key: cord-1043056-ufx7t7c4
authors: Leth, S; Gunst, J D; Mathiasen, V D; Hansen, K S; Søgaard, O S; Østergaard, L; Jensen-Fangel, S; Storgaard, M; Agergaard, J
title: Persistent symptoms in hospitalized patients recovering from COVID-19 in Denmark
date: 2021-01-29
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab042
sha: 055348269f3c6fc4e9c81d4ef1b6cb784577dceb
doc_id: 1043056
cord_uid: ufx7t7c4

BACKGROUND: Although persistent symptoms after Coronavirus disease 2019 (COVID-19) are emerging as a major complication to the infection, data on the diversity and duration of symptoms are needed. METHODS: Patients aged ≥18 years with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 and hospitalized at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, in the period March 11th to May 15th, were offered follow up after hospitalization. On admission, comprehensive symptom and medical history were collected, including demographic characteristics, duration of symptoms, comorbidities and concomitant medication. At discharge, patients were offered follow-up consultations – either by telephone or in-person visit – at 6 and 12 weeks at our Post-COVID-19 outpatient clinic to assess whether symptoms present at admission had resolved. RESULTS: During the inclusion period, 71 patients were admitted with COVID-19. Of these, 10 patients died, 3 were transferred to another region, 4 declined to participate and 5 were lost to follow-up before 12 weeks evaluation. Thus, 49 patients were included. Overall, 96% reported one or more persisting symptoms at 12 weeks follow-up. Main symptoms were fatigue, dyspnea, cough, chemosensory dysfunction, and headache. CONCLUSION: A wide range of persistent symptoms in patients recovering from COVID-19 were present 12 weeks after hospitalization calling for larger descriptive studies and interdisciplinary research collaborations.

As of January 6 th 2021, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of Coronavirus disease 2019 (COVID- 19) , has infected more than 86 million individuals globally spread across 191 countries causing more than one million related deaths [1] . In Denmark, 3, 979 ,917 individuals have been tested for SARS-CoV-2 as of January 6 th 2021. Of those, 172,779 individuals have tested positive, 142,057 have recovered from infection and 1420 (0,8%) individuals have died with COVID-19 [2] .

The variation of symptomatology and severity during hospitalization with COVID-19 quickly became known during the first wave of the pandemic. The clinical features ranges from asymptomatic carriers to severe pneumonia and multiorgan failure with need of intensive care treatment [3] [4] [5] .

Emerging data suggest that COVID-19 can result in long-term symptoms from several organ systems in a subgroup of individuals recovering from acute infection. Primary reported long-term symptoms include cognitive impairment, fatigue, chest pain , dyspnea, cough and impaired smell and taste [6] [7] [8] . These findings raise important major questions about the long-term health consequences of COVID-19. Thus, we are in urgent need of more evidence about the duration of organ specific symptoms and complications that appear after the initial phase of COVID-19. This applies for hospitalized and non-hospitalized patients in order to describe and understand the full spectrum of COVID-19. Finally, these data will inform public health and social policy tailoring.

In this study, we demonstrate diverse persistent symptoms 12 weeks after discharge with COVID-19 in adult patients.

Patients eligible for inclusion were hospitalized at Aarhus University Hospital, Denmark. Aarhus University Hospital has a catchment area of 300,000 citizens and has approximately 850 beds. The In this report we describe patients hospitalized between March 11 th and May 15 th , during the first wave of the COVID-19 epidemic in Denmark. On admission, a comprehensive symptom and medical history was obtained and registered in the patient journal, including duration of symptoms, demographic characteristics, comorbidities, and concomitant medication. After discharge, patients were offered follow-up consultations. First consultation by telephone -at ≥ 6 weeks and 2 nd consultation in-person visit or consultation by telephone at ≥12 weeks. Data analysis were done corresponding to day 42 and 84 -i.e., how many reported the specific symptom on day 42 and 84, respectively, after discharge.

Here patients were interviewed according to a COVID-19 specific, structured interview guide addressing organ specific symptoms to assess whether the symptoms present at admission had resolved or new symptoms had emerged (Appendix 1). The interview guide was designed to identify and systematically record previous and current symptoms listed in table 2. Cognitive function was assessed by the validated orientation-memory-concentration (OMC) test [9] . An OMC score of 24 or below was interpreted as impaired. Patients with dyspnea were asked whether they had dyspnea at rest, when walking, walking up hill or at strenuous physical activity. Severe dyspnea was defined as A c c e p t e d M a n u s c r i p t 5 dyspnea at rest or when walking (equaling Medical Research Council dyspnea score [3] [4] [5] [10]. An individual interdisciplinary assessment was subsequently offered if needed. Data were analyzed using Stata Intercooled version 11. We used multivariate logistic regression analysis to identify independent risk factors for persistent COVID-19 symptoms. For calculation of odds ratios (ORs) for risk factors of persistent symptoms, logistic regression was used. Covariates included in the multivariate logistic regression model were age, sex, BMI, comorbidity and smoking. P values below 0.05 were considered statistically significant.

Each patient provided written informed consent. All data was registered in a secure REDCap database hosted at Clinical Trial Unit, Aarhus University [11] . Data collection was approved by Central Denmark Region (reference 1-45-70-5-20). The registry-and questionnaire-based design did not require ethics approval (Danish Committee Act, Section 14, Subsection 2), which was confirmed by the Regional Ethics Committee (reference 1-10-72-181-20).

Between March 11 th and May 15 th , 71 patients were admitted to our department. Of these, 7 patients died in hospital, 3 died 1-6 weeks after discharge from hospital and 3 were transferred to another region and were therefore not eligible for the study. Of 58 eligible patients, 4 subsequently declined follow-up and 5 were lost to follow-up before 12 weeks evaluation. Thus, 49 patients contributed with full data and were included in the study.

The median age of the 49 patients included was 58 years (interquartile range (IQR) 43-78) and 57% (n=28) were female. A majority of the patients were Caucasians (86%, n=42). Median days from onset of symptoms to hospitalization were 8 days (IQR 4-10) and patients were hospitalized for a median of 6 days (IQR 3-10). Six patients (12%) required intensive care treatment during their A c c e p t e d M a n u s c r i p t 6 hospitalization. Patients had a median body mass index (BMI) of 27.5 kg/m 2 (IQR 24.5-32.7), 63% never smoked and 63% had one or more comorbidities with hypertension being the most prevalent.

The study population is summarized in TABLE 1.

Symptoms during hospitalization and at subsequent follow-up consultations are summarized in TABLE 2. The first follow-up consultation was performed at median 51 days (IQR 46-59.5) after discharge and the second follow-up consultation was performed at median 128 days (IQR 98-148).

At hospitalization, the most common symptoms registered were cough (92%), fatigue (63%), dyspnea (61%), headache (48%), and myalgia (47%). Symptoms from the gastrointestinal system also predominated with 39% reporting nausea, 37% had diarrhea and 20% abdominal pain. Further, 11% and 17% reported smell and taste impairment, respectively.

Data analysis performed corresponding to day 42 showed that 86% reported presence of one or more symptoms. The most frequent symptoms were fatigue (65%), dyspnea (53%), subjective difficulties concentrating (39%) and impaired smell (35%) and taste (33%). Overall, 51%, 69% and 18% reported symptoms which could originate from the central and peripheral nervous, cardiopulmonary and gastrointestinal system, respectively. Data analysis performed corresponding to day 84 showed that 96% reported presence of one or more symptoms. Consistent with findings at the first follow-up consultation, predominating symptoms were fatigue (63%), dyspnea (53%) and difficulties concentrating (45% A c c e p t e d M a n u s c r i p t 7 Overall, 57%, 67% and 16% reported symptoms which could originate from the central and peripheral nervous, cardiopulmonary and gastrointestinal system, respectively.

Altogether, these data suggest long-term persistence of COVID-19 related symptoms.

Age, BMI, smoking and comorbidity are known predisposing factors for severe COVID-19 [12] [13] [14] [15] . Using multivariate logistic regression analyses we evaluated the covariates age, BMI, smoking and comorbidity as potential independent risk factors for the most common persistent symptoms: fatigue, dyspnea and difficulties concentrating. We calculated the OR for fatigue, dyspnea and impaired concentration based on each of these potential risk factors: age over vs under 60 years, BMI over vs under 25 kg/m 2 , smoker and previous smoker vs non-smoker and comorbidity vs no comorbidity. Here we found a significant reduced OR of difficulties concentration if current (or previous) smoker. Besides that, we found no significant OR for persistent symptoms following admission for COVID-19 for any of the other listed known risk-factors for severe COVID-19 (SUPPLEMENTARY TABLE) .

Among 49 patients included in this cohort study, a concerning 86% and 96% reported presence of one or more symptoms at 6-and 12-weeks follow-up, respectively, after onset of COVID-19 related symptoms.

The primary persistent symptoms at 6-and 12-weeks follow-up were fatigue, dyspnea, impaired concentration, cough and impaired smell and taste, consistent with the literature so far.

Symptoms after hospitalization were reported in an early study including 143 patients discharged after COVID-19 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy [6] .

A c c e p t e d M a n u s c r i p t 8 The patients were assessed in an outpatient clinic at a mean of 60.3 (standard deviation, 13.6) days after onset of the first COVID-19 symptom. Only 13% were free of any COVID-19 related symptom, while 32% had one or two symptoms and 55% had three or more. As in our study, dominating symptoms were fatigue, dyspnea, arthralgia, chest pain and cough.

A few studies have addressed persistent symptoms in non-hospitalized patients. In a multicenter study from the USA, 292 non-hospitalized patients were contacted 7-21 days after a positive SARS-CoV-2 PCR test. They found that 92% had symptoms at the time of the test and that 35% of these still had symptoms at a telephone interview (median 16 days after the time of the test) -primarily driven by fatigue, cough, headache, and shortness of breath [16] . These early findings should merit equal attention and resources allocated to follow and assess both hospitalized and non-hospitalized patients for persistent symptoms following COVID-19.

Focusing on the different organ systems, we found that 69% and 67% had one or more symptoms originating from the cardiopulmonary system at 6-and 12-weeks follow-up with dyspnea, cough and chest pain being the main dominating complaints. In line with these findings, a recent observational cohort study of 100 patients who had recovered from COVID-19 showed that 78 patients had abnormal findings on cardiovascular magnetic resonance imaging (MRI) and 60 patients showed signs of ongoing inflammation at a median of 71 days after the diagnosis. Thirty-six percent of the cohort reported dyspnea and unusual fatigue [17] . These findings were substantiated in a study examining the heart by MRI of 26 SARS-CoV-2 positive athletes who did not require hospitalization [18] . Here, 46% had evidence of myocarditis or prior myocardial injury 12-53 days after their positive test result. Similar reports have emerged on pulmonary sequelae in patients recovering from COVID-19 with persistent symptoms and radiologic abnormalities consistent with pulmonary dysfunction months after the acute phase of COVID-19 [19, 20] .

A c c e p t e d M a n u s c r i p t 9 We found that 51% and 57% had one or more symptoms potentially originating from the central and peripheral nervous system at the two follow-up time points. Dominating symptoms here were headache, paresthesia and chemosensory dysfunction (smell and taste impairment). Some of these post-COVID-19 symptoms resemble those of patients recovering from e.g. encephalitis and to some degree meningitis. It has been suggested that coronaviruses are able to reach the central nervous system through hematogenous or neural propagation possibly through the olfactory nerve -which, in part, could explain chemosensory dysfunction [21] [22] [23] . In line with our observations, minor neurological manifestations have been reported in SARS-CoV-2 positive patients such as headache, confusion and "brain fog" [23] , but also more severe neurological manifestations as cerebral ischemic stroke, cerebral perfusion abnormalities, leptomeningeal enhancement have been described [24] .

Persisting symptoms from multiple organs could reflect the wide distribution of the preferred SARS-CoV-2 host receptor, angiotensin-converting enzyme 2 (ACE 2), in different tissues such as the epithelium of the intestine, the kidney and blood vessels, the endothelial cells in the lungs but also the central nervous system [12, 25, 26] . As viral replication accelerates, the epithelial-endothelial barrier integrity is compromised accentuating the inflammatory response which may explain the lymphocytic endotheliitis observed in postmortem pathology examination of the heart, kidney, liver, and lung in patients who died of COVID-19 [27] [28] [29] [30] . This inflammatory phase could contribute to the wide range of persistent symptoms in patients recovering from COVID-19.

Persistent symptoms following other coronaviruses, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are also well described. A recent meta-analysis A c c e p t e d M a n u s c r i p t 10 described clinical long-term outcomes of adult SARS and MERS survivors. The meta-analysis included 28 studies and 2820 patients. Pooled analysis revealed that several complications were common up to 6 months after discharge such as lung function abnormalities (27%), psychological impairment including posttraumatic stress disorder (38%), depression (33%) and anxiety (30%) as well as reduced exercise capacity and health related quality of life [31] . Given that SARS and MERS belong to the same family of virus as SARS-CoV-2, lessons learned from long term sequalae following MERS and SARS should help guide clinician in how to monitor the range of physical and mental health impairments in patients suffering from persistent symptoms following COVID-19.

In our study, we tended to find more patients with paresthesia and difficulties concentrating at 12 compared to 6 weeks after discharge from hospital. Cognitive impairment and neurological sequalae are also frequently observed in other patient groups recovering from severe infectious diseases. In a study of 516 older severe-sepsis survivors (mean age 76.9 years), they found that severe-sepsis was associated with a nearly 3-fold increase in the odds of moderate to severe cognitive impairment after discharge and further emergence of new symptoms after discharge as compared with 4517 patients who survived a non-sepsis hospitalization [32] .

In our study, though small numbers, we found a significant reduced OR of challenged concentration if current (or previous) smoker. Smoking has previously been associated with cognitive impairment [33] , why this finding remains to be addressed in large scale studies. Besides this, we found no increased OR of persistent symptoms 12 weeks after the acute phase of COVID-19 when looking at risk factors such as age, sex, BMI or co-morbidity emphasizing that persistent symptoms can occur in previously healthy young people. However, in a large prospective cohort study from New York including 5279 patients admitted with COVID-19 older age, high BMI as well as multimorbidity were associated to not having returned to usual state of health 14-21 days after detection of SARS-CoV-2 [34] .

A c c e p t e d M a n u s c r i p t 11 Unfortunately, we did not systematically collected data on quality of life or whether patients had returned to their baseline health after hospitalization for COVID-19. In a recent study, 120 patients were interviewed by phone at a mean of 110.9 days after discharge with COVID-19. Of the active workers (56 patients), 38 patients had gone back to work at the time of the phone interview, and further, amongst the 39 patients who had regular sports activity before their hospitalization with COVID-19, 28 patients have been able to resume physical activity, but at a lower level for 18 patients [35] . Similar, in another study including 100 patients, discharged after hospitalization for COVID-19, were interviewed by phone 4 to 8 weeks after discharge (mean 48 days) using the EQ5D screening tool to access mobility, personal care, usual activities, pain and anxiety/depression. Of the 100 included patients, 68 patients were managed in hospital wards without needing intensive care unit (ICU) care (ward group). Here a clinically significant drop in EQ5D in 68.8% of the ICU group and in 45.6% of the ward group was observed, suggesting prolonged recovery in quality of life [36] .

It should be noted, that we became increasingly aware of symptoms present at follow-up, that were not systematically registered during primary admission or initially during follow-up, why these findings are not systematically reported here. These symptoms include heart palpation, burning sensation in the chest, dizziness, memory loss, muscle weakness, fluctuating skin rash and hair loss. Though we illustrate the presence of persistent symptoms through a systematic interview, some limitations should be acknowledged. First, the small homogenic sample size. Second, the single center setup which requires confirmation in larger scales. Third, the lack of a control group. Fourth, the lack of objective measurements. Fifth, these data only address hospitalized patients -potential persistent symptoms following COVID-19 in non-hospitalized might differ and finally, loss to follow up may have introduced selection bias.

A c c e p t e d M a n u s c r i p t 13

In this study, we observed persistence of COVID-19 related symptoms. More specifically, 86% and 96% reported presence of one or more symptoms at 6 and 12 weeks, respectively, after onset of COVID-19 related symptoms as compared to prior hospitalization with COVID-19. The dominating symptoms were fatigue, dyspnea, cough, chemosensory dysfunction, and headache. Overall, there is an urgent need for well-designed longitudinal multi-national and -site studies. In such studies, a clear definition of inclusion criteria, uniform definitions of outcomes and ways to measure these are necessary in order to continuously translate evidence of this new disease into the best possible interdisciplinary assessment and treatment for the affected patients.

A c c e p t e d M a n u s c r i p t 14 

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