key: cord-0942839-fxwszm22
authors: Petersen, Maria Skaalum; Kristiansen, Marnar Fríðheim; Hanusson, Katrin Dahl; Danielsen, Marjun Eivindardóttir; á Steig, Bjarni; Gaini, Shahin; Strøm, Marin; Weihe, Pál
title: Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients
date: 2020-11-30
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1792
sha: 85632776fc431f26218e17bdd4cb5973a489b26b
doc_id: 942839
cord_uid: fxwszm22

BACKGROUND: Little is known about long-term recovery from COVID-19 disease, especially in non-hospitalized individuals. In this longitudinal study we present symptoms registered during the acute phase as well as long COVID, i.e. long-lasting COVID-19 symptoms, in patients from the Faroe Islands. METHODS: All consecutive patients with confirmed RT-PCR testing from April to June 2020 were invited to participate in this study for the assessment of long COVID. Demographic and clinical characteristics and self-reported acute and persistent symptoms were assessed using a standardized detailed questionnaire administered at enrollment and at repeated phone interviews in the period 22 (th) April to Aug 16 (th). RESULTS: Of the 180 participants (96.3% of the 187 eligible COVID-19 patients), 53.1% reported persistence of at least one symptom after a mean of 125 days after symptoms onset, 33.3% reported one or two symptoms and 19.4% three or more symptoms. At the last follow-up, 46.7% were asymptomatic compared with 4.4 % during the acute phase. The most prevalent persistent symptoms were fatigue, loss of smell and taste, and arthralgias. CONCLUSIONS: Our results show that it might take months for symptoms to resolve, even among non-hospitalized persons with mild illness course in the acute phase. Continued monitoring for long COVID is needed.

The literature on the inpatient course of illness of coronavirus disease 2019 (COVID-19) has rapidly grown over the past several months [1] ; however, little is known about the long-term recovery from COVID-19 in non-hospitalized individuals. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the respiratory system, causing for example, interstitial pneumonia and acute respiratory distress syndrome [2] . However, the clinical long-term consequences after recovery of acute COVID-19 is uncertain, and most studies have focused on severe patients in hospital settings. Very few studies have prospectively assessed persistence of symptoms in COVID-19 patients, or long COVID, the term recently proposed in Nature [3] . As of yet there is no consensus on the terminology surrounding "long COVID", but long COVID simply refers to a lengthy period of illness, without making assumptions on the underlying cause. An Italian study found that in patients discharged from the hospital after recovery from COVID-19, 87.4% reported persistence of at least one symptom, particularly fatigue and dyspnea [4] , while a Chinese longitudinal study reported that 49.6% of recovered patients had one or more common symptoms, including physical decline, fatigue, and myalgia three months after discharge [5] .

The majority of COVID-19 patients are, however, not hospitalized, and it is necessary to quantify and characterize long COVID in those not hospitalized to get the full picture of the public health challenge imposed by the pandemic.

In the Faroe Islands, the first point of evidence found that 89% of patients with COVID-19 presented with symptoms (Kristiansen et al. under peer review); the most prevalent symptoms were fever, headache and cough. Furthermore, the intensive testing regime in the Faroe Islands implies that the number of unregistered patients is probably very low [6] which makes this an opportune setting for investigating persistence of symptoms among initially mild patients of COVID-19. Therefore, we performed this longitudinal study M a n u s c r i p t 4 with the aim to describe symptoms in the acute phase and especially long COVID in mainly non-hospitalized patients from the Faroe Islands.

All consecutive patients diagnosed with COVID-19 confirmed by RT-PCR testing of an oropharyngeal swab between 3 March and 22 April 2020 were invited to participate in the study. A task force consisting of medical doctors was established under the Ministry of Health in response to COVID-19, to monitor all isolated diagnosed COVID-19 patients, and their quarantined contacts. The task force recorded baseline symptoms as well as date of onset, date of recovery, and hospitalization. All diagnosed patients were asked permission to be contacted by the research team, with the purpose of assessing persistent symptoms of disease.

Upon acceptance, data on specific symptoms potentially associated with COVID-19 were obtained using a detailed standardized questionnaire administered at enrollment, and subsequently repeated through phone interviews, to evaluate any persistent symptoms. The number of interviews was dependent on how long symptoms persisted, and the time from onset of symptoms to first interview. Time from the acute phase to first interview varied mainly due to a workload at times higher than projected among the interviewers. However, all patients received a minimum of two follow-up calls. If a participant reported symptoms to have ceased at an assessment or reported symptoms to be stable at two consecutive assessment occasions, and more than two months had passed since the acute phase, the follow-up was terminated. Patients were asked to retrospectively recall the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the phone interview. The symptoms could be rated as mild, moderate, or severe. With small children (0-15 years), the parents were asked to estimate their A c c e p t e d M a n u s c r i p t 5 children's symptoms. In addition, basic background information was collected, such as education, smoking, self-rated health, medication use, and chronic diseases. The fatigue impact scale was used to ask patients to score their fatigue. It is a self-reported questionnaire that consists of 8 items, each describing one possible experience of fatigue. Individuals were asked to rate the extent to which fatigue has been a problem for them in regard to each of these items, on a scale ranging from 0 (no problem) to 4 (extreme problem) [7] .

The Faroese Ethics Committee and Data Protection Agency have approved this study.

Data collection began on 21 April and ended in August 2020, and informed consent was obtained from all participants.

Descriptive results are presented with mean and standard deviations (SD) for continuous variables and with number and percentages for categorical variables. We used the χ² test, Fisher's exact test, or Mann-Whitney U test to compare groups, e.g., individuals with and without persistent symptoms, age groups etc. where appropriate. Of note, age was divided into the following age groups: 0-17, 18-34, 35-49, 50 to 66, and 67+years. ANOVA test was used to compare normally distributed variables such as mean number of symptoms. All analyses were performed using SPSS version 25. P (two-tailed) < 0.05 was considered statistically significant.

A total of 187 patients were potentially eligible for the follow-up assessment; five individuals (3%) did not wish to participate, and two were not reached (1%). Thus, 180 individuals were included in the study. The mean (SD, range) age was 39.9 (19.4, 0-93), and 98 (54%) were women. Only eight individuals were hospitalized. The mean length of hospital stay was two During the acute phase of COVID-19, 4.4% (n=8) were asymptomatic and 7.2% (n=13) reported one or two symptoms while more than 30% had nine or more symptoms (table 2) . At the last follow up 46.7% (n=84) were asymptomatic, while 33.3% (n=60) reported 1 or 2 symptoms, and 19.4% (n=35) 3 or more symptoms. The most prevalent symptoms during the acute phase were fatigue, fever, headache, chills, and loss of smell and taste, while the most persistent symptoms were fatigue, loss of smell and taste, and arthralgias (figure 1). The same symptoms, apart from fever and chills, were reported as the most common severe symptoms reported during acute COVID-19 disease, while the most persisting severe symptoms at last follow-up (n=15) were fatigue, loss of smell and taste, and arthralgias (table 3) . Of note, 1% did not report these symptoms in the acute phase but reported symptoms at the last follow-up. Among those experiencing fatigue during the acute phase (n=127) and at the last follow up (n=53), the fatigue impact scale score was in mean (SD) 1.8 (1.1) and 1.2 (1.0) , respectively. None of the participants reported fever or any signs or symptoms of acute illness at the follow-up.

Age-stratified analysis revealed a statistically significant difference in occurrence and number of symptoms between different age groups. During the acute COVID-19 phase an overall difference in the presence of symptoms across age groups (yes/no) (p<0.0001) was observed, with a significantly higher proportion reporting any symptom in the age groups from 18 to 66 years, compared with the youngest and the oldest (p= 0.01 -p=0.005) ( Supplementary Fig 1) . The youngest age group (0-17 years) reported significantly fewer symptoms, compared with age groups 35-49 (p=0.03) and 50-67 (p=0.03), but comparable symptoms with the oldest age group (67+). Otherwise, there were no differences across age groups in the presence, the amount, or regarding severity of symptoms (Supplementary Fig. 1 and 2).

At the follow-up, symptoms persisted significantly more frequently among individuals in the age group 50-66 compared with the youngest groups (0-17 years, p=0.003; 18-34 years, p=0.001), but not with the two other groups. There was no difference regarding the presence or severity of persistent symptoms, but symptoms seemed to be more persistent with increasing age (Supplementary Fig. 3 ).

No differences were found in presence or severity of symptoms with regard to hospitalization, sex, smoking, self-reported medication use, or chronic diseases overall, or for A c c e p t e d M a n u s c r i p t 8 each of the most prevalent diseases (hypertension, asthma, hypercholesterolemia, or diabetes type 2) (data not shown).

In this study, we followed 180 individuals after recovery from active COVID-19 for the assessment of long COVID. In the study population, 53.1% reported persistence of at least one symptom after a mean of 125 days, in particular fatigue, loss of smell and taste, and arthralgia. Most studies to date have focused on symptoms duration and clinical outcomes in adults hospitalized with severe COVID-19 [4, 5, 8, 9] . Our results show that it might take months for symptoms to resolve, and for patients to return to normal health, even among nonhospitalized patients. More than half of the participants reported symptoms for a period of 125 days after active disease, with variable severity; 8.9% reported severe persistent symptoms. Further, analyzing paired data revealed that loss of smell and fatigue was the symptom that most patients reported both during the acute COVID-19 phase and the last follow-up.

An Italian study (n=147) assessed persistent symptoms in patients discharged from hospital after recovery from COVID-19 and found that after a mean of 60.3 days, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea [4] . In our study sample the occurrence of persistent symptoms is somewhat lower (53.1%), which might be expected due to longer follow-up and since our sample represents all COVID-19 disease courses, i.e. mild, moderate, severe disease, and only 8 hospitalized patients. Another longitudinal study from China (n=538) reported that 49.6% of recovered patients who had been hospitalized had one or more common symptoms, including physical decline, fatigue, A c c e p t e d M a n u s c r i p t 9 and myalgia three months after discharge [5] . This result is more in line with our estimate of 53.1%, despite that our study almost entirely included non-hospitalized patients; only eight patients have been hospitalized. Thus, our results reveal that long COVID with variable severity occur in a high proportion of individuals affected by COVID-19, even among those with mild disease courses in the acute phase.

No gender difference was observed in prevalence of acute or long-term symptoms, and similarly symptom occurrence did not vary according to pre-existing chronic disease, smoking status, or medication use. This stands somewhat in contrast to other studies [5] , but may reflect differences in the study samples. Our study sample consists of relatively young COVID-19 patients with generally mild courses. On the other hand, low statistical power might explain that we are not able to substantiate any differences according to sex or morbidity.

Age, however, seems to play a role in the symptom presentation. The middle-aged individuals seem most affected in the acute phase with the highest occurrence of presenting with symptoms, the highest mean number of symptoms, and the highest frequency of severe symptoms ( Supplementary Fig. 3 ). However, in the post COVID-19 period, a tendency of relatively more persistent symptoms with increasing age was observed. The difference between the proportion reporting any symptom diminished with age from 51% reduction among the youngest age group to 17% among the oldest. Thus, the symptoms, although at a lower prevalence, seem to be more persistent among the oldest age group. 

Our results show it might take months for symptoms to resolve, even among non-hospitalized persons with milder illness course in the acute phase. The most persistent symptoms reported were fatigue, loss of smell and taste, and arthralgia. Studying the symptoms of COVID-19 and long COVID is critical for understanding the full natural history of the disease, accurately predicting the disease's cumulative impact beyond hospitalization and mortality and continues monitoring for long COVID is needed. Our results highlight the need to quantify long COVID properly and accurately to create better guidance on how to improve investigation in patients with enduring symptoms. To further study long COVID in Faroese patients, a comprehensive medical assessment with detailed history and physical examination is now offered to all study participants. M a n u s c r i p t 18 

Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

The New Challenge of Geriatrics: Saving Frail Older People from the SARS-COV-2 Pandemic Infection

Long COVID: let patients help define long-lasting COVID symptoms

Persistent Symptoms in Patients After Acute COVID-19

Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

Seroprevalence of SARS-CoV-2-Specific Antibodies, Faroe Islands

Quality of life research : an international journal of quality of life aspects of treatment

Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Clinical Characteristics of Coronavirus Disease 2019 in China

Spread of SARS-CoV-2 in the Icelandic Population

Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship

Clinical characteristics of 3,062 COVID-19 patients: a metaanalysis

Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo'

Acute COVID-19 phase Last post COVID-19 follow-up

The work was supported by the cooperation's p/f Krúnborg and Bortartún. We wish to thank all participating individuals. The authors declare that they have no conflicts of interest.

None

A c c e p t e d M a n u s c r i p t 13 A c c e p t e d M a n u s c r i p t 19 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t