ORIGINAL ARTICLE https://doi.org/10.1590/1516-3180.2020.00365.R1.08092020 Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection: an observational retrospective study Israel Júnior Borges do NascimentoI, Luiz Ricardo PintoII, Valéria Alves FernandesIII, Israel Molina RomeroIV, João Antonio de Queiroz OliveiraV, Milena Soriano MarcolinoVI, Maria Fátima LeiteVII University Hospital and School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte (MG), Brazil ABSTRACT PharmD. Clinical Pathologist and Medical Research I BACKGROUND: Since February 2020, data on the clinical features of patients infected by severe acute Specialist, University Hospital and School of Medicine, Universidade Federal de Minas Gerais, respiratory syndrome coronavirus 2 (SARS-CoV-2) and their clinical evolution have been gathered and Belo Horizonte (MG), Brazil; Medical Research intensively discussed, especially in countries with dramatic dissemination of this disease. Specialist, School of Medicine, Medical College of OBJECTIVE: To assess the clinical features of Brazilian patients with SARS-CoV-2 and analyze its local epi- Wisconsin, Milwaukee, Wisconsin, United States. demiological features. orcid.org/0000-0001-5240-0493 DESIGN AND SETTING: Observational retrospective study conducted using data from an official electron- II PhD. Full Professor, Department of Production ic platform for recording confirmed SARS-CoV-2 cases. Engineering, School of Engineering, METHODS: We extracted data from patients based in the state of Pernambuco who were registered on Universidade Federal de Minas Gerais, Belo the platform of the Center for Strategic Health Surveillance Information, between February 26 and May Horizonte (MG), Brazil. 25, 2020. Clinical signs/symptoms, case evolution over time, distribution of confirmed, recovered and fatal orcid.org/0000-0001-5082-9595 cases and relationship between age group and gender were assessed. RESULTS: We included 28,854 patients who were positive for SARS-CoV-2 (56.13% females), of median MSc, PhD. Researcher, University Hospital and III School of Medicine, Universidade Federal de age 44.18 years. SARS-CoV-2 infection was most frequent among adults aged 30-39 years. Among cases Minas Gerais, Belo Horizonte (MG), Brazil. that progressed to death, the most frequent age range was 70-79 years. Overall, the mortality rate in the orcid.org/0000-0003-1731-4738 cohort was 8.06%; recovery rate, 30.7%; and hospital admission rate (up to the end of follow-up), 17.3%. The average length of time between symptom onset and death was 10.3 days. The most commonly re- IV MD, PhD. Medical Researcher, Department ported symptoms were coughing (42.39%), fever (38.03%) and dyspnea/respiratory distress with oxygen of Infectious Diseases, Vall d’Hebron Hospital, saturation < 95% (30.98%). Barcelona, Spain; Medical Researcher, Instituto Renê Rachou, Fiocruz Minas, Belo Horizonte (MG), Brazil. CONCLUSION: Coughing, fever and dyspnea/respiratory distress with oxygen saturation < 95% were the orcid.org/0000-0001-6642-7515 commonest symptoms. The case-fatality rate was 8.06% and the hospitalization rate, 17.3%. V PharmB, MSc. Doctoral Student, University Hospital and School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brazil. orcid.org/0000-0003-3116-4713 INTRODUCTION The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 VI MD, PhD. Full Professor, University Hospital and School of Medicine, Universidade Federal de (SARS-CoV-2) has been associated with a greater number of deaths occurring more rapidly Minas Gerais, Belo Horizonte (MG), Brazil. than had been observed among previously leading causes of mortality, such as unintentional orcid.org/0000-0003-4278-3771 injuries, stroke and heart diseases. As of July 6, 2020, more than 11,495,412 confirmed cases VII PharmD, PhD. Full Professor, Department of have been reported, along with more than 535,185 officially notified deaths.1 In developing Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, countries, specific data regarding incidence, local clinical manifestations, radiological and labo- Belo Horizonte (MG), Brazil. ratory abnormalities and requirements for establishment of differential diagnoses considering orcid.org/0000-0001-9709-8865 local peculiarities still remain obscure and are often insufficient. In Brazil, as of June 15, 2020, KEY WORDS (MeSH terms): 1,603,055 cases and 64,867 deaths had been legally counted.1 Severe acute respiratory syndrome coronavirus So far, according to studies conducted in developed countries, the typical signs and symp- 2 [supplementary concept]. toms of the novel 2019 coronavirus are fever, coughing (with or without sputum), sore throat, COVID-19 [supplementary concept]. Coronavirus infections. and shortness of breath (with or without associated respiratory distress comprising oxygen sat- Mandatory reporting. uration < 95.0%).2,3 However, new symptomatic profiles are being described in the literature, Public reporting of healthcare data. almost on a daily basis. Manifestations such as acute olfactory disorders, acute hyposmia and AUTHORS’ KEY WORDS: anosmia, dysgeusia and dermatological complaints might also be present with the onset of coro- Infectious diseases. navirus disease (COVID-19).4-7 nCoV-2019. Novel coronavirus. Although several studies have already described symptom profiles for patients in European 2019-nCoV infections. and Asian-Pacific countries, at present there is no study providing detailed information 2019 novel coronavirus infection. within the Brazilian populational setting. Indeed, few papers on COVID-19 symptom profiles 490 Sao Paulo Med J. 2020; 138(6):490-7 Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection: an observational retrospective study | ORIGINAL ARTICLE have been published in developing and poor or middle-income between February 26 and May 25, 2020, and who were regis- countries. Additionally, the studies relating to the settings of tered on the government’s online platform for suspected cases developing countries have been either case series, typically with were eligible for inclusion in this study. At the platform inter- fewer than 100 patients, or case reports, which do not neces- face, patients are enrolled as “suspected cases – under investi- sarily describe the real epidemiological status of either low or gation” and as soon the laboratory result has been shared with middle-income countries.8-10 None of these studies assessed the the requesting healthcare center, the designated medical pro- most common clinical presentations of the novel coronavirus in vider can update the patients’ status to “negative for SARS-CoV-2 Brazilian patients. Nor did they attempt to investigate differences infection” or “positive for SARS-CoV-2 infection”, based on the in clinical presentation or underlying diseases among patients report from the real-time quantitative polymerase chain reaction infected with this novel virus. (RT-qPCR). There is also the possibility of providing results relat- ing to alternative causes of infection that might be investigated OBJECTIVE (such as influenza A or B). In this study, we aimed to assess the clinical features of Brazilian In our study, only patients with confirmed SARS-CoV-2 patients infected with SARS-CoV-2 and to analyze patient mor- were included in the descriptive analysis. Therefore, patients were tality and the need for hospital admission. excluded if their laboratory result was negative for SARS-CoV-2. All the infected patients included in the present study had METHODS tested positive for SARS-CoV-2 through use of RT-qPCR on samples from nasopharyngeal or oropharyngeal specimens. Study design The eligibility criterion for a positive diagnosis of SARS-CoV-2 This was an observational retrospective study, based on indi- infection was that at least one gene region was recognized and vidual data from Brazilian patients that were collected from amplified as positive for viral proteins (nucleocapsid and open the Center for Strategic Health Surveillance Information of the reading frame). Health Secretariat of the Brazilian Ministry of Health. This gov- Informed consent was not required because we used second- ernment branch targets early detection through establish- ary data from an official database. The RT-qPCR assay was per- ing continuous monitoring, in order to deliver adequate solu- formed either in the Central Public Health Laboratory (LACEN) tions for public healthcare emergencies such as COVID-19. or in private diagnostic laboratories. Ethical approval was obtained from a local ethics committee (ref- erence number 30350820.5.0000.0008), which was granted on Variables and outcomes April 13, 2020. The study authors did not have any contact with The main primary variable of the study was clinical manifestation the patients described here, and did not deliver any pharmaco- of SARS-CoV-2 infection among the patients, along with catego- logical or non-pharmacological intervention to them. rization of these patients according to the outcome at the end of the follow-up period (i.e. on May 25, 2020). Thus, the patients Settings who had been enrolled were classified into five outcome All the confirmed patients included in this study were admitted groups. Patients with a definitive clinical status were stratified to primary care centers, private clinics or hospital facilities in the as “Recovered” (patients who after medical assessment were state of Pernambuco, in northeastern Brazil. According to offi- considered not to present active infection) or “Died” (patients cial governmental reports, as of June 10, 2020, Pernambuco had who progressed to death) and were compared with each other. the seventh largest number of confirmed cases in Brazil (41,010 Similarly, individuals with a transient clinical status (i.e. awaiting accumulated cases).11 Overall, with a total area of 98,311 square case improvement or worsening) were categorized as “Domestic kilometers, Pernambuco has around 8.8 million inhabitants, and quarantine” (patients who had been directed to place themselves in 2017 was considered to have a medium human development in isolation at home), “Admitted to hospital care” (patients who, index (0.67).12,13 However, because of regional discrepancies on May 25, 2020, were in a hospital, either in an isolation ward within this state regarding access to education, life expectancy or in an ordinary hospital bed) or “Admitted to intensive care and per capita income, it should be noted that several municipal- unit (ICU)” (patients who, on May 25, 2020, were hospitalized ities in the state have low human development indexes (< 0.50). in an ICU). Exploratory variables such as the case distribution according Participants to age group and gender, temporal distribution of included cases, All patients, regardless age, who presented to any healthcare time elapsed between notification and death and time elapsed facility (public or private) with suspected SARS-CoV-2 infection between symptom onset and death were also analyzed. Sao Paulo Med J. 2020; 138(6):490-7 491 ORIGINAL ARTICLE | Borges do Nascimento IJ, Pinto LR, Fernandes VA, Romero IM, Oliveira JAQ, Marcolino MS, Leite MF Data sources and measurements RESULTS In Brazil, a country with both single and multi-payer sys- tems (public and private healthcare systems, respectively), Participants’ characteristics notification of all confirmed SARS-CoV-2 cases (clinically Overall, the cases of 54,235 patients were retrieved from the gov- classified as influenza-like syndrome or severe acute respi- ernmental database up to May 25, 2020. Of these, 28,854 patients ratory syndrome) has become mandatory since March 2020. had a confirmed laboratory diagnosis of SARS-CoV-2, 22,034 These cases are registered in online servers and the records were negative for virus detection and 3,347 were waiting for lab- are subsequently processed. The notification and data regis- oratory results. tration are performed by healthcare personnel and once the In the study sample (infected patients; n = 28,854), the laboratory result has been disclosed to the medical facility, median age was 44.18 years and 56.13% were female, with the designated medical provider can update the diagnosis sta- a male to female ratio of 0.78. The largest proportion of the tus in the system. infected patients was aged between 30 and 39 years (n = 6,949; Influenza-like illness is defined as febrile sensation or fever, 24.08%). Information on underlying diseases was not reported associated with coughing or sore throat or running nose or short- for all patients, and it was not possible to know which patients ness of breath. Severe acute respiratory syndrome is defined as did not have underlying diseases, or in which cases some vari- influenza-like symptoms with dyspnea/respiratory distress or per- ables were missing. Among the patients with any descrip- sistent thoracic pressure or oxygen saturation < 95% in ambient tions of preexisting comorbidities, hypertension (n = 863), air or peripheral cyanosis. diabetes (n = 533), obesity (n = 110), chronic renal failure For non-hospitalized patients, such as patients attended in the (n = 90), history of stroke (n = 85) and asthma (n = 63) were primary care sector or at private clinics, the “e-SUS VE” is the final the most prevalent ones. Among all the patients included, 22 online host system for all suspected cases. On the other hand, cases (0.07%) were classified as having an additional ongoing viral of severe acute respiratory syndrome and deaths need to be noti- coinfection (either influenza A or influenza B) at the time of fied through the Information System for Influenza Epidemiological the notification. Surveillance (Sistema de Informação de Vigilância Epidemiológica da Gripe, SIVEP-Gripe). In the state of Pernambuco, which is Descriptive data potentially the most transparent state in Brazil with regard to After distribution of the patients into definitive outcomes, data sharing and epidemiological surveillance, reports from both 8,863 patients (30.7%) were considered to have recovered of systems are periodically integrated and compiled into a single the infection, while 2,328 (8.06%) died due to complications online platform.13 from the infection. Male patients were more likely to prog- All data associated with clinical symptoms and signs, previ- ress to death (55.0%) (Table 1). For both genders, the major- ous health history and epidemiological features were extracted ity of fatalities occurred in the group of patients older than from the electronic panel of cases of novel coronavirus infection 60 years. Among females, the majority of deaths were among in the state of Pernambuco, Brazil. Two experienced medical individuals older than 80 years, while among male individu- research specialists reviewed and abstracted the data. After ini- als, patients aged between 60 and 69 years progressed to death tial processing, the data were entered into a computerized data- more frequently. Female patients recovered more frequently base (Microsoft SQL Server, version 2019, United States) and than did males (62.63%). were cross-checked. Regarding transient outcomes, 4,771 individuals (16.5%) were admitted to an isolation ward, 1,442 (5.0%) were directed to place Study size and statistics themselves in domestic quarantine and 227 (0.78%) were hospital- No formal sample size calculation was carried out, because ized in an intensive care unit. For 10,996 patients with confirmed of the observational and convenience-sampling nature of the SARS-CoV-2 infection (38%), the final outcome was not available study. The statistical evaluation included descriptive analy- or not declared. sis on the study population and comparisons between groups In the overall cohort of confirmed patients, the median length using the chi-square test. We defined differences as statisti- of time from symptom onset to regulatory notification was 7.0 cally significant if the P-value was < 0.05. Categorical variables days (interquartile range, IQR 4.0-10.0). Among patients who were expressed as the number and its respective percentage. progressed to death, the median length of time between symp- The Statistical Package for the Social Sciences (SPSS), version tom onset and notification was 5.0 days (IQR 3.0-8.0), while the 20.0 (IBM, New York, United States) was used to obtain math- median length of time between symptom onset and death was 8.0 ematical evaluations. days (IQR 5.0-14.0). 492 Sao Paulo Med J. 2020; 138(6):490-7 Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection: an observational retrospective study | ORIGINAL ARTICLE Analysis on the clinical characteristics of confirmed cases of recovered and between patients who were admitted to an isolation SARS-CoV-2 ward and those who were admitted to an ICU, for each symptom A summary of the clinical manifestations of the 28,854 con- and comorbidity, is shown in Table 2. firmed cases of SARS-CoV-2 infection is shown in Table 2. Overall, signs or symptoms of some type were registered in rela- DISCUSSION tion to 17,631 patients (61.10%). Thus, notifications were made Over the last few weeks, Brazil has become the epicenter of the in the cases of 38.9% (n = 11,223) of the confirmed patients and novel coronavirus pandemic.14-16 With the global impact of these cases were registered in the database. However, none of the the novel coronavirus, it is important to highlight that differ- clinical information was precisely inserted. ent populations can manifest different clinical symptoms and The main clinical manifestations observed among the can progress differently over the natural course of the infection. patients comprised coughing (with or without sputum) (42.39%), Overall, the most commonly reported clinical features consisted fever (38.03%), dyspnea or respiratory distress with oxygen sat- of coughing (with or without sputum) (42.39%), fever (38.03%) uration lower than 95% (30.98%), sore throat or odynophagia and dyspnea or respiratory distress with oxygen saturation lower (16.79%), myalgia (4.90%) and headache (3.63%). Less com- than 95% (30.44%). mon symptoms such as anosmia (2.77%), adynamia or asthe- Our results showed slightly lower prevalences for most observed nia (1.88%), dysgeusia or loss of taste (1.6%) and hyporexia clinical features and comorbidities, compared with previous stud- (0.047%) were also reported. ies.3 Severe illness (defined as patients requiring hospitalization) Comparison between the patients who recovered and those who occurred in 17.3% of the patients. Indeed, fever and dyspnea were died showed that dyspnea or respiratory distress with oxygen satu- remarkably more frequently reported among fatalities. In addition, ration < 95% (29.0% versus 88.0%) and fever (59.0% versus 64.0%) dyspnea and oxygen saturation < 95% were shown to be contrib- were significantly more frequent among the patients who died. uting factors for admission to an ICU. Sore throat was more frequent among the patients who recovered With regard to underlying diseases, the comorbidities most (39.0% versus 9.0%). Comparison between patients hospitalized in often registered were hypertension, diabetes, obesity and chronic an isolation ward and patients in an ICU showed that fever (67.0 renal failure. Additionally, taking into account underlying patholog- versus 60.0%) was significantly more frequently observed among ical conditions, we observed that there was an association between the patients in an isolation ward. Among the patients admitted to the presence of comorbidities and worse progression of the disease. an ICU, there was higher frequency of manifestation of dyspnea Regarding coexistence of underlying conditions, we perceived that than among those in an isolation ward (74.0 versus 87.0%). the frequency of comorbidities was slightly lower among the cases Hypertension, diabetes and obesity were more frequently reported here than in previously published data.2 However, this reported among patients admitted to an ICU and among the patients may have been mainly caused by the singularities of the hospi- who died. A complete description of underlying diseases observed tal environment and the features of the emergency department. among the patients included, along with comparisons between In emergency departments, it is very frequently impossible to patients who progressed to death (case-fatalities) and patients who obtain a detailed medical history. Table 1. Age distribution among the patients described in the data retrieved Confirmed cases Recovered cases Case-fatalities (deaths) (n = 28,854) (n = 8,863) (n = 2,328) Age groups n (%) n (%) n (%) Female Male Female Male Female Male 0 to 9 years 444 (1.53) 373 (1.29) 156 (1.76) 140 (1.56) 6 (0.25) 5 (0.21) 10 to 19 years 178 (0.61) 143 (0.49) 42 (0.47) 36 (0.40) 4 (0.17) 4 (0.17) 20 to 29 years 2,018 (6.99) 1,262 (4.36) 764 (8.62) 408 (4.60) 14 (0.60) 15 (0.64) 30 to 39 years 4,171 (14.45) 2,778 (9.62) 1,768 (19.95) 926 (10.43) 24 (1.03) 54 (2.32) 40 to 49 years 3,717 (12.88) 2,861 (9.91) 1,509 (17.02) 882 (9.94) 60 (2.57) 127 (5.46) 50 to 59 years 2,552 (8.84) 2,098 (7.26) 886 (9.99) 546 (6.15) 150 (6.44) 179 (7.69) 60 to 69 years 1,325 (4.59) 1,376 (4.75) 237 (2.68) 208 (2.34) 246 (10.57) 315 (13.54) 70 to 79 years 947 (3.28) 1,059 (3.66) 102 (1.16) 98 (1.10) 258 (11.09) 312 (13.40) > 80 years 846 (2.93) 706 (2.43) 87 (0.98) 68 (0.75) 286 (12.29) 269 (11.56) Total 16,198 (56.13) 12,656 (43.87) 5,551 (62.63) 3,312 (37.37) 1,048 (45.01) 1,280 (54.99) During the analyzed period, there were 22 confirmed co-infection of influenza A or influenza B. In addition, there were 54,235 cases registered in the database (including suspected, confirmed and negative cases). Sao Paulo Med J. 2020; 138(6):490-7 493 ORIGINAL ARTICLE | Borges do Nascimento IJ, Pinto LR, Fernandes VA, Romero IM, Oliveira JAQ, Marcolino MS, Leite MF Even though disease profiling for COVID-19 has been rep- of abruptly increasing the number of patients seeking medical licated and implemented in several countries, this was the first consultations.17 In association with Brazil’s large territorial pro- study to describe its main clinical characteristics and outcome portions, it is also a country with social and economic inequali- distribution in Brazil using a substantial number of patients. ties, which consequently influences the health status of its inhab- Brazil is a country with continental geographical proportions itants.18 Thus, as the novel coronavirus has disseminated across and has a wide spectrum of tropical infectious diseases (most of the country, the impact of the disease on low-income popula- them neglected), such as Chagas disease, leishmaniasis and den- tions has been increasing substantially, thus resulting in serious gue. However, to date, no previous diseases has had the impact negative effects among these citizens. Table 2. Clinical data from confirmed cases of SARS-CoV-2 infection in the state of Pernambuco, Brazil (data up to May 25, 2020) Comparison Comparison Admitted between Domestic Case- Admitted between Recovered to isolation patients Clinical presentation of confirmed patients quarantine fatalities to ICU recovered and (n = 8,863) ward admitted to (n = 17,631) (n = 1,442) (n = 2,328) (n = 227) case-fatality n (%) (n = 4,771) isolation ward n (%) n (%) n (%) patients n (%) and ICU (P-value) (P-value) Coughing (n = 12,232) 874 (0.60) 6,124 (0.69) 1,574 (0.67) 3,512 (0.73) 148 (0.65) 0.169 0.005 Fever (n = 10,976) 853 (0.59) 5,256 (0.59) 1,493 (0.64) 3,236 (0.67) 138 (0.60) < 0.001 0.027 Dyspnea or respiratory distress with SpO2 507 (0.35) 2,619 (0.29) 2,057 (0.88) 3,559 (0.74) 199 (0.87) < 0.001 < 0.001 < 95% (n = 8,941) Sore throat or odynophagia (n = 4,847) 460 (0.31) 3,470 (0.39) 216 (0.09) 664 (0.13) 37 (0.16) < 0.001 0.313 Myalgia (n = 1,416) 460 (0.31) 333 (0.03) 99 (0.04) 513 (0.10) 11 (0.04) 0.270 0.005 Vomiting or nausea or diarrhea (n = 1,293) 186 (0.12) 316 (0.03) 191 (0.08) 582 (0.12) 18 (0.07) < 0.001 0.053 Headache (n = 1,049) 277 (0.19) 352 (0.03) 51 (0.02) 361 (0.07) 8 (0.03) < 0.001 0.023 Anosmia (n = 801) 223 (0.15) 284 (0.03) 31 (0.01) 257 (0.05) 6 (0.02) < 0.001 0.070 Adynamia or asthenia (n = 545) 55 (0.03) 120 (0.01) 77 (0.02) 287 (0.06) 6 (0.02) < 0.001 0.035 Dysgeusia or loss of taste (n = 490) 170 (0.11) 218 (0.02) 20 (< 0.01) 77 (0.01) 5 (0.02) < 0.001 0.495 Hyporexia (n = 138) 10 (< 0.01) 10 (< 0.01) 31 (0.01) 85 (0.01) 2 (< 0.01) < 0.001 0.311 Abdominal pain (n = 88) 7 (< 0.01) 13 (< 0.01) 19 (< 0.01) 48 (0.01) 1 (< 0.01) < 0.001 0.398 Sneezing (n = 46) 9 (< 0.01) 27 (< 0.01) 1 (< 0.01) 9 (< 0.01) - 0.025 0.512 Eye pain (n = 20) 5 (< 0.01) 16 (< 0.01) 2 (< 0.01) 3 (< 0.01) - 0.724 0.705 Chest pain (n = 12) 3 (< 0.01) 4 (< 0.01) 1 (< 0.01) 4 (< 0.01) - 0.965 0.663 Running nose (n = 9) 4 (< 0.01) 154 (0.01) 19 (< 0.01) 2 (< 0.01) - < 0.001 0.758 Asymptomatic (n = 9) 1 (< 0.01) 5 (< 0.01) 1 (< 0.01) 2 (< 0.01) - 0.803 0.758 Not declared or not available (n = 1,339) 279 (0.19) 704 (0.07) 107 (0.04) 239 (0.05) 10 (0.04) < 0.001 0.683 Comorbidities Hypertension (n = 863) 17 (0.01) 63 (< 0.01) 643 (0.27) 126 (0.02) 14 (0.06) < 0.001 0.002 Diabetes (n = 533) 1 (< 0.01) 182 (0.02) 309 (0.13) 35 (< 0.01) 6 (0.02) < 0.001 0.002 Obesity (BMI > 25 kg/m2) (n = 110) 1 (< 0.01) 6 (< 0.01) 86 (0.03) 14 (< 0.01) 3 (0.01) < 0.001 0.009 Chronic renal failure (any stage) (n = 90) - 2 (< 0.01) 76 (0.03) 11 (< 0.01) 1 (< 0.01) < 0.001 0.528 History of stroke (n = 85) - 2 (< 0.01) 72 (0.03) 10 (< 0.01) 1 (< 0.01) < 0.001 0.468 Asthma (n = 63) - 12 (< 0.01) 35 (0.01) 14 (< 0.01) 2 (< 0.01) < 0.001 0.126 Chronic obstructive pulmonary disease (n = 48) - 5 (< 0.01) 36 (0.01) 4 (< 0.01) 3 (0.01) < 0.001 < 0.001 Any neoplasia (n = 33) - 3 (< 0.01) 26 (0.01) 4 (< 0.01) - < 0.001 0.663 History of myocardial infarction (n = 32) - 1 (< 0.01) 27 (0.01) 3 (< 0.01) 1 (< 0.01) < 0.001 0.049 Chronic liver disease or hepatitis (n = 11) - 1 (< 0.01) 5 (< 0.01) 5 (< 0.01) - < 0.001 0.626 HIV infection (under control or not) (n = 9) - 3 (< 0.01) 4 (< 0.01) 2 (< 0.01) - 0.018 0.758 Transplanted (n = 3) - - 2 (< 0.01) 1 (< 0.01) - 0.006 0.827 Alcoholism (n = 1) - - 1 (< 0.01) - - 0.051 - Without comorbidities or not declared or 866 (0.60) 3,640 (0.41) 767 (0.32) 2,882 (0.60) 153 (0.67) < 0.001 0.035 not available (n = 8,308) ICU = intensive care unit; BMI = body mass index; HIV = human immunodeficiency virus. It is important to state that the comparison shown above relates to: 1) Comparison between patients who progressed to death (case-fatalities) and patients who recovered; and 2) Comparison between patients who were admitted to an isolation ward and those admitted to an ICU. Therefore, for each symptom and comorbidity category, we performed statistical analysis to check whether there was any group-to-group significant difference. 494 Sao Paulo Med J. 2020; 138(6):490-7 Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection: an observational retrospective study | ORIGINAL ARTICLE The extensive spectrum of reported symptoms during admis- Thus, especially in settings where social and economic discrepan- sion (with several body systems involved), together with the wide cies prevail, this disease is of extreme importance, considering its range of severity (from asymptomatic cases to severely ill patients), social, economic or public health-related impacts. may potentially cause an initial misdiagnosis, especially for patients Although the total number of individuals infected with SARS- whose first RT-qPCR is negative.4 We found that the frequency of CoV-2 may have been underestimated, this disease is an important reports on anosmia/hyposmia and other minor symptoms as der- public healthcare issue in Brazil and in developing countries across matological manifestations was low. However, considering that the the globe. Taking into account the entire year of 2018 (when the total reporting of these symptoms only started in mid-April, medical care number of deaths in the state of Pernambuco was 62,011), the cur- for these manifestations in our cohort within a Brazilian setting may rent number of fatalities resulting from SARS-CoV-2-related infec- have been delayed or been given less attention. Nevertheless, sev- tions corresponds to the same mortality rate for all other infectious eral studies have already reported that these particular symp- diseases aggregated (including flu, tuberculosis, all forms of hepa- toms are highly sensitive for diagnosing the disease.4 In addition, titis and HIV).20 In relation to the body of literature, the mortality developing countries like those in Latin America and Africa have rate observed in our study was slightly higher than rates seen in their own endemic diseases that are currently presenting increas- other settings such as China and Italy.20-23 ing incidence. This increases the challenge involved in reaching a Our data suggested that the mortality rate among male Brazilian conclusive final diagnostic hypothesis.19 subjects was higher than the rate among females. This had also Fever was more prevalent among the patients who died than been observed in previous studies.3 Even though it was perceived among those who required hospital admission. However, we hypoth- that female patients accounted for 56.0% of the total number of esized that this may have been due to lack of completion of the confirmed cases of infection, there was a higher mortality rate reporting questionnaire. Patients who needed hospital care may among male patients (55.0%). have less frequently filled out the entire questionnaire. There are different hypotheses to explain this fact. Initially, it was In our study, the majority of the symptoms were associated suggested that women might be less susceptible to viral infections with alternative infections, such as influenza, rhinovirus, dengue than men due to higher production of circulating antibodies along fever or gastroenteritis. Therefore, we highlight the fact that in with prolonged levels of these biomarkers.22,23 Additionally, another areas in which concomitant outbreaks may have been occurring factor that might explain the lower susceptibility of female patients in parallel, use of differential diagnosis should always be borne in to the novel coronavirus infection is their production of estrogen mind. Through this, presence of potential secondary pathogens can and immune factors linked to X chromosomes.24 In women, the be ruled out and clinical management of greater accuracy can be double X chromosome affects the immune system with regard to implemented for patients for whom a differential diagnosis could expression of several elements, such as the expression of toll-like not yet be established. receptor 7 (TLR7).25 Since TLRs are expressed at higher levels in In our study, 8% (n = 2,328) of the patients with SARS- women and their expression leads to higher immune responses, it CoV-2 infection progressed to death (in less than three months). has been suggested that these two associated factors might therefore The mortality rate in the state of Pernambuco was also slightly increase resistance to viral infections. Another cell-related expla- higher than the Brazilian national average, possibly because of nation for the higher immunoprotection among female patients the economic peculiarities of the region and because of lack than among male patients relates to CD4+ T cells.26 Expression of of hospital infrastructure for severe cases.20 In addition, the these cells is higher in women and, thus, a state of higher immune explanations for this higher mortality rate may relate to delayed response may be achieved in females than in males, which also diagnosis of the disease, fundamentally caused by limitations on would provide a more protected status.25,26 Lastly, but not least, the availability of laboratory tests and trained medical person- cultural features can also account for the imbalanced mortality nel. The explanations may even relate to patients’ fear of seeking rate between male and female patients. medical care in the early stage of the disease. This would conse- In Brazil, promotion of healthcare policies for women has quently favor greater severity of clinical condition at the time brought this population closer to healthcare facilities, both for of late hospital admission. elective medical procedures and for emergencies.27,28 In addition, Furthermore, in the state of Pernambuco, a significant num- especially in traditional areas like northeastern Brazil, the stereo- ber of municipalities face either geographical or structural diffi- type of the masculine image, depicted as the family progenitor culties with regard to accessing appropriate medical treatment. who never gets sick, can also be related to this sociocultural fea- One compelling example of these challenges is that, by the end of ture.20,30 Thus, even with the observed disparity of confirmed cases the period analyzed (May 25, 2020), 98% of the beds available for between males and females, male patients are at higher risk of a COVID-19 patients (in isolation wards or ICUs) were occupied. fatal outcome than are female patients. Sao Paulo Med J. 2020; 138(6):490-7 495 ORIGINAL ARTICLE | Borges do Nascimento IJ, Pinto LR, Fernandes VA, Romero IM, Oliveira JAQ, Marcolino MS, Leite MF The main strength of the current study was that laboratory data REFERENCES on more than 28,000 confirmed cases were examined. Patients who 1. Johns Hopkins, Coronavirus Resource Center. COVID-19 Dashboard only had a clinical diagnosis and thus might have been infected of the Center for Systems Science and Engineering (CSSE) at Johns with other diseases instead were excluded. Moreover, we included Hopkins University (JHU). Available from: https://coronavirus.jhu.edu/ patients from different municipalities in the state of Pernambuco, map.html. Accessed in 2020 (Jul 3). which provided us with a more heterogeneous dataset, as well as 2. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease more representative and less biased sample selection. 2019 in China. N Engl J Med. 2020;382(18):1708-20. PMID: 32109013; Essentially, the main limitation of the study related to patient doi: 10.1056/NEJMoa2002032. admission, which could be either to isolation wards or to intensive 3. Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel Coronavirus care units. Furthermore, at the time of admission via an emergency Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis. J department, the notification sheet might not have been completely Clin Med. 2020;9(4):941. PMID: 32235486; doi: 10.3390/jcm9040941. filled out. This would be due to high demand (several patients 4. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and Ageusia: Common arriving hourly), insufficiency of medical personnel and presence Findings in COVID-19 Patients. Laryngoscope. 2020;130(7):1787. PMID: of severe cases that required more attention. Additionally, data 32237238; doi: 10.1002/lary.28692. entry done from multiple locations by many different profession- 5. Gilani S, Roditi R, Naraghi M. COVID-19 and anosmia in Tehran, Iran. als would lead to inherent contrasts regarding the use of medical Med Hypotheses. 2020;141:109757. PMID: 32344276; doi: 10.1016/j. terms and descriptions, which would also result in heterogeneity mehy.2020.109757. of form-filling. Thus, it was sometimes impossible to obtain com- 6. Joob B, Wiwanitkit V. COVID-19 can present with a rash and be mistaken plete and accurate medical histories, including information about for dengue. J Am Acad Dermatol. 2020;82(5):e177. PMID: 32213305; underlying diseases and a more detailed description of symptoms. doi: 10.1016/j.jaad.2020.03.036. Nonetheless, we believe that for healthcare decision-makers and 7. Sociedade Brasileira de Dermatologia. Manifestações na pele devido à medical researchers, a description of the Brazilian framework of COVID-19 causadas pelo vírus SARS-CoV-2: fatos e fotos até 17 de abril the current pandemic is of utmost importance, in order to under- de 2020. Available from: https://www.sbd.org.br/mm/cms/2020/04/21/ stand more specifically the scenario in this country. artigo-manifestacoes-pele-dr-paulo-criado-revisado-final.pdf. Accessed in 2020 (Jul 3). CONCLUSION 8. Muniz BC, Milito MA, Marchiori E. COVID-19 − Computed tomography findings The novel coronavirus has been dramatically affecting developing in two patients in Petrópolis, Rio de Janeiro, Brazil. Rev Soc Bras Med Trop. countries like Brazil. In this country, the disease has been shown 2020;53:e20200147. PMID: 32321099; doi: 10.1590/0037-8682-0147-2020. to have a broad range of symptoms and severity, including com- 9. Chate RC, Fonseca EKUN, Passos RBD, et al. Presentation of pulmonary mon symptoms such as coughing, fever, dyspnea and sore throat. infection on CT in COVID-19: initial experience in Brazil. J Bras Pneumol. Given the overall all-cause mortality rate of 8.06%, it is impor- 2020;46(2):e20200121. PMID: 32294718; doi: 10.36416/1806-3756/e20200121. tant that preventive non-pharmacological interventions should 10. Bastos LS, Niquini RP, Lana RM, et al. COVID-19 e hospitalizações por be endorsed by healthcare authorities until such time that a safe SRAG no Brasil: uma comparação até a 12a semana epidemiológica de and universally available vaccine has been produced. In view 2020 [COVID-19 and hospitalizations for SARI in Brazil: a comparison of the statistical difference between patients who progressed to up to the 12th epidemiological week of 2020]. Cad Saude Publica. death and those who recovered, regarding the presence of dys- 2020;34(4):e00070120. PMID: 32321075; doi: 10.1590/0102-311X00070120. pnea or respiratory distress with oxygen saturation < 95% and 11. Ministério da Saúde. Brasil. Painel Coronavirus. Available from: https:// fever, medical providers should consider the presence of these covid.saude.gov.br. Accessed in 2020 (Jul 3). conditions to be important prognostic factors. 12. Governo do Estado do Pernambuco. Geografia de Pernambuco. Available We emphasize the importance of mandatory reporting systems from: http://www.pe.gov.br/conheca/geografia/. Accessed in 2020 (Jul 3). in terms of enabling better understanding of the distribution and 13. Ministério da Economia. Brasil. Radar IDHM: evolução do ISHM e de seus evolution of infectious diseases in Brazil. We therefore recommend índices componentes no período de 2012 a 2017. Brasília: IPEA, PNUD, that better and more complete investigation of medical histories FJP; 2019. Available from: http://atlasbrasil.org.br/2013/data/rawData/ and better reporting should be implemented in medical units Radar%20IDHM%20PNADC_2019_Book.pdf. Accessed in 2020 (Jul 3). across the country. At the present time, researchers around the 14. Secretaria do Planejamento e Gestão, Secretaria de Saúde, Agência world should focus their efforts on undertaking high-quality stud- Estadual de Tecnologia da Informação. Painel de casos de doença ies to assess the effectiveness of the most-used pharmacological pelo coronavirus 2019 (COVID-19) em Pernambuco, no Brasil e no and non-pharmacological interventions, in addition to the mul- Mundo. Available from: https://dados.seplag.pe.gov.br/apps/corona. tiple ongoing immunization therapy trials. html. Accessed in 2020 (Jul 3). 496 Sao Paulo Med J. 2020; 138(6):490-7 Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection: an observational retrospective study | ORIGINAL ARTICLE 15. Menezes PL, Garner DM, Valenti VE. Brazil is projected to be the 30. Gomes R, Nascimento EF, Araújo FC. Por que os homens buscam menos next global COVID-19 pandemic epicenter. medRxiv preprint. doi: os serviços de saúde do que as mulheres? As explicações de homens 10.1101/2020.04.28.20083675. com baixa escolaridade e homens com ensino superior [Why do men 16. Darlington S, Crespo G, John T. Latin America is now the “epicenter of use health services less than women? Explanations by men with low the outbreak,” says health official. CNN. Available from: https://edition. versus higher education]. Cad Saude Publica 2007;23(3):565-74. PMID: cnn.com/2020/05/26/americas/latin-america-coronavirus-toll-intl/ 17334571; doi: 10.1590/s0102-311x2007000300015. index.html. Accessed in 2020 (Jul 3). 17. Lindoso JA, Lindoso AA. Neglected tropical diseases in Brazil. Rev Inst Authors’ contributions: Borges do Nascimento IJ: conceptualization, final Med Trop Sao Paulo. 2009;51(5):247-53. PMID: 19893976; doi: 10.1590/ approval of the version to be published, data curation, formal analysis, s0036-46652009000500003. methodology, writing-review & editing and investigation (all items 18. Barros MB. Social inequality in health: revisiting moments and trends in equally); Pinto LR: data curation (equal), conceptualization, formal analysis 50 years of publication of RSP. Rev Saude Publica. 2017;51(0):17. PMID: (equal) and methodology (equal); Fernandes VA: conceptualization 28355334; doi: 10.1590/S1518-8787.2017051000156. (equal), data curation (equal), formal analysis (equal) and investigation 19. TelessaúdeRS. Universidade Federal do Rio Grande do Sul. Quais são os (equal); Romero IM: conceptualization (equal), data curation (equal), diagnósticos diferenciais da COVID-19? 2020. Available from: https:// formal analysis (equal) and project administration (equal); Oliveira JAQ: www.ufrgs.br/telessauders/perguntas/quais-sao-os-diagnosticos- conceptualization (equal), formal analysis, methodology (equal) and diferenciais-da-covid-19/. Accessed in 2020 (Jul 3). project administration (equal); Marcolino MS: conceptualization (equal), 20. Ministério da Saúde. Secretaria de Vigilância em Saúde. Sistema de data curation (equal), formal analysis (equal), funding acquisition (equal), Informação sobre Mortalidade – SIM. Available from: http://tabnet.datasus. investigation (equal), methodology (equal) and project administration gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def. Accessed in 2020 (Jul 3). (equal); and Leite MF: conceptualization (equal), data curation (equal), 21. Lippi G, Mattiuzzi C, Sanchis-Gomar F, Henry BM. Clinical and formal analysis (equal), funding acquisition (equal), investigation (equal), demographic characteristics of patients dying from COVID-19 in Italy methodology (equal) and project administration (equal). All authors vs China. [published online ahead of print, 2020 Apr 10]. J Med Virol. actively contributed to the discussion of the results of the study, reviewed 2020;10.1002/jmv.25860. PMID: 32275075; doi: 10.1002/jmv.25860. and approved the final version to be released 22. Li LQ, Huang T, Wang YG, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. Sources of funding: Conselho Nacional de Desenvolvimento 2020;92(6):577-83. PMID: 32162702; doi: 10.1002/jmv.25757. Científico e Tecnológico (CNPq) – grant numbers 115293/2019-1 and 23. Bernardi S, Toffoli B, Tonon F, et al. Sex Differences in Proatherogenic 162996/2019-5; Fundação de Amparo à Pesquisa do Estado de Minas Cytokine Levels. Int J Mol Sci. 2020;21(11):3861. PMID: 32485823; doi: Gerais (FAPEMIG) – grant number APQ-00208-20; and Liver Center at 10.3390/ijms21113861. Universidade Federal de Minas Gerais 24. Ter Horst R, Jaeger M, Smeekens SP, et al. Host and Environmental Conflicts of interest: We declare that we did not have any competing interests Factors Influencing Individual Human Cytokine Responses. Cell. 2016;167(4):1111-24. PMID: 27814508; doi: 10.1016/j.cell.2016.10.018. Date of first submission: July 6, 2020 25. Arnold AP. The organizational-activational hypothesis as the foundation for Last received: July 29, 2020 a unified theory of sexual differentiation of all mammalian tissues. Horm Accepted: September 8, 2020 Behav. 2009;55(5):570-8. PMID: 19446073; doi: 10.1016/j.yhbeh.2009.03.011. 26. Conti P, Younes A. Coronavirus COV-19/SARS-CoV-2 affects women Address for correspondence: less than men: clinical response to viral infection. J Biol Regul Homeost Israel Júnior Borges do Nascimento Agents. 2020;34(2):10.23812. Available from: https://pesquisa.bvsalud.org/ Av. Professor Alfredo Balena, 110 — 1o andar — Ala Sul — Sala 107 controlecancer/resource/pt/mdl-32253888. Accessed in 2020 (Jul 3). Santa Efigênia — Belo Horizonte (MG) — Brasil 27. Qureshi S, Medzhitov R. Toll-like receptors and their role in experimental CEP 30130-100 models of microbial infection. Genes Immun. 2003;4(2):87-94. PMID: Tel. (+1) 860 869 7285 12618855; doi: 10.1038/sj.gene.6363937. Cel. (+55 31) 99744-0897 28. De Oliveira MM, Daher DV, Da Silva JL, Andrade SS. Men’s health in question: E-mail: israeljbn@ufmg.br seeking assistance in primary health care. Cienc Saude Colet. 2015;20(1):273- 8. PMID: 25650621; doi: 10.1590/1413-81232014201.21732013. 29. Gomes R. Sexualidade Masculina, Gênero e Saúde. Rio de Janeiro: Fiocruz; 2008. © 2020 by Associação Paulista de Medicina This is an open access article distributed under the terms of the Creative Commons license. Sao Paulo Med J. 2020; 138(6):490-7 497