibodies in RT-PCR+HCWs, acco ding o age g oup (below o abo e 50 yea s old). E o ba s ep esen mean wi h s anda d de ia ion. *p=0.012. (D) Co ela ion be ween age and an i-SARS-CoV-2 IgG an ibodies in RT-PCR+HCWs. , Pea son co ela ion coe icien . cu en conce ns a ound he p esymp oma ic o asymp oma ic ansmission o SARS-CoV-2 among HCWs and pa ien s (9,14– 16). As i al shedding and in ec iousness a e highe in he 2– 3 days p io o symp om onse and apidly dec ease he ea e (26,27), a high p opo ion o con agion occu s du ing he p esymp oma ic s age (18,26). In addi ion, asymp oma ic (17, 22,28,29) and mild disease o ms wi h limi ed uppe espi a o y symp oms a e now widely ecognized (23,27) and may escape igilance p o ocols, mo e ocused on he p esence o e e , cough, and dyspnea. This was ce ainly he case in ou clus e , in which es ing o all HCWs o he depa men , whe he symp oma ic o no , was i al o iden i y cases and con ain he ou b eak. The e o e, in heal hca e se ings, con inuous mask use, social dis ancing, and mild-symp om moni o ing should be adop ed among HCWs, oge he wi h p oac i e es ing s a egies, o accoun o po en ial p e/asymp oma ic ca ie s (15). The ou b eak had a p o ound epe cussion in he clinical ac i i y o he depa men . In ec ed subjec s had p o ac ed symp oms and we e away om wo k o a ound 1 mon h. In addi ion, p olonged i al shedding (up o 51 days) led o equen RT-PCR epe i ion (median 5 es s) un il cu e was con i med, consuming subs an ial esou ces. Ou indings ega ding i al RNA swab posi i i y a e longe han p e iously epo ed (20,30–32), which may be ela ed o di e ences in specimen collec ion (double naso- and o opha yngeal swab in ou s udy), s udy popula ion, o disease se e i y. In e es ingly, simila nasopha yngeal i al loads in pa ien s wi h mild and se e e disease ha e been epo ed (30) al hough a sepa a e s udy concluded o he wise (33). Mo eo e , some da a sugges ha a posi i e RT-PCR does no deno e he ac ual p esence o iable i us, especially a e he i s week (27,34). Howe e , his is no ye ully es ablished, and we would, he e o e, ad oca e o 2 consecu i e nega i e es s be o e HCWs e u n o wo k. In e ec , 21/59 (36%) o epea es s we e posi i e, and in 5 ins ances, a posi i e o inde e mina e es ollowed a i s nega i e esul , highligh ing he di icul ies o in e p e a ion (34). F on ie s in Medicine | www. on ie sin.o g 6Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men FIGURE 3 | Flow cha o RMD pa ien sc eening o symp oms sugges i e o COVID-19. Pa ien s wi h possible con ac s wi h heal hca e wo ke s wi h posi i e e e se ansc ip ion-polyme ase chain eac ion (RT-PCR) o se e e acu e espi a o y co ona i us 2 (SARS-CoV-2) in he pe iod o Ma ch 2–13, 2020, we e con ac ed by elephone and sc eened o COVID-19 symp oms s a ing wi hin he subsequen 14 days. See Me hods o de ails. All HCWs had a mild- o-mode a e disease cou se, and he e we e no majo complica ions. We belie e he posi i e ou come o he coho is mainly ela ed o he young mean age wi h only 2 HCWs olde han 60 yea s. Al e na i ely, a lowe ini ial i al exposu e load could also explain an o e all milde pheno ype (33). Ne e heless, mos o he in ec ed HCWs (93%) de eloped an immune esponse, which ended o be mo e obus in olde indi iduals. This, in u n, may be seconda y o a mo e se e e clinical cou se, known o be s ongly associa ed wi h age (20,35). A possible explana ion o his inding could be a highe peak i al load, also p e iously shown o be posi i ely co ela ed wi h age (30). Indeed, we highligh ha 2/13 (15.4%) IgG-posi i e HCWs, bo h unde 30 yea s old and wi h a e y mild disease cou se, had bo de line IgG indexes. Ne e heless, o he ac o s, such as T-cell–media ed immuni y (36–38), may be in ol ed, as 1 HCW in he 40- o 50-yea -old ange who had cough and 2 posi i e RT-PCR es s did no de elop IgG an ibodies 47 days pos -symp om onse . Conco dance be ween se ology and RT-PCR was o he wise excellen , con i ming p e ious epo s (20,30,31). Al hough i canno be comple ely excluded, his sugges s he e we e no alse-nega i e RT-PCR esul s, including in symp oma ic HCWs. Finally, seconda y ansmission o a mino i y o pa ien s did occu om 4 HCWs who we e asymp oma ic (75%) o had mild uppe ai way symp oms (25%), mos ly in close p oximi y con ac . As one o he con i med cases only con ac ed wi h HCW 24 (nega i e RT-PCR and se ology), we canno exclude undisclosed communi y con agion o nosocomial ansmission h ough omi es (39). Also, we admi ha pa ien s wi h nega i e/missing RT-PCR could be alse nega i e o undiagnosed cases, possibly due o a la ge in e al be ween symp om onse and es ing. O no e, all con ac s occu ed when p e en i e measu es had al eady been adop ed, and 80% o ace- o- ace clinical ac i i y had been de e ed, which migh explain he low numbe o in ec ed pa ien s. We admi he possibili y ha con agion could ha e ollowed he opposi e ou e (p e/asymp oma ic pa ien s o HCWs) al hough symp om iming does sugges o he wise. No wi hs anding he ad anced age and long- e m use o cs/bDMARDs and low-dose glucoco icoids in hal he cases, all pa ien s had a a o able ou come. This is in acco dance wi h ecen da a ha did no demons a e an inc eased incidence o se e e disease in RMD pa ien s (40,41). Ou s udy has some limi a ions. Due o i s eal-li e na u e, clinical assessmen and RT-PCR iming we e clinically based F on ie s in Medicine | www. on ie sin.o g 7Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men TABLE 2 | Clinical ea u es o RMD pa ien s wi h con i med o suspec ed COVID-19. Pa ien ID 1 2 3 4 5 6 7 8 Age/Sex 52/F 90/F 68/F 55/F 83/F 70/F 46/F 68/F Rheuma ic disease RA/SLE o e lap GCA Vi al eac i e a h i is ( esol ed) APS Sa coidosis RA PsA Ro a o cu endinopa hy Disease du a ion 11.1 y 10.1 y 7.7 mo 2.2 y 13.7 y 4.7 mo 15.7 y 11.2 mo Disease ac i i y Low Remission Remission No e en s Remission Low Mode a e Low/mild Como bidi ies HT, hea dx, COPD HT, CV dx, OP HT, COPD HT, CV dx, COPD HT, hea dx, ILD, CKD Dyspepsia, sphe ocy osis N/A HT, u e ine cance (pas ) Smoking s a us Pas Pas Pas Ac i e Ne e Ne e Ne e Ne e DMARDs (dose, mg) AZT (150), LEF (20) MTX (12.5/w), denosumab (60/6 mo) No No No MTX (15/w), HCQ (400) IFX (3/kg) No Glucoco icoids (dose, mg) DFZ (9) PDN (5) No No No PDN (7.5) No No NSAIDs No No Nimesulide No Aceme acin No Aceme acin No ACEi/ARB Ramip il No No Pe indop il Ramip il No No Lisinop il HCW con ac (#) RT-PCR– (24) RT-PCR+(1) RT-PCR+(1) RT-PCR+(14) RT-PCR+(1) RT-PCR+(7) RT-PCR+(1) RT-PCR+(1) Con ac da e 9/3/2020 11/3/2020 9/3/2020 9/3/2020 9/3/2020 11/3/2020 11/3/2020 11/3/2020 Con ac ype US (shoulde ) Meso he apy (shoulde ) Consul a ion Consul a ion Meso he apy (lumba spine) Consul a ion Meso he apy (heel) Meso he apy (shoulde ) Con ac du a ion 15min 10 min 30 min 30 min 10 min 30 min 10 min 10 min Days om con ac o symp om onse 9 2 4 4 4 3 4 4 COVID-19 symp oms (o de o appea ance) (1) F , Mal, F g, Hdx, Rhin, Cgh; (2) Ansm, Dysg (1) Mal, F g. Myalg, A h, Cgh; (2) F , Hdx, Rhin; (3) Chx, Dysp, Ansm, Dysg (1) Mal, F g, Hdx, Th , Cgh, A h; (2) Ansm, Dysg; (3) GI, Dizz (1) Mal, Hdx, Rhin, Myalg. GI; (2) Cgh, F g; (3) Ansm, Dysg (1) F , Mal, Fa , Hdx, Rhin, A h, Myalg, Dizz (1) Abd, GI; (2) Rhin, Cgh; (3) Chx, Hdx (1) F g, Cgh; (2) Dysg (3) Hdx, Abd (1) Mal, F g, Hdx, Th , Cgh; (2) Abd, GI; (3) F , Myalg, Dizz Diagnos ic RT-PCR es (symp om day) Posi i e (13) Posi i e (4) Inconclusi e (11) Nega i e (21) Nega i e (9) N/A Nega i e (8) N/A Nega i e (8) Symp om du a ion 14 20 30 21 31 25 29 28 Hospi aliza ion (days) No Yes (10) No No No No No No ICU admission N/A No N/A N/A N/A N/A N/A N/A Complica ions No No No No No No No No Ta ge ed ea men No HCQ, LOP+RIT No No No No No No T ea men changes ↓DFZ 6 mg Suspended MTX No No ↑NSAID eq No No No Ou come Cu e Cu e Cu e Cu e Cu e Cu e Cu e Cu e Days o 2 nega i e es s 34 20 N/A N/A N/A N/A N/A N/A Abd, abdominal pain; ACEi, angio ensin-con e ing enzyme inhibi o s; Ansm, anosmia; APS, an iphospholipid synd ome; ARB, angio ensin-II ecep o blocke s; A h, a h algia; AZT, aza hiop ine; Chx, ches pain/ igh ness; Cgh, cough; CKD, ch onic kidney disease; COPD, ch onic obs uc i e pulmona y disease; COVID-19, co ona i us disease 2019; CV, ce eb o ascula ; dx, disease; DFZ, de lazaco ; Dizz, dizziness/ e igo; DMARDs, disease-modi ying an i- heuma ic d ugs; Dysg, dysgeusia; Dysp, dyspnoea; F eq, equency; F g, a igue; F , e e ; GCA, gian cell a e i is; GI, gas oin es inal, including nausea, omi ing, dia hea; HCQ, hyd oxychlo oquine; HCW, heal hca e wo ke ; Hdx, headache; HT, hype ension; ICU, in ensi e ca e uni ; IFX, in liximab; ILD, in e s i ial lung disease; LEF, le lunomide; LOP, lopina i ; Mal, malaise; mo, mon hs; MTX, me ho exa e; N/A, no applicable; NSAIDs, non-s e oidal an i-in lamma o y d ugs; OP, os eopo osis; PDN, p ednisolone; PsA, pso ia ic a h i is; RA, heuma oid a h i is; RIT, i ona i ; Rhin, hino hea; RMD, heuma ic and musculoskele al diseases; RT-PCR, e e se ansc ip ion-polyme ase chain eac ion; SLE, sys emic lupus e y hema osus; Th , so e h oa ; US, ul asound; w, weeks; y, yea s. and di e ed sligh ly be ween subjec s. As compu ed omog aphy was no pe o med, we canno comple ely exclude COVID-19 pneumonia. Two ellows could no be es ed o se ology upon inishing hei cle kship. Also, 9% o he iden i ied RMD pa ien s could no be eached. In conclusion, we demons a e ha a COVID-19 ou b eak can occu among HCWs and heuma ic pa ien s, sp eading o e he p esymp oma ic s age and e ol ing wi h mild- o-mode a e symp oms, delayed i al shedding, and p olonged eco e y. F on ie s in Medicine | www. on ie sin.o g 8Sep embe 2020 | Volume 7 | A icle 576162 Romão e al. COVID-19 Ou b eak in Rheuma ology Depa men DATA AVAILABILITY STATEMENT All da ase s p esen ed in his s udy a e included in he a icle/Supplemen a y Ma e ial. ETHICS STATEMENT This s udy was e iewed and app o ed by Comissão de É ica do Cen o Académico de Medicina de Lisboa ( e e ence 171/20). The pa ien s/pa icipan s p o ided hei w i en in o med consen o pa icipa e in his s udy. W i en in o med consen was ob ained om he indi idual(s) o he publica ion o any po en ially iden i iable images o da a included in his a icle. AUTHOR CONTRIBUTIONS VR, FO-R, and JF designed he p ojec , collec ed and analyzed he da a, and d a ed he manusc ip . AC-M, PM, SB, and JS-D con ac ed pa ien s and ob ained he ele an clinical da a. LM-G and ES-L coo dina ed he occupa ional heal h esponse. HP and JC conduc ed labo a o y es ing, including RT-PCR and se ology. NK and JR o e iewed clinical moni o ing and da a collec ion o heal hca e wo ke s. All membe s o he CHULN Rheuma ology Depa men (collabo a i e g oup) ac i ely pa icipa ed in da a acquisi ion. All au ho s ha e con ibu ed o s udy concep ion and design and au ho s ha e c i ically e iewed he manusc ip o impo an in ellec ual con en and ha e ead and app o ed i s inal e sion. ACKNOWLEDGMENTS We acknowledge Ms. Sand a Guima ães, Ms. Vene anda Ba oca, and Ms. Inalda San os om he CHULN Rheuma ology Depa men o hei assis ance o s udy p ocedu es. We hank D . Ál a o Ay es Pe ei a and D . Tiago Ma ques om he CHULN In ec ious Diseases Depa men o he clinical suppo in e alua ing con i med and suspicious cases. We hank D . Cla a Almeida om he CHULN Occupa ional Heal h Depa men o he con ibu ion ega ding se ological assay esul s. This manusc ip has been eleased as a p e-p in a medRxi (42). COLLABORATIVE GROUP AUTHORSHIP The CHULN Rheuma ology Depa men : Manuel An ónio (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Ped o Á ila-Ribei o (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Ri a Ba os (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Raquel Campanilho-Ma ques (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po uga; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Susana Capela (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Inês Co dei o (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Bianca C is ea (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; In e nal Medicine 1 Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal); Edua do Dou ado (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Luís Gaião (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal); Raquel F ei as (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Depa men , Hospi al Ga cia de O a, Almada, Po ugal); Ca la Maciei a (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal); Joana Ma ins-Ma inho (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Ana Te esa Melo (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Ca los Mi anda Rosa (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal); Ma ga ida Mon ei o (Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e , Lisbon, Po ugal; Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal); Lila F on ie s in Medicine | www. on ie sin.o g 9Sep embe 2020 | Volume 7 | A icle 576162