‘Travel Meine and Infectious Disease xx (nx) sk Content lists available at ScienceDisest Travel Medicine and Infectious Disease Journal homepage: www.clsevier.com/locateltmsid Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis Alfonso J. Rodriguez-Morales*"", Jaime A. Cardona-Ospina’”**%"1, Estefania Gutiérrez-Ocampo", Rhuvi Villamizar-Pefia’, Yeimer Holguin-Rivera’, Juan Pablo Escalera-Antezana", Lucia Elena Alvarado-Arnez’, D. Katterine Bonilla-Aldana”**', Carlos Franco-Paredes™"", Andrés F. Henao-Martinez', Alberto Paniz-Mondolfi’"°?", Guillermo J. Lagos-Grisales', Eduardo Ramfrez-Vallejo’, Jose A. Sudrez'', Lysien I. Zambrano’, Wilmer E. Villamil-Gémez"*""", Graciela J. Balbin-Ramon*", Ali A. Rabaan", Harapan Harapan™”, Kuldeep Dhama", Hiroshi Nishiura’, Hiromitsu Kataoka", Tauseef Ahmad“, Ranjit Sah“, On behalf of the Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19) ‘reat Hea at een Rear Group acy of Heath Scenes, Una Tenia de Pera, Ree, Rr, Comba Gro deinen Beis, Fac of Med, Func Unies Aroma de is Andries, Per, Rra,Cloia Cant an Tropa Metin, Zs ant Trav Mac, Asin Clade feo. Bo DC, Clans Commi Tre Mean Parone of crus Deas (APD Perr, Rural, Cam “Maser Cnc! Fencing en Bases, Unrest dS La. Pre ‘ig de sat cn anid Fou of Heath Sees, Ute Tecoligea de ere, Per, Roi, Clone Sense de vet en ects Brora Mena Top Fac of Medkne,Panain Ura Ana de as Arras, ee, Rela Gone "Bg nets css Tropa Metre Resch Gro, Inst pra a Ivete Ces Boo Ste, ere, Rua, Cooma "esta Pans Tanay/UNIRANZ, Cicetomb Baia Natal Repent for Tasha Pram. Mino Hea La Px, Bata “barr anos (51200), erst annem Cnsevaron Resch Ge (OBC) ania Unverstara urrama dels Andria Se Pra "Dit of lifes Dare, Dearne of Mein, Une of Catal Anca Mel Cer, urns, CO, USA * Hp fn de Mee Foo Gamen, Mec Cy, Meco * Larry of Medical Merle, Daren Peta, Mle an Cite Men, The Moun Sint Hap eakn Sol of Metin Meu Sint “Litre de Seatac Ce gure de ars, Ings de sds Avra (IDEA), Crea, Cares, Venza “Int de ents Bees ID 7c Venn dl Cla Cabo, fs. Lar Venza "Inver SI See Pa, Cla Reach Depart Comanrav Gres de x de eS, aad ly, Panama “apart of Ppa cnt Marpogl Scr, Sol of Mada Sc Unerad Nacional aon de Hondas (UNA, Tp, Heda “yeas Dues and denon Cant Recarh Grp Hp! Unverstar de Slo, Sela, See Caan ‘Pravana del Drcorade de Mina Tal SUE Care, Unves etAn, Baru, Cosa "Hosa de Berges Jse Csi Uo. Lin, Pe "Meer Daprse ebry des Hpi Avance Hear, Dra Saul Ara “Meet sear Ui, Soha of Men, Unerstes Sh Kuta Handa Ach, Idan "Trea Dae Con. Sal of Metin, Crests Sih Kul, Band Ach Ida “Deparment of Moding, Set of Mea, Unestas ych Kus, Baa Aceh, nea = Ds of Paty CAR Ion Vertary Rear Ist tog 248122 Barly, Ua Pras Ina “Grama Sta! fete, Hate Uierty Ri 150 Nh 7 Come, Ke, Spyre- Hotkaid, 0 858 Jopar * Hamas Ue Schoo Mein Inert Mi rt Dn, Depron of Carl, Haar, Sis, pan * Dgronet of Edema Health Sus, cha of Pale Heth Soest Utes Na 21009, Chine ‘Rey Later of Evora Meine Premerine My of Baton Schon of bt Hs Sons Unversity, Nong, China Digarmen of MerbeogTsan Uno Teach Het, Inn of Modine Ratan No * Coresponding autor. Public Heath and Infection Research Group, Faculty of Health Sciences, Universidad Tecnoégica de Pereira, Pereira, Risaralda Colombia Email adres: crodriguerm@utp.etu.co (Ad. Rodriguer Morales) URL itps/worlancovdorg Oe Sa, "Both authors contbuted equals. Order was decided by seniority htp://do.og/10.1016/}.mae.2020.101623 Received 29 February 2020; Received in revised form 11 March 2020; Accepted 11 March 2020 1477-8939/ © 2020 Elsevier id All rights reserved ‘lease cite this arcle as Alfonso J. Redriguea Morales eval, Travel Medicine and Infections Disease, eps//dok.org/10.1016/)tmaid 2020.1016823As are Moraes, ea ARTICLE INFO ower ‘hia tue Taterstany pene ‘Trae Metin nd eins sae ee Ge) ene ABSTRACT Inyoduction: An epidemic of Coronavirus Disease 2019 (COVID-19) began ln December 2019 in China leading to Public Health Emergency of Intemational Concern (PHEIC). Clinical, laboratory, and imaging features have eon partaly characterized in some observational studies. No systematie reviews on COVID-19 have been published eo date ‘Methods: We performed a systematic Iterature review with meta-analysis, using thee databases to asses lineal, laboratory, imaging features, and outcomes of COVID-19 confirmed cases. Observational studies and ‘locate reports, were inclided, and analyzed separately. We performed a random-ffects model metanayste to caleulate poled prevalences snd 95% confidence interval OSC. Results: 660 artieles were retrieved forthe timeframe (1/1/2020-2/28/2020). After screening, 27 ares were ‘elected fr full ext astestnent, 19 being finally included for qualitative and quantitative analyses, Additonal, 59 case report articles Were included and analyzed separately. For 656 pallets, fever (887%, USK {545-52.9%), cough (57.6%, 95 40.8-75.4%) and dyspnea 45.6%, 95NCT 10.9-80.4%) were the most ‘prevalent manifestations. Among the patients, 20.3% (954C] 10.0-80.6) required intensive cae unit (ICU) 52.5% presented with acute respiatory discs syndrome (ARDS) (95%Cl 13.7-51.8), 62% (95NCl 3.1-8:3) ‘with shock Some 1.5% (2541 62-2156) of hexane patients ad fatal outcomes (nse aaityrte, CR). {Conclision: COVID-19 brings «huge burden to heahare flies, epedaly in patents with comorbidities. OU was require for approximately 20% of polymorbi, COVID-19 infected patients and hospitalization was sssoclted with a CFR of > 12%, As tls virus spreads glolly, counties need to urgently prepare human resources, inastucture ad facies to teat severe COVIDAIS 1. Introd Jat, Rationale ‘The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2), formerly known as the 2019 novel Coronavirus (2019-nC0V), is a nevily emerging zoonotic agent chat appeared in December 2019 and ‘causes the Coronavirus Disease 2019 (COVID-19) [1]. This pathogen result in a syndrome leading in some cases toa critial ere respiratory ‘condition, that requires specialized management at intensive care units (CU) in many of them [2-7]. The SARS-CoY-2, taxonomically, is eur rently part of the species ofthe SARS-related coronaviruses that belong to the subgenus Sarbecovirus. Together with the subgenuses Embecov irus, Hidecovrus, Merbecovius, and Nobecovius, that aze part of the ‘genus Betacoronavrus (order Nidovrales, suborder Coridovirinea; fa ily Coronavirida; subfamily Coronavirinae) (8-14) Other Betacoronaviruses before have cased epidemics over the last ‘nwo decades in Asa, ass the case of SARS-CoV in 2002-2003 in China 110,15,16}, and later with the Middle East Respiratory Syndrome (MERS-CoV) in 2012-2013 in Saudi Arabia [17-20]. As expected, several similarities and differences in the epidemiology, clinical fe tures, and management of SARS, MERS, and COVID have been ident fied [3-5,20-23}. These are enveloped positivestrand RNA viruses Isolated from bats that share sequence homology with isolates from humans, suggesting bats as natural hosts and reservoirs (9,25-27). [Although the elineal picture of SARS, MERS, and COVID-19 ssoms to be similar, differences were noted [,5,21,28] since early reports. A fll linical characterization of this disease, as well as its laboratory and Image characteristics, is require. Although only «wo months have elapsed since the emergence of ‘COVID-L0, some studies and case reports have been already published ln major international selentfe and medical journals, from China and ‘other countries with travel- and non-travel-rlated cases (7,13,29,30} Many of these reports have started to answer elinieal questions, in: eluding evolution and outcomes, as well as potential sk factors, and clinical, laboratory and image findings; however, a systematic review to ‘consolidate what has heen learned from each study or reported case i to-date missing. Although systematic reviews and meta-analyses usually include randomized clinical trials (RCTs) and aim to provide a more precise estimate ofthe effet ofa treatment or risk fetor for disease, also have been extensively used, especially during the last decades, (0 synthesized observational studies (31-32). In many situatons, RCTS are not feasible or available, and only data from observational studies are accessible [38]. This isthe case forthe clinical, laboratory, and image features of COVID-9. 2. Objectives ‘To summarize the clinical, laboratory, and image features of COVID- 10 reported in currently available observational studies. ‘To examine the outcome of COVID-19 cases, including risk factors, the proportion of patients requiring ICU and those with fatal out 1 To assess the prevalence of comorbidities among COVID-I9 con- firmed cases. 3. Methods 3.1, Prowocol and registration ‘This protocol follows the recommendations established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [34], and i has been reported inthe International Prospective Register of Systematic Reviews (PROSPERO) database (ID 170643), 32. Blgbily ereria ‘We included published peer-reviewed articles that reported cases with demographical, clinical, laboratory, and image features of real time reverse transcriptase polymerase chain reaction (#RT-PCR) cor- firmed SARS-CoV-2 Infection. For assessing clineal, laboratory and imaging characteristics eligible study designs were case-control, cohort studies, case reports, and case series, For assessing risk factors and toutcames only observational scudies were included. Article language limi was not set, and we included publications from January 1, 2020 until Pebruary 23, 2020, Review articles, opinion articles and letters not presenting original data were excluded, as well as studies reporting cases with incomplete information.As are Moraes, ea 3.3, Information sources an search strateey ‘We conducted a systematic review using Medline/PubMed, Scopus, and Web of Science. The following search terms used: “Novel cor fonavirus,” “Novel coronavirus 2019", "2019 nCoV", “COVID-19", ‘Wuhan eoronavinis,” “Wuhan pneumonia,” and “SARS-CoV-2,” The searches were concluded by February 23, 2020, and four different re searchers independently evaluated search result 34, Sty selection ‘The results ofthe initial search strategy were first sereened by ttle ‘and abstract. The fll texts of relevant articles were examined for in clusion and exclusion erteria (Fig. 1). When an article reported dv plicate information from the same patent, the information of both re Ports was combined in order to obtain complete data, but only counted a a single ease. Observational studies that reported the proportion of ‘symptoms, laboratory characteristics and risk factors were included for ‘quantitative synthesis (meta-analysis). Case reports were not included for the meta-analysis, a6 they do not have a denominator for any ‘Trae Metin nd eins sae ee Ge) ene variables, but descriptive statistics were applied to them, o summarize their findings 5, Data collection process and data items Data extraction forms including information on the type of pub: lication, the publishing institution, country, year and date of publica tion, the number of reported cases, of eases at ICU, age, sex, co morbidities, clinical features (eg, fever, cough), laboratory findings (eg, white blood cell counts [WBC], biochemistry), imaging (ex, chest X-ray), complications (eg, acute respiratory distress syndrome, ARDS), outcome (eg, death) were filed independently by four in vestgators. A fifth researcher checked the article list and data extrac Udons to ensure there were no duplicate articles or duplicate informacion of the same patient and also resolved discrepancies about study nel 3.6, Assessment of methodological quality and risk of Bas For quality assessment, we used the Quality Appraisal of Case Series Records identified through ‘Additional records || Additional records identified 4 PubMed database Identified though Scopus || through Web of Sciences searching database searching database searching : (o= 450) (n= 185) (o=25) 2 Records nde cto heen iach ofinfermtion on (n=67) ‘molecular diagnosis (n=3) Fen aries ended Fun aes ss dhe tolcet niomaton : aan ‘eee ce Sees Couper dentin ——_ |_| «oo ‘ncaa teen ster nln auarate tess meta-analysis) on Fig 1. study selection and characters.As are Moraes, ea ‘Studies Checklist ofthe IHE and specifically the critical appraisal tol to assess the quality of cross-sectional studies (AXIS) [35,26]. Publication bias was asessed using a funnel-plot. A randoneffects model was used to calelate the pooled prevalence and 9594Cl, given variable degrees oF data heterogeneity, and given the inherent heterogeneity in any sys tematie review of studies from the published lteraure. Egger test for publication bias was also performed. 7, Statistical proach Unie discordance for variables was eesolved by converting ll units to a standard. measurement for that variable. Percentages and means = standard deviation (SDs) were calculated to describe the Aisebutions of categorical and continuous variables, respectively. ‘Since indvidal patient information was not available forall patients, ‘we report weighted means and SDs. The baseline data were analyzed sing the Stata version 14.0, licensed for Universidad Tecnologica de Pei, ‘The meta-analyses were performed wsing Stata, and the software OOpendetafAnalyst} [97] and Comprehensive Meta Analysis ve2.3* licensed for Universidad Teenoldgiea de Pereira, Colombia. Pooled prevalences and their 95% confidence intervals (95% Cl) wer used summarize the weighted effect size for each study grouping variable using the binary random-effeets model (the weighting took into on sideration the sample sizes ofthe individual tue), xcept for median ‘age, where a continuous randomeffect model was applied (DeSimo: nadir procedure) (8,3) Measures of heterogeneity, inchuding Cochran Q statistic, the F index, andthe tatsqared test, were ertimated and reported. We per formed subgroup analyses by age groups (adults or children). And meta-analyses foreach ofthe variables of interest 4, Results 4.1. Study selection and characteristics A tox of 660 articles were retrieved using the search strategy, in cluding 39 cose reports. After screening by abstract and title, 64 articles ‘were selected for fulltext assessment. Of these, six were excluded due to lack of information on molecular diagnosis, and $8 were included for ‘qualitative analysis, 19 of them for quantitative meta-analysis and 39 ‘ease reports for descriptive analysis (ig. 1). The main charaeteristes of ‘Trae Metin nd eins sae ee Ge) ene the included studies are shown in Table 1. Our review included 19 studies that were published between January 1, 2020, and February 21, 2020, most of them from China (18) and one from Australia (Table 1), ineluding a total of 2874 patients, ranging from a case series of 9 [0] toa cross-sectional study of 1590 [411 Although as of Maceh 9, 2020, there have been more than 111,000 eases reported, these have not been included and published in studies avalable in the literature. Most studies were eross-sectional (15), and four were case series (Tables 1-5). We analyzed 42 variables for the meta-analyses (Table 6). Publication bias was assessed with a funnel plot for the standard ervor by logit event, with no evidence of bias (Pig. $1). Additionally, the Egger test (P = 0.801) suggested that there was no notable evidence of publication bias. 4.2, Demographical characteristics and comorbidities ‘The mean age of patients across 18 studies was SI.97 years old (959CI 46.06-57.89), being male 55.9% (95%CI 51.6-60.196). Patents presented in 36.89 of cases with comorbidities (QS8iCI 24,748.05), the most significant being hypertension (18.6%, 9536CI 8.1-29.0%), cardiovascular disease (14.4%, 95%CI 5.7-23.1%6), and diabetes (11.9%, 9596C 9.1-14.68), among others (Table 6) Pig. $2), 4.3. Clinical manifestations and laboratory findings Regarding the clinical manifestations, fever (88.7%, 95%C1 £84,5-92.9%), cough (57.696, 95%CI 40.8-74.4%) and dyspnea (45.6%, 95%6C1 10.9-80.410) were the most prevalent clinical manifestations (Table 6) Fever frequency was significantly higher in adults compared {o children (02.8%, 959%CT 89.4-96.2%; Versus 43.9%, 95%CI 28.2-59.68) (Pig, $2) Regarding laboratory findings, decrease albumin (75.8%, 95%C1 30.5-100.0%), high Greactive protein (58.3%, 95%%CI 21.8-94.79), and high lactate dehydrogenase (LDH) (57.0%, 95%CI 38.0-76.0), lymphopenia (43.196, 9594CT 18,9-67.3), and high erythrocyte sedi mentation rate (ESR) (41.8%, 95%C] 0.0-92.8), were the most pre valent laboratory results (Table 6) (Fig. 2), 44, Imaging, complications, and outcomes Atthe chest X-rays, the pneumonia compromise was predominantly bilateral (72.95, 959C158.6-87.1), with image findings ground-glass ‘Table 1 Charaterisics ofthe incu studies on COVID-19, 2020 ll patients confirmed by teatime RT-PCR, Ate owl Dae (ABUDD)—Ganey Seay pe eee ‘wotcrnirNcr ‘onision Rept oo a se ection oa hein tet ou ai (Gos seta eI tera Newt ous Cain (Goss sein on hn a Lest ove hin, (owen 4 ‘hug a Radiolny ous cain (oss seta reo (hen et a. Chins Tube Repie Ds x06 cain, (Goss sein (ear Wang ea saa cam ei (Goss sectional wr Kaietal ‘ain ets oom ain (oss (cs hang ea sata ou ain, (os setiona for Tootal {in ne De oa hi (rors tions rc} COV I9 tex Austin Team Ropot outa Retin Chasctonal cy Yuering ea Barf outa chine (Gomera va eta, Preprint Lancet outs hin ‘se sre va Feng ea Radiology oats hi ie seres ca, ang a Lanes Only outa Chine oe cna ay ‘hans et. hin J Tuberc Respir Dis 02/15 Cie Gemies fo Feng ea hin 3 Pte oat? Cai Geese: vs Wang (hin Pete on Gri Grove sctina va nea ase Rep Med wat Ce Comctina o |WICHIHPNCI, Wohan Municipal Commission of Health and Health on Pneumonia of New Coronavins Infection. MM/DD, Month, Day * quality score ranged, 0-20. asedon the Appaisl Tool for Cres-Setonal Sadie, AXIS [25]‘Trae Metin nd eins sae ee Ge) ene As are Moraes, ea ponodos ou ‘jgaese ow * “josie pj aubuunbas yun axe> assoqu ‘991 Aba \HUONY “GC/HIN “UonDaIu suIANUOIND MOK JO EOWA UO YESH PUE BDH JO WOSSHED TRAPIENA UEURM ONAHHADINM, oz wor wos es woe Pr er eZ.) rem agoes, ovat aoe woe, emote vest puto wot 6 ot ce Gene mn wen 8 at ano war Gar 1 2 a ano ve su (oe ise (ezys @ = emo ream cs cron or 2 Gwe emE 8 Sis 6 eto oo wat Gs ers Gens LW LIME oe oo a 108) pum simu nay) deEEIONE) wojauAdGH segEIA snIPRIDHIED : mene WON AaleN ORES av 2ocany 'SDOGRS Kp a fo SHIPTON PE THBURIFIDN AQ] SSRANNIND WTNTOWSG caraen,As are Moraes, ea ‘Trae Metin nd eins sae ee Ge) ene ‘Table 3 Clinical characteristics ofthe study sujet ‘Astor Dae NNO) Reece ow DD) Reve Cou Sore MalinorSptum ‘Headache Haanopss Diathoos Dyspaow| Theat fatigue —_proguction wacHNONG 01/20 136 0000) 136 4000) 1360000) (64 Quolnetal 0124 00H 1056) 00 1843) NaH 303) 249 12H) BES) (1 seal 0129 an (hen a 3 m@) HoH SEN nar san 22D 2619 EL ‘ge a 21 14667) 9429) 686) sa43) re hen et a 2D oss 21020 Bann ean 269) 4038) 17686 (66) Wang iia 608m) MER) 24 THC) OSH — 9S) wun Bey a fasta n2G18) 6482 en 64 BE) 76H ao) 09 LH hang ea 628) 61462) saan 28433, 107 for Toetat ro} Ov team 5 ey ney oy using el e va let, 2% a2 Ges 650) sas7 269 7) eg ta 21 8a57) BET sas) NE2Z aR) ca, Ung eta 1590 tay any eta, S88 S656 teak) AHH) tor ang eat 1% 50n3) 1067 vs Wang era 4 7@D 13082 Po Kioto eta, 2 51081) w769, 60759) 3a15) mes) 6 \WMICHEHPNCI, Wuhan Municipal Commission of Helth and Health on Pneumonia of New Coronaviris Infection. MDD, Mont, Day. Not avilable, not report ‘opacity in 68.5% (9594CI 51.8-85.2) (Table 6) (Fig, $2) in those with X- ray results Among the patients, 20.39% (9595CI 10.0-30.695) who required ICU, 328% presenting with ARDS (954CI 13.7-51.8), 13.096 with acute cardiac injury (9594CI 4.1-21.9%), 7.9% with acute kidney injury (854CI 1.8-14.09), 6.2% (959/CI 3.1-9.3%) with shock and 13.9% (O5HCI 6.2-21.5%6) had fatal outcomes (Table 6), RNAemia (detection ‘of viral RNA in blood) was teported 96.8% of the al patients (95%6CT (94.9-98.796) (Table 6) (Pig, $2), and also in nasopharyngeal aspirates, (xa), 45, Case reports ‘We found 39 case report articles (Table S1, summarizing 126 eases, ‘of COVIDA9, The mean age was 47.9 y-old (SD 22.2), being male {69.0196 of those with sex identified in the article (Table 7). From the total, 10.3% presented hypertension as comorbidty, followed by other conditions. The more common clinical features were fever (77.0%), ‘cough (55.696), and myalgia (31.086), among others (Table 7). Re garding the laboratory findings, lymphopenia was the more frequent (23.88), followed by high C-reactive protein (22.2%) and high aspar- tate transaminase (AST) (7-98). At the chest Xray, 46% presented _groune:-gass opacity, with bilateral compromise in 39.7% of the po tient, All the ease reports had RNAnemia, For the complications, 7.1% presented with ARDS, and 1.6% with secondary infections, among ‘others, Most ofthe cases described in these case reports were hospita lized (74.686, with a fatality rate of 15.9% (Table 7). 5. Discussion Over the last two months, more than 156,000 cases of a new in- fectious disease have been confirmed in China and other countries in Asia, Pacific, Europe, Aiea, and the Americas [22,23,42-44]. The COVIDA9 is an emerging condition that primarily dhreatens the pre paredness and biosecurity conditions of all countries on this planet #5]. Preparedness at different levels, facing a new clinical disease, ‘demands efforts in epidemiological, diagnostic, therapeutic, and pre ventive fields during a potential pandemie [46], that threatens to spread to new territories (> 115) and areas with the risk of epidemics. Clinical, laboratory, image findings, as well as the factors associated with evolution of the disease and outcomes, constitute ertieal knowl: edge that should be carefully studied when a new infectious disease emerges. Recently, in this context of the COVID-19 outbreak, several ‘questions have been raised, ineluding what i the fll spectrum of dis ease severity (which can range from asymptomatic, 19 symptomatic butt, to severe, to requiring hospitalization, to fatal)? [47]. In thls systematic review and randomeffeets meta-analysis, we tied (0 in ‘tally summarize clinial data on COVID-19 confirmed cases that were published duting the first weeks ofthe outbreak. We managed to ana- lyze more than 780 patients for major clinical manifestations and up to half of them for their associated significant laboratory findings. Our findings are robust due to the pooled results after combining all the studies, which can be seen in forest plts for each ofthe variables. We wed a randomeffeets meta-analysis model. This involves an assump: tion that the effects being estimated in the different studies are not {dontca, but follow some distribution. For random-effecs analyses, the pooled estimate and 9596CIs refer to the center of the distribution of pooled prevalence but do not describe the width of the distribution. Often the pooled estimate and its 958CI are quoted in isolation as an alternative estimate of the quantity evaluated in a fxed-effect mete snalysis, which is inappropriate. The 9594CI from a random effects meta-analysis describes uncertainty in the location of the mean of systematically different prevalence inthe different studies [38,39] {As expected from initial observations in China (4,5,11}, COVID-19 patients presente predominantly with fever and cough, which appears o be more frequent in adults than children, as well as dyspnea, and miyalaia, among other clinical festures. This was consistently found not only in the studies metaanalyzed here but also in the case reports in- cluded in thie systematic review. Fever frequency is similar in SARS and 'MERS, but the cough frequency is higher in SARS and COVID-19 than MERS (< 5096) (28,48,49] In SARS and MERS, diarthea is reported in 20-25% of patients [50], here we found it in less than 78, atthe studies (Table 6) and ease reports (Table 7). OF note, in the case report, riyalgia was the third most common reported symptom after fever and cough. Most patients requited hospitalization, often attributed to the patient's comorbidities, a observed in a third of the cases. We found‘Trae Metin nd eins sae ee Ge) ene As are Moraes, ea uuny ‘LIV sseumsuen ayemndey sy ssustospcysp seer HET “6 "YOR ACVINN “WORD ssHAMONeD MON JO eMOUMDU WO KIFH PUB YREH Jo VoRSUW TEER UNE ‘ponodar 30 sygepo48 YON = sues SAHIN ral 2 tw wor wns wreeat Gol OL wens Lan eos ewe sve ott —@sos (ewe woos We eve won woos 8 fe ao wweoyaz was woe, (ne cree ee e900 or) 79 (HED Ree) RL EHDA (OBI eH (FONE (eso se (HE Gers — wees ere yy qe una woo. outer ouume fang 3 mCompiea AE Vuh poresmea emey ‘WH ABM ASVWBML wgo_sueT MwDdoyR>T spoon oa a0 nea NN ie socnny SERS KOR a SISOBHINH GOWOGET‘Trae Metin nd eins sae ee Ge) ene As are Moraes, ea sey supe ane ‘LSy “Po SH oC aM ano Ns no f0a HUOK “AQUI ONDE, eaINUOIND MX Jo BAIDU! Ho HOHE PO ome woe woe one ae wor west creer was ew (os se eos ose woe rane ae eens eww eum pois Ainpsag “enn ‘apd eames ss SOV HaBeNIC oe newpaAs are Moraes, ea ‘Trae Metin nd eins sae ee Ge) ene ‘Table 6 Meta-analysis outcomes (randomfets mode.” Varae Name ofSuaie Neon yo) /Praiece(s) 95ND ae 18 5197 wenesre 2a sade ease ISG? —— 0001 1a é ma ome 1a 4949 mao ao < O00 ‘erties 7 368 27489 «SSCA gm. BOON Hypertension 5 156 Brmo 33 anges ma Gol = OmML Caron diese ‘ 1a Sram as 4520 aoe mn =O Dates 8 9 S1ike Seb 4088 000000 ara Conic abstraction pulmonary dass 6 is Deo S413 (00000002 Malignancies, 6 25 0742 75) MAG 000 ‘cat manfeanos| oust 5 6 fame ye Grr may ote “= 0001 Dyson 3 ase Tassos 636 Ladess sede at“ oaot Maa o ie ” Ba Gama Me esta 0017 Dt Stun production 6 as Tota SM) Stok 8473 80H =. Sie thet 5 i109 2eio? haa S39 Ooo = BOOT Headache 5 a0 $7102 S84 SKB 0000000782, ory ns Deer Amin 2 78 snsi0n0 128242958 a0) = 001 High Greet posi 6 ssa 21897 3 7234 98M 020 = MOL igs DH 5 so joreo an Son’ ase aoe $29 of the deaths occurring in China (2,085), fol- lowed by lay with 24.72% (1,441). This fers from the CFR founcl in our systematic review and may be explained by the fact that eases re quiring medical attention in hospitals were the patients included in the studies selected for analysis, and that consequently they consulted with an advanced stage of disease leading to hospitalization. Even, from the truce epidemiological data reported by the countries, some of them have reported a higher proportion of deaths, as isthe case of Australia (8.75%), China (3.8686), Iran (4.886), Ialy (6.81%, 1,441 deaths/ 21,157 eases), Argentina (8.39%), and Iraq (10.09%). Thus, the CFR in diferent settings needs further reassessment. More studies are needed to elucidate the risk fators fr severe illness and death. This will allow for the identification of groups most likely to have poor outcomes so thar we can focus on prevention and treatment efforts? [47] [After the development of this systematic review (SR), and even, availabilty on a preprint server, online Feb. 25, 2020 (htips//ww. preprint.org/manusript/202002.0378/¥3); a bref systematic review and meta-analysis, only addressing few variables, such as fever, cough, muscle soreness or fatigue, ARDS, abnormal chest CT, patients in crt tical condition and death of patients with COVID-19, was published (Feb, 28, 2020) [58]. This review was based on ten studies, using a random effect model, as we did. On March 12, 2020 (wo days before the proofs correction of this article), another systematic review was electronically published ahead at Intemational Journal of Infectious Diseases. (hitps//dol.org/10.1016 /;.id.2020.08.017), assessing the prevalence of comorbidities inthe COVID-19 infection patients and the risk of underlying diseases in severe patients compared to non-severe patients. They found similar results: fever (91%, 9594CI 86-97%), fl lowed by cough (67%, 95%CI 59-76%), fatigue (51%, 95%CI 34-68%), and dyspnea (30%, 95%CI 21-40%). The most prevalent comorbidity were hypertension (17%, 95%CI 14-229), and diabetes (8%, 95%C1 6-1100 ), followed by cardiovascular diseases (5¥9, 95%CI 4-70), and respiratory system disease (29%, OSWCI 1-396). They did not assessed other clinical manifestations, nor any laboratory or imaging findings, nor complications. Comparing thelr Findings [58] with our, they found fever in 89.8% (O5NiCI_81.8-945%) of patients, this SR found 88.7% (O5%Cl 845-02.0%), but we assessed diferences, as mentioned above, be tween adults and children, and they did not. For cough, based on the 95%6C, there were not significant differences too, between that SR and the current, 72.23% (958CI 65.7-78.28) versus 57.6% (O5%CI 40.8-74.40). For fatigue, there is @ variation in frequency between both studies, 42.5% (O59CI 21.3-65.286) versus 29.4% (95%CI 19.8-39.0%), Sun et al did not assess other clinieal manifestations [56], we were able to do it for eight of the studies included in this systematie review. Both reviews are clear and consistent in that more than 80%% of the patients presented with fever, more than half with cough, and more than a third with fatigue. That SR di not assess any laboratory findings, but evaluated the frequency of patients presenting ADRS which was found to be 14.8% (95WCl 46-20.61), which was also consistent with our study, 32.89% (950CI 13.7-51.8%6), whichAs are Moraes, ea although higher, was not significantly so, For patients admitted to ICU, there were also small diferences. Sun et al. found 18.1% (05%CL 127-2438), however, we identified that 20.39% required intensive ‘rtical care (9596CI 10.0-20.64). The major difference between both studies wos in the last variable assesed ie. the case fatality rote. Sun et al. report 4.3% (9546CI 2,7-6.196) and we report a rate of 13.9% (O5HiCt 6.2-21.5%), which is significantly higher. Finally, Sun et al. ‘only included studies, but not ease reports, as we di, which provided additonal consistent findings of the clinical, laboratory, imaging and ‘evolution characteristics of patents with confirmed COVID-18. Our results showed that there is stil need for more comprehensive clinical studies, including short and long -term follow-up cohort as sessments. More studies from outside China, where there are more than, 100 patients diagnosed with COVID-19, a fs the ease of South Korea, Italy, and Japan [59,60], will contribute othe growing volume of data, in addition to the growing number of studies appearing from China Even more, the situation with the erulse ship Diamond Princes, docked in Yokohama, Japan, with 3711 passengers, approximately 20% of the infcted, with 7 deaths, is also a valuable chance to better characterize ‘COVID-L9, Clinical evidence synthesized in this review is mainly de rived from China, although for case reports, ten of the thirty-two ‘countries with confirmed cases {7,12,29,30], have published some of them (Table 7). Further clinical data is erucil co elucidate the elinical spectrum of the disease. The clinical experience stemming from coun tries now dealing with an ever increasing number of eases such as Italy {161}, Singapore, Hong Kong, Nepal [7] Iran, and Malaysia inthe form ‘of case reports, ease series, or large observational studies will be most Important. Up to now, regardless whether of report type (eross sec tional studies or case reports) the clinical findings are consistent, but more data are needed to define the risk factors for admission in ICU and for fatal outcomes. However, data suggest that older age and co- ‘morbidities pay a vital role in influencing severe disease and negative clinical outeomes. These data would be useful to guide patient risk ‘groups management in the current epidemic, especially in those cour tries about to receive cases, as isthe situation in Latin America. COVID- 130 cases have been confirmed in Brazil, Mexico and in all the countries ‘of South America, and in most of the Central Ameriea and the Car ‘bean subregions, as of the time of proof correction (March 14, 2020) 62]. In these and other resource-constrsined settings, e.g. Africa, supplies chains, ineluding those for drugs, masks and personal protec tion equipment, will be challenged, ‘The results of this systematic review highlight the clinical, labora: tory, and imaging findings that may assist clinicians anywhere in the {lobe in suspecting the possibility of COVID-19 infection in those with recent travel to areas with ongoing transmission or among contacts of ‘confirmed cases. Early recognition of cases will allow clinicians to en sure adequate clinical monitoring, institution of supportive interven Hons, and preventing further transmission by implementing infection ‘control measures [29,56,63], There isa need for prospective studies to ‘evaluate the epidemiology, pathogenesis, duration of viral shedding, ‘and the clnial spectrum of disease asociated with this emerging viral Infection (29,5663), To effectively protect populations and healthcare workers in the face of arrival and spreading of this emerging vieal pathogen, constant ‘evaluation of available evidence is essential to guide clinical urpicion, «agnosis, management, and mitigation of transmission of COVID-18. 5.1, Limitations ‘This review has several limitations. Few studies are available for Inclusion. Most are from China. Now urgently, data from Italy are re ‘quired. Ie would be better to include as many studies with a broad [geographic scope, to get @ more comprehensive understanding of COVIDI9, More detailed patient information, particularly regarding clinical outcomes, was unavailable in most studies atthe time of ana Iyses; however, the data in this review permit a frst synthesis of the ‘Trae Metin nd eins sae ee Ge) ene clinical and laboratory characteristics of COVID-19. Our systematic review and meta analysis found a CFR of over 130. As we discussed earlier, the differences between the crude fatality rate (< 3.5%) and that Found among hospitalized patents inthe selected studies included here may be explained by the fact that cases reqring medical attention in hospitals consulted with a more advanced stage of disease. 6. Conclusions Infection with COVID-19 is associated with significant morbidity especially in patients with chronical medial conditions. At least one- filth of cases require supportive care in medical intensive care units, which is especially limited in most developing countries. Despite the Implementation of optimal supportive interventions, cose fatality sate among hospitalized patients is more than 10%, Similar to other viral respiratory pathogens, COVID-19 presents in the majority of cases with a rapidly progressive course of fever, cough and dyspnea. Important distinguishing factors are leukopenia and the rapid progression to ARDS. Fliiting a history of recent travel to areas with ongoing out breaks ofthis emerging pathogen or contact with a confirmed case of COVID-19, should prompt clinicians to initiate isolation precautions and obtain laboratory confirmation. Additional research is needed to ‘elucidate viral and host factors in the pathogenesis of severe and fatal infections Author contributions AIRM and JACO formulated the research question, designed the study, developed the preliminary search strategy, and drafted the manuscript. EGO, RV, YHR refined the search steategy by conducting iterative database queries and incorporating nev search terms. £60, BY, YHR, and AJRM searched and collected the articles. JACO, AJRM, and DKBA conducted the quality assessment. All authors critically re Viewed the manuscript for relevant intellectual content. All authors have read and approved the final version of the manuscript. Funding source Universidad Tecnoligica de Pereira. Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19) (wi. laneoviehorg). Study sponsors had no role inthe study design, in the collection, analysis and interpretation of data; in the writing of the ‘manuseript; and in the decision to submit the manuseript for publics Won, Ethical approval Approval was not require. CCRediT authorship contribution statement Alfonso J. Rodriguez-Morales: Conceptlization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original drat, Writing - review & editing. Jaime |A. Cardona-Ospina: Conceptulization, Data cutation, Formal ans- lysis, Funding acquisition, Investigation, Methodology, Project admin- |station, Resources, Software, Supervision, Validation, Visualization, Writing ~ original draft, Writing - review & editing. Estefanta Gutiérrez-Ocampo: Data curation, Writing - review & editing. Rhuvi Villamizar-Pefa: Data curation, Writing - review & editing. Yeimer Holguin-Rivera: Daca curation, Writing review & editing. Juan Pablo Escalera-Antezana: Writing - review & editing. Lucia Flena Alvarado- Amex: Writing - review & editing, D. Katterine Bonilla-Aldana: Supervision, Validation, Visualization, Writing - original dra, Writing review & editing. Carlos Franco-Paredes: Writing - review & eating.As are Moraes, ea Anglrés F, Henao-Martinez: Writing - review & editing. Alberto Paniz~ ‘Mondolfi: Writing - review & editing. Guillermo J. Lagos-Grisales: ‘Writing - review & editing. Fduardo Ramirez-Vallejo: Writing -review & editing. Jose A. Sudrez: Writing ~ review & editing. Lysien I Zambrano: Writing - review & editing. Wilmer E. Writing - review & editing. Graciela J. Balbin-Ramon: Writing - re- ‘view & editing. Ali A. Rabaan: Writing - review & editing. Harapan Harapan: Writing - review & editing. Kuldeep Dhama: Writing - re Jew & editing. Hiroshi Nishiura: Writing - review & editing. Hiromitsu Kataoka: Writing - review & editing. Tauseef Ahmad: Writing - review & editing. Ranjit Sah: Writing - review & editing Declaration of competing interest All authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential ‘Acknowledgments Contents ofthis article have been presented in conferences at the [ESE Hospital Santa Montea, Dosquebrads, Risaralda, Colombia, March 6, 2020; Universidad Tecnologica de Pereira, Risaalda, Colombia, ‘Symposium on Neglected Tropical Diseases, February 1, 2020, and Fundacidn Universitaria Auténoma de las Américas, Peceira,Risaralda, Colombia, February 20, 2020 and subsequently by Facebook Live Appendix A. Supplementary data ‘Supplementary data to this article ean be found online at hitps:// doi.org/10.1016/)maid.2020.101623. References (0) Boni Alda DK, Da Rodger Moras A. Revising he oe eth “oprah nth cet of COMID- 1 nthe eyo i rg dow, Adv Ain Vet Sl 20208:247 ‘ha Zn, Wang WX Yang B80 eC A novel eons fom isi pra a Chine ged SB p/n 1 16/ ‘poeuinonia associated with the 2019 novel coronavirus iicating person-0-peson crus a ty ofa aly her Lanse 200 hier 10.010 Sotaowrancays01s4, Gen ts 3 a ete tn tsi sy, Une 200 kp ay 0070217 Ine wi 21 onl oer in aha, Ch ane 0509607 506, ‘he L Emerg understandings of 01200 Lacet 200,953. bp nylotoierstiaberaceniao foro A Soh R Rede Moraes Tal BK, J Of HG t The fe 2019 nove coronovirs eas in ep Lact net Ds 20020279 Sena De. Vio mer We asa AA Rodger Mores A. Una ‘eva suena bal MID 19, etme per cr Save 318 ‘in Ot, oars Mores AJ Camacho Moro Nendo amir H, ode Sabon iA, Avr Moreno G Ant emg oot is 0 cn Cer the 2019 noel Cronies (COV 19). ae 20002 ona Te. Era D CoC, SR. ee ery, A nove Cero asottd her act espe some. N EJ Mea Sposeaee 958-68 120. Guan Wa, Woe, Zhou, To Yl aly amin dani i ‘ea iso aol oni nected poco N gh Bed 200 Ip /aoer/To oso. Pan 27, Napen TV, Ln OC, Syen TV, Nguyen HT, Le Ht: tpn {orn hunantassion noel cronavs nto Engl Ned 3820 pe doco 10 1036/NE MeO 22 Pecapial WA Pog K Ratcaton AC, ssa Woo of & Ta ‘Sever anne eros N Engl Me 8am 82100-8 po, ry/losarnmiconie tne A Severe ee ropiay syne sen ooni— the Gis and hn ates the Cavs Sy rp. oR 3a. Sada sod se cane Pree, van Ge Wer 9, Boe HR, ec a a @ fo 1 @ a 81 fo no an na os) a, us ‘Trae Metin nd eins sae ee Ge) ene andi na) Med 2009:2481967-76, ker, Fouder Shen Rimes GF van Anson Gv Rl SEW, an css, Pata yer VARS nd MERS: ren ina lat emergence Nat Rv Mobi 9169452994 ‘Aiawg JA, Cate P aymptomate Mile Et Respstey Sao crear DS 0) srt es pes incr ins Memih 1A. MRSC oon een epinty ee» vw of prevention mess ow Me ne 95015 Fontana DE, umes Raa Monte oP, Rani , ai Moni ats se a SARS, MERC ad sow the 20% Ca tive we trig cngh abet ccnviees-m onc spe Tw Ho int bola, {AVTawtig J, ami Mesh 2. Travel npn omen cons ‘or ath gration Novel conan 1.900 ston ep 10- So ir 208 hp, win ck ours eres Station reo 20190 strep nope aer =hA 2.2020 itor ent Orston.Psemona imo cae Ch. re ‘wo nes don tenor 210 poeumonit unkown as " beronnenta ‘ig YoY. Stu i DL, nl onan ato ‘ta it pats ah SARS-COV pcos ban ange ‘terest, serio ane ep es 020 hips 3 {Oholerati secon 2Boo dina 2 eX Qi. Rl btwn ct Cag and Cina odin far das (OOD 1) pork male Sty At An Rangel 20 UEDA, fa Dr We han, Cmcron oy Co a A major teat of ‘cer ate eau saione ery Kg WEg ied 205348 086 4 ‘Tang ki, Hosa Yooh Wang chan Young Metal Achar ces fsa apn on nae Tesiges Mores A Mago K, Kenge Pt D, Scgeina (Sng hl woe sd th 19 onl coins Tr ed nt a sano 2 Yang AL Wang XG, Ma 8, ang Wt a. Apia abe Sait it ew Con petal be og are Bint ies avd Ronn K A, Cal che of opi porns th 2010860 itn Ma Wl 2D, ong fron ira ebay, Yong Yay Mya, Kina Tere Of unereainnet cnr conv (9 080 ton siaton sing ipa preg eon rca fhe Cin Mod 3209 ihn Sutnpars is narsnera deg thon neonin sen tm pny era oe 5 abe es tor Govan, Benvona B Agel 5, ks M The et two ie of 2019 61 wi coy 1 wn ‘53 a 155) oo wo 8) (oo (2 a, (wa) cy (66 wo (os) oy oy om a va va, os 8, ‘Trae Metin nd eins sae ee Ge) ene Ca¥ nal: whee dhe come fon? J Med ik 2020 it://d/10.1002/ joven tiie Mocks 1, Calle V, aks Antena, Mees CA, ant U, Scared cas rw Med ie De ROIOWGIS cay Anger P Loe Chaves Shiga, Rodig Mores ‘AT nea tre to bel eat” 2019 wwe conan 0-00) Sta ice ca we etree cnt ry 2, ‘om be ati asa ce or Tove Meine LAB Tay Ms et Ds RASTSERsnRSHUREsONKA RunDaRERARTRTER Sm aseR BA, p/w. whan goven/Foeweb shone” Ghng emi A Mes, Phang Huang M, Zeng aC imaging fetes OF 219 pve coins (na Rainy. BT 200290. Ghent ete Le Wein; lk Shag eo Aa of na ates of 3 tt th 209 nel nn poi, nn ee ‘ang, Ho eG 2, hag a Ca characteris of 198 sme pets th 2019 nove! eevee pee wha, nm J Am ed Asoc 2000, hp aoe T0001 anas000 Se Kal Fann, DY, Lu W, Wn MF, MJ, Cnc characersi of oe coronviseass inter span bes Province Cun Me Cg) Sp. wipe" arg/10057/exsoooaenncor ae {Gin Lin MWe i 2G, Dal CS, a Epes an tine “arnrsisof pol coos ncn ling 1 patents te an, Ginn Am Md aoe 202. hip. oko 10.1001 ama 2020102%. ‘TOAK Tong OF, Can Vip. Chan KL Wa TC, Chan JO, eal Consent int anit 280 ay ovtD-19 atonal lcdeat Room Sellars Team. COVID-9, Asal eo Seiler 2 250. an, Cua Zhou. Wag Y, 1, 2 ital CT igs a epoca Changs ptt te nvel eave pcan (219600: = sof Green Ra 8 n/t LA YSU, Zhang D, Tang She Chen Xn Te piety and ‘el chartrir2019 nove cornaie nein ng Cia {Sion cra SN Pern ava SSRN sens Fan er, Son, Gul Ling 8 i, Tine cour of ing changes chest Fag rcovery to 209 ool cen (COVD-1) porno Rion. 20000570 Fen kin ¥ Wane XF, Yang GD, Zeng 2, un CMe Lay of CT fates of 5 Che wh 2009 vel oes itn. gran Re 2 ase. ian XF, Yoo hen YS, Chen J Bo YM, Ven Rt (ne nd ct Semilla characteris 124 cen with 2019 nove cornet Speumes, thon Eke 2a 050008.