key: cord-0790394-4qlwf00l authors: Romao, V. C.; Oliveira-Ramos, F.; Cruz-Machado, A. R.; Martins, P.; Barreira, S.; Silva-Dinis, J.; Galaio, L.; Proenca, H.; Melo Cristino, J.; Sacadura-Leite, E.; Khmelinskii, N.; Romeu, J. C.; Fonseca, J. E.; Department, CHULN Rheumatology title: A COVID-19 outbreak in a rheumatology department upon the early days of the pandemic date: 2020-06-08 journal: nan DOI: 10.1101/2020.06.05.20107011 sha: 23e0cd1c4683d7fd18143312aa72c90b7af42410 doc_id: 790394 cord_uid: 4qlwf00l Objectives: To describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department, early in the pandemic. Methods: Symptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms. Results: 14/34 HCWs (41%; 40{+/-}14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnoea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28{+/-}18 days), viral shedding (31{+/-}10 days post-symptom onset, range 15-51) and work absence (29{+/-}28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response, with higher IgG-index in individuals over 50 years (14.5{+/-}7.7 vs 5.0{+/-}4.4, p=0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalisation, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly-symptomatic (1/8) HCW. Conclusions: A COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognised, and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals. Following the initial descriptions in early January 2020 of a novel form of severe pneumonia in patients from Wuhan, China, 1-4 the coronavirus disease 2019 (COVID-19) quickly spread at a global level. On January 30, the World Health Organization declared it a public health emergency of international concern, 5 subsequently updated to pandemic on March 11. 6 After the first reported case in Portugal (March 2), exponential growth led to major restrictive measures. 7 Consistently high infection rates among healthcare workers (HCWs) have been reported in several hard-hit countries such as China, 8, 9 Italy, 10 Spain, 11 or the United States, 12 despite adequate safety measures. 13 One possibility is that in-hospital transmission, among patients and HCWs, might be a key form of contagion. 9, 14, 15 This is particularly relevant given the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whereby presymptomatic/asymptomatic contamination is likely to play a major role in disease spreading. [14] [15] [16] [17] [18] [19] In the early days of the pandemic, most focus was given to severe clinical pictures, 2, 8, 9, 20 while reports on mild or asymptomatic disease were scarce. 21, 22 This may have contributed to an initial oversight of more general, less severe manifestations, such as upper respiratory and digestive symptoms. 23 These milder disease forms might be easily undervalued, including by HCWs responding to the pandemic. In healthcare facilities, this may facilitate the generalised spread among HCWs, who can serve as disease-transmission agents. 9,14-16 Such fact may be particularly relevant in outpatient-oriented departments with a high volume of clinical activity (e.g., rheumatology). In addition, rheumatology practice requires daily close physical contact with patients with rheumatic-musculoskeletal diseases (RMDs), who are often immunosuppressed and have an increased infectious risk. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint In the present report, we aim to describe our experience with a COVID-19 outbreak within our department, upon the initial weeks of the pandemic, highlighting clinical, virological and immunological outcomes of HCWs and RMD patients. Over the week of 9-15 March, several HCWs of our rheumatology department developed mild symptoms compatible with COVID-19. All staff (symptomatic/asymptomatic) underwent screening for SARS-CoV-2 on 15-16 March. Double naso-oropharyngeal swabs were obtained, and samples were tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR; cobas ® SARS-CoV-2 kit, cobas ® 6800 System, Roche Diagnostics, USA). All the confirmed and suspected cases were quarantined and referred to public health authorities. Daily remote clinical monitoring of HCWs was conducted by 2 asymptomatic rheumatologists, in conjunction with public health and occupational medicine specialists. Testing of HCWs was repeated (i) 7-14 days after the first negative test in subjects with persisting symptoms; (ii) 5-7 days following the resolution of fever and improvement in respiratory symptoms in confirmed cases. 24 Two consecutive negative tests were required to confirm viral shedding cessation and allow return to work. 25 Immunological response to SARS-CoV-2 was evaluated by chemiluminescent immunoassay (MAGLUMI ® 800 CLIA System, MAGLUMI ® 2019-nCoV (SARS-CoV-2) IgM/IgG-kits, Snibe Co., Ltd., China) in all HCWs, following symptom resolution and double-negative RT-PCR in confirmed cases. We contacted patients observed during the previous 2 weeks in the day care unit, outpatient clinic and procedures room, who had possible contacts with confirmed RT-PCR-positive HCWs. Each patient was screened for suggestive symptoms and requested to remain in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint isolation for 14 days post-contact with the department. Patients with symptoms compatible with COVID-19 were referred to the national health system hotline and signalled to health authorities, who had also received the list of screened patients. All HCWs of the rheumatology department who were working during 2-13 March, including visiting fellows, were invited to participate in this study. A standardised questionnaire was administered to collect demographic data, symptom characterisation, disease course and outcome, treatment, comorbidities, and concomitant therapy. Results of laboratory and imaging studies performed, including RT-PCR and IgG/IgM for SARS-CoV-2 were reviewed. Disease course was classified as mild, moderate (requiring physical examination and laboratory/imaging studies) or severe (requiring hospitalisation). Moreover, patients observed in the department between 2-13 March who developed symptoms suggestive of COVID-19 had an appointment scheduled, upon definite resolution, for clinical observation. The same data were collected as for HCWs, in addition to variables related to the RMD and associated treatment. Patients observed in the period of interest who did not develop COVID-19 symptoms, or did so outside the 14-day window after the last contact with the department, were excluded. All study participants signed a study-specific informed consent. This study was approved by the Lisbon Academic Medical Centre Ethics Committee (reference 171/20). Demographic and clinical characteristics were presented as frequency, mean±standard deviation or median (interquartile range [IQR]), as applicable. Comparison of continuous variables between HCW groups was performed using Kruskal-Wallis (3 groups) or Mann-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint Whitney U-test (2 groups). Categorical variables were compared using Chi-square or Fisher's exact test. Agreement between RT-PCR and serological tests was done using Kappa-statistic. Pearson correlation was applied to study the relation of IgG humoral response and clinical variables. Statistical analyses were performed using Stata-12.1 for Mac (StataCorp, College Station, USA) and GraphPad-Prism-7 for MacOS (GraphPad Software, USA). P-value was considered significant at p<0.05. subjects had a previous history of cardiovascular disease and/or metabolic syndrome, whereas 3/14 (21%) had a diagnosis of immune-mediated inflammatory disease (IMID; one of whom treated with methotrexate 15mg/week). Importantly, 5/14 (36%) HCWs did not develop fever, which lasted ≤3 days in 4/9 (44%) remaining cases. Cough was also absent in the same proportion (36%). Of note, 7/14 (50%) subjects did not develop any of the manifestations of the typical COVID-19 triad prior to the positive RT-PCR test, which were completely missing in 3 cases (21%) throughout the disease. In turn, milder symptoms were already present during the week prior to the outbreak identification in several instances. Anosmia and dysgeusia were present in over half the cases, including 1 subject (HCW6) who did not develop fever, cough or dyspnoea. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint The majority of cases (11/14, 79%) had a benign course. There were no hospitalisations, but 3/14 HCWs (age category 40-70, with relevant comorbidities) underwent clinical, laboratory and radiographic evaluation 7-12 days after symptom onset, due to persistent fever, cough, chest pain and/or shortness of breath. Lymphopaenia (1/3), thrombocytopaenia (1/3), raised lactate dehydrogenase (1/3), D-dimers (2/3), fibrinogen (2/3), and C-reactive protein (CRP; 2/3) were identified, but hypoxaemia and radiographic signs of COVID-19 pneumonia were absent. Seven subjects (50%) were treated with hydroxychloroquine (400mg/day, median 9 days, range 7-14 days) and 4 received concomitant azithromycin (500mg/day, 5 days). One Eleven subjects developed various symptoms but tested negative, even upon retesting ( Table 1 , Figure 1 ). These HCWs reported complaints of cough (55%), rhinorrhoea (45%), sore throat (82%), and other symptoms in similar frequency and duration to confirmed cases, over the same time frame. However, fever, fatigue, malaise, headache, myalgia, anosmia, and dysgeusia All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint were significantly less common. Notably, these HCWs had a comparable demographic and comorbidity profile to those with positive RT-PCR and the 9 asymptomatic subjects with negative RT-PCR (Table 1) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint 1.10AU/mL) compared to other RT-PCR-positive subjects. In addition, HCW10 had an IgG index below the positive threshold, despite 2 positive RT-PCR tests, no immunosuppression, and comparable evaluation timing and clinical course. Within the RT-PCR-positive group, considerable variation was seen in the antibody response ( Figure 2B ). Notably, subjects over 50 years had a higher mean IgG index (14.5±7.7AU/mL)) than younger individuals (5.0±4.4AU/mL, p=0.012; Figure 2C ). Although the numbers are small, the 3 older HCWs who had an IgG index above 10AU/mL presented a more severe disease course, with high fever and cough, and 2 of them had raised D-dimers, fibrinogen and CRP. In contrast, the remainder older HCW had a mild course with limited rhinorrhoea and gastrointestinal symptoms, and developed a lower IgG index (4.99AU/mL). Nevertheless, a positive trend was observed in the correlation between age and IgG index (Pearson r=0.53, p=0.051; Figure 2D ). No other clinical factor was associated with antibody response, including sex, treatment, or presence/duration of fever, cough or dyspnoea. A total of 617 patients were identified as having had a potential risk contact, 561 (91%) of whom were contacted by telephone and screened for COVID-19 symptoms starting within the 14-day window (Figure 3 ). We identified 8 (1.3% of total) female patients (mean age 66.8±14.9 years) who developed symptoms compatible with COVID-19 (Table 2) . Six patients had a diagnosis of an inflammatory RMD, 3 were treated with conventional synthetic diseasemodifying anti-rheumatic drugs (csDMARDs) and glucocorticoids and 2 with biologic DMARDs (bDMARDs). All contacts took place within the same 2 days (9 and 11 March), all but one were with a confirmed infected HCW, and patients denied additional suspicious contacts. Contact tracing for Patient-1 within the department confirmed it to be limited to a All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint symptomatic physician with negative RT-PCR and serology (HCW24). Importantly, in 7/8 cases, the HCW was asymptomatic at the time of contact, and 1 patient (Patient-6) had a consultation with a physician (HCW7) presenting only mild serous rhinorrhea. Of note, 5/8 contacts were in the context of diagnostic (ultrasound) or therapeutic procedures (mesotherapy), which involved prolonged close physician-patient contact. Patients developed symptoms on average 4.3±2.1 days (range 2-9) after the contact. Half reported fever, 88% had cough, and only 1 patient reported dyspnoea. General and upper airway symptoms were common, including anosmia (50%) and dysgeusia (63%). Nasopharyngeal swabs were performed in 6/8 cases (8.8±3.1 days post-symptom onset), 2 of which were positive for SARS-CoV-2 and 1 was inconclusive. Two patients were not tested due to difficulty in reaching health authorities or personal choice (self-isolation). Patients with negative/unavailable test still had suggestive COVID-19 symptoms. All but one patient had a mild-to-moderate course and were clinically recovered after an average of 24.8±5.9 days. A woman in her 90's with giant cell arteritis and relevant cardiovascular comorbidities, exposed to long-term methotrexate and low-dose glucocorticoids, was hospitalised after 6 days of fever and 3 days of worsening chest pain and dyspnoea. She required oxygen therapy, received a combination of hydroxychloroquine (400mg/day) and lopinavir/ritonavir (800/200mg/day), and was discharged after 10 days. Importantly, none of the patients experienced a flare of the baseline RMD. Our study provides important lessons on the vulnerability and impact of a COVID-19 outbreak within a large rheumatology department, at a time when universal surgical mask use was not recommended. Over a single week, 41% of HCWs were confirmed to be infected by SARS-CoV-2, and an additional 32% developed mostly overlapping symptoms. While we could not All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint detect the index case, the spread of the contagion was fast and occurred when almost all HCWs were asymptomatic or exhibited only minor symptoms, easily dismissed or attributed to another concurrent viral disease. These findings are in accordance with current concerns around the presymptomatic or asymptomatic transmission of SARS-CoV-2 among HCWs and patients. 9,14-16 As viral shedding and infectiousness are higher in the 2-3 days prior to symptom onset and rapidly decrease thereafter, 26,27 a high proportion of contagion occurs during the presymptomatic stage. 18, 26 In addition, asymptomatic 17, 22, 28, 29 and mild disease forms with limited upper respiratory symptoms are now widely recognised, 23, 27 and may escape vigilance protocols, more focused on the presence of fever, cough, and dyspnoea. This was certainly the case in our cluster, where testing of all HCWs of the department, whether symptomatic or not, was vital to identify cases and contain the outbreak. Therefore, in healthcare settings, continuous mask use, social distancing, and mild-symptom monitoring should be adopted among HCWs, together with proactive testing strategies, to account for potential pre/asymptomatic carriers. 15 The outbreak had a profound repercussion in the clinical activity of the department. Infected subjects had protracted symptoms and were away from work for around 1 month. In addition, prolonged viral shedding (up to 51 days) led to frequent RT-PCR repetition (median 5 tests) until cure was confirmed, consuming substantial resources. Our findings regarding viral RNA swab positivity are longer than previously reported, 20,30-32 which may be related to differences in specimen collection (double naso-and oropharyngeal swab in our study), study population, or disease severity. Interestingly, similar nasopharyngeal viral load in patients with mild and severe disease have been reported, 30 although a separate study concluded otherwise. 33 Moreover, some data suggest that a positive RT-PCR does not denote the actual presence of viable virus, especially after the first week. 27, 34 However, this is not yet fully established, and we would therefore advocate for 2 consecutive negative tests before HCWs return to work. In All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint effect, 21/59 (36%) of repeat tests were positive, and in 5 instances a positive or indeterminate test followed a first negative result, highlighting the difficulties of interpretation. 34 All HCWs had a mild-to-moderate disease course and there were no major complications. We believe the positive outcome of the cohort is mainly related to the young mean age, with only 2 HCWs older than 60-years. Alternatively, a lower initial viral exposure load could also explain an overall milder phenotype. 33 Nevertheless, most of the infected HCWs (93%) developed an immune response, which tended to be more robust in older individuals. This, in turn, may be secondary to a more severe clinical course, known to be strongly associated with age. 20,35 A possible explanation for this finding could be a higher peak viral load, also previously shown to be positively correlated with age. 30 Finally, secondary transmission to a minority of patients did occur, from 4 HCWs who were asymptomatic (75%) or had mild upper airway symptoms (25%), mostly in a close proximity contact. As one of the confirmed cases only contacted with HCW24 (negative RT-PCR and serology), we cannot exclude undisclosed community contagion or nosocomial transmission through fomites. 39 Also, we admit patients with negative/missing RT-PCR could be falsenegative or undiagnosed cases, possibly due to a larger interval between symptom onset and testing. Of note, all contacts occurred when preventive measures had already been adopted and 80% of face-to-face clinical activity had been deferred, which might explain the low number All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint of infected patients. We admit the possibility that contagion could have followed the opposite route (pre/asymptomatic patients-to-HCWs), although symptom timing does suggest otherwise. Notwithstanding the advanced age and long-term use of cs/bDMARDs and glucocorticoids in half the cases, all patients had a favourable outcome. This is in accordance with the largest series to date of patients with IMIDs, failing to show an increase in the incidence of severe disease. 40 Our study has some limitations. Due to its real-life nature, clinical assessment and RT-PCR timing were clinically-based and differed slightly between subjects. As computed tomography was not performed, we cannot completely exclude COVID-19 pneumonia. Two fellows could not be tested for serology upon finishing their clerkship. Also, 9% of the identified RMD patients could not be reached. In conclusion, we demonstrate that a COVID-19 outbreak can occur among HCWs and rheumatic patients, spreading over the presymptomatic stage, and evolving with mild-tomoderate symptoms, delayed viral shedding and prolonged recovery. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. Data are available on reasonable request. All data relevant to the study are included in the article or in the supplementary files. Other data are available on reasonable request. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint ---ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin-II receptor blockers; chronic obstructive pulmonary disease; DMARDs, disease-modifying anti-rheumatic drugs; IMID, immune-mediated inflammatory disease; NSAIDs, non-steroidal anti-inflammatory drugs. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . Distribution of anti-SARS-CoV-2 IgG antibodies in RT-PCR+ HCWs, according to age group (below or above 50 years old). *p=0.012. D. Correlation between age and anti-SARS-CoV-2 IgG antibodies in RT-PCR+ HCWs. r, Pearson correlation coefficient. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20107011 doi: medRxiv preprint World Health Organization. Pneumonia of unknown cause -China A novel coronavirus from patients with pneumonia in China Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle A pneumonia outbreak associated with a new coronavirus of probable bat origin World Health Organization. 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We thank Dr Álvaro Ayres Pereira and Dr Tiago Marques, from the CHULN Infectious Diseases Department, for the clinical support in evaluating confirmed and suspicious cases. We thank RT-PCR- (24) RT-PCR+ (1) RT-PCR+ (1) RT-PCR+ (14) RT-PCR+ (1) RT-PCR+ (7) RT-PCR+ (1) RT-PCR+ (1) Contact date 9/3/2020 11/3/2020 9/3/2020 9/3/2020 9/3/2020 11/3/2020 11/3/2020 11/3/2020