Associations of Post-Acute COVID syndrome with physiological and clinical measures 10 months after hospitalization in patients of the first wave

Published:November 25, 2021DOI:https://doi.org/10.1016/j.ejim.2021.10.031

      Highlights

      • Prevalence of symptoms high 10 months after acute COVID-19 disease.
      • Lung function and exercise capacity close to normal after 10 months.
      • No correlation between symptoms and somatic functional impairments.
      • Correlation between scores for depression/HrQoL and major symptoms.

      Abstract

      Background

      For a better understanding of the factors underlying the Post-Acute COVID Syndrome, we studied the relationship between symptoms and functional alterations in COVID-19 patients 10 months after hospitalization.

      Methods

      One-hundred-one patients hospitalized between March 1st and June 30th 2020 participated in a follow-up visit for an assessment of clinical history, comorbidities, lung function, physical capacity and symptoms, including the SGRQ for health-related quality of life, PHQ-9-D for depression, and SOMS-2 J for somatoform disorders. Data were analyzed by univariate comparisons and multiple logistic regression analyses.

      Results

      Median age was 60 years, 42% were female, 76% had at least one comorbidity, the median length of the hospital stay was 8 days, 19% had been on the ICU. The most prevalent symptoms included shortness of breath (49%), fatigue (49%) and cognitive impairment (39%). Signs of major depression (PHQ-9-D ≥ 10) occurred in 28%/2% (p < 0.05) of patients with/without self-reported cognitive impairment, with median total SGRQ score being 25.4/5.3 (p < 0.05). There were associations between shortness of breath and BMI, SGRQ and hemoglobin levels; between fatigue, SGRQ and PHQ-9-D; and between cognitive impairment and PHQ-9-D (p < 0.05 each) but not with lung function or physical capacity. Characteristics of the acute disease were not related to symptoms.

      Conclusions

      The findings demonstrate that 10 months after discharge from a hospital stay due to COVID-19, the percentages of patients with symptoms were high. Symptoms showed a consistent pattern but could not be attributed to altered lung function or physical capacity. Our results suggest a role for alternative etiologies including psychosocial factors.

      Keywords

      1. Introduction

      Since the beginning of the COVID-19 pandemic in 2020, in Germany almost 3.8 million inhabitants have been positively tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [

      Robert Koch Institut (2021), COVID-19: Fallzahlen in deutschland und weltweit, in: rki.de, 11/08/2021, https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Fallzahlen.html, accessed: 11/08/2021.

      ], and 91,803 inhabitants have been reported as having died from or in association with SARS-CoV-2 [

      European Centre for disease prevention and control (2021), COVID-19 situation update for the EU/EEA, as of 10 August 2021, in: ecdc.europa.eu, 10/08/2021, https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea, accessed: 08/08/2021.

      ]. The spectrum of clinical signs and manifestations ranges from asymptomatic, mild influenza-like signs such as fever, cough and sore throat to severe pneumonias with respiratory failure, multi-organ failure and death [
      • Richardson S.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area.
      ,
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Chen N.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Wiersinga W.J.
      • et al.
      Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.
      ,
      • Wang D.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan.
      ]. Age and comorbidities are the most important risk factors for a clinically severe course or death [
      • Budweiser S.
      • et al.
      Patients' treatment limitations as predictive factor for mortality in COVID-19: results from hospitalized patients of a hotspot region for SARS-CoV-2 infections.
      ,
      • Dorjee K.
      • et al.
      Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: a comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients.
      ,
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ]. The Bavarian region of Rosenheim was among the German hotspots in the first wave, and from March to June 2020, 526 patients were hospitalized in three hospitals of the RoMed health care provider. Of these, in total 27% died, specifically 20% of patients treated on normal wards and 49% of patients of intensive care units (ICU) [
      • Budweiser S.
      • et al.
      Patients' treatment limitations as predictive factor for mortality in COVID-19: results from hospitalized patients of a hotspot region for SARS-CoV-2 infections.
      ].
      Many patients who survived still report complaints weeks or months after initial recovery [
      • Boari G.E.M.
      • et al.
      Short-term consequences of SARS-CoV-2-related pneumonia: a follow up study.
      ,
      • Carvalho-Schneider C.
      • et al.
      Follow-up of adults with noncritical COVID-19 two months after symptom onset.
      ,
      • Logue J.K.
      • et al.
      Sequelae in adults at 6 months after COVID-19 infection.
      ,
      • Mahmud R.
      • et al.
      Post-COVID-19 syndrome among symptomatic COVID-19 patients: a prospective cohort study in a tertiary care center of Bangladesh.
      ,
      • Nehme M.
      • et al.
      Prevalence of symptoms more than seven months after diagnosis of symptomatic COVID-19 in an outpatient setting.
      ,
      • Vaes A.W.
      • et al.
      Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members.
      ,
      • Carfi A.
      • et al.
      Persistent symptoms in patients after acute COVID-19.
      ,
      • Augustin M.
      • et al.
      Post-COVID syndrome in non-hospitalized patients with COVID-19: a longitudinal prospective cohort study.
      ,
      • Kuehn B.M.
      Most patients hospitalized with COVID-19 have lasting symptoms.
      ,
      • Nasserie T.
      • et al.
      Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review.
      ,
      Writing Committee for the Comebac Study Group
      Four-month clinical status of a cohort of patients after hospitalization for COVID-19.
      ]. If the complaints or health-disorders persist for more than 4 weeks and cannot be explained by another disease, the set of signs and symptoms is termed „Post-Acute COVID Syndrome“ (PACS), which includes sequelae occurring after ≥ 12 weeks [

      Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19. Lledó, G., Sellares J., Brotons C., Sans M., Díez, J., Blanco J., Bassat Q., Sarukhan A., Campins M., Guerri R., Miró J.M., de Sanjose, S. (2021), Post-Acute COVID Syndrome (PACS): definition, impact and management, in: isglobal.org, http://hdl.handle.net/2445/178471, accessed: 11/10/2021.

      ]. It can comprise impairments in cognitive function and well-being [
      • Gautam N.
      • et al.
      Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection.
      ,
      • Raman B.
      • et al.
      Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
      ,
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ], as well as impairments of lung function [
      • Gautam N.
      • et al.
      Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection.
      ,
      • Bellan M.
      • et al.
      Respiratory and psychophysical sequelae among patients with COVID-19 four months after hospital discharge.
      ,
      • Ekbom E.
      • et al.
      Impaired diffusing capacity for carbon monoxide is common in critically ill COVID-19 patients at four months post-discharge.
      ,
      • Guler S.A.
      • et al.
      Pulmonary function and radiological features four months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
      ,
      • Sibila O.
      • et al.
      Lung function sequelae in COVID-19 patients 3 months after hospital discharge.
      ,
      • Smet J.
      • et al.
      Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection.
      ,
      • Havervall S.
      • et al.
      Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers.
      ] and 6 min walk distance (6-MWD) [
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ,
      • Huang C.
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ], which only partially correlate with the severity of the acute disease [
      • Mahmud R.
      • et al.
      Post-COVID-19 syndrome among symptomatic COVID-19 patients: a prospective cohort study in a tertiary care center of Bangladesh.
      ,
      • Raman B.
      • et al.
      Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
      ,
      • Huang C.
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ,
      • Abdallah S.J.
      • et al.
      Symptoms, pulmonary function and functional capacity four months after COVID-19.
      ,
      • Fernandez-de-Las-Penas C.
      • et al.
      Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: a systematic review and meta-analysis.
      ,
      • Riou M.
      • et al.
      Respiratory follow-up after hospitalization for COVID-19: who and when?.
      ,
      • Strumiliene E.
      • et al.
      Follow-up analysis of pulmonary function, exercise capacity, radiological changes, and quality of life two months after recovery from SARS-CoV-2 pneumonia.
      ]. Fatigue, shortness of breath and deteriorations of the sense of smelling and taste are the most prevalent complaints [
      • Fernandez-de-Las-Penas C.
      • et al.
      Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: a systematic review and meta-analysis.
      ].
      The etiology of these symptoms and their relationship to organ dysfunction are debated, including pulmonological, cardio-vascular, neurological, and psycho-social factors [

      National Institue for Health and Care Excellence (2021), COVID-19 rapid guideline: managing the long-term effects of COVID-19, in: NICE Guidance, https://www.nice.org.uk/guidance/ng188, accessed: 11/08/2021.

      ]. Early reports suggested that in patients with mild acute disease 3 months after hospital admission the subjective impairments did not correspond to impairments in functional measures [
      • Arnold D.T.
      • et al.
      Patient outcomes after hospitalization with COVID-19 and implications for follow-up: results from a prospective UK cohort.
      ]. This, however, might change with longer follow-up time. Recent reports already covered follow-up periods of up to 12 months [
      • Yan X.
      • et al.
      Follow-up study of pulmonary function among COVID-19 survivors 1 year after recovery.
      ,
      • Seessle J.
      • et al.
      Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
      ], but there are no data on the relationship between symptoms and physiological impairments after the rather long follow-up time of 10 months in hospitalized patients. We addressed this question using a panel of functional assessments and questionnaires collecting data on depression, respiratory health-related quality of life (HrQoL) and potential somatization, with the specific aims, (a) to identify the prevalence of major symptoms, (b) to assess their relationship to functional and clinical characteristics.

      2. Material and methods

      2.1 Patient characteristics

      The analysis was based on 526 patients hospitalized between March 1st and June 30th 2020 in one of three RoMed hospitals (Rosenheim, Wasserburg, Bad Aibling) with a positive PCR test for SARS-CoV-2. In the period up to 1st December 2020, finally 166/526 patients (32%) had died. Among the 360 survivors, 95 patients (26%) were excluded (61 not capable of informed consent, 23 due to positive PCR test without clinical correlate, 7 not traceable, 4 without sufficient proficiency in German or English language). Thus, 265 patients (74%) remained for follow-up.

      2.2 Recruitment for follow-up

      In a first step, patients were contacted by post mail and invited to participate in a follow-up visit in the Rosenheim hospital; 102 of 265 patients (38%) sent their formal informed consent, whereas 6 patients denied and 157 did not respond. One of the 102 patients did not attend the visit, thus 101 patients remained for an out-patient follow-up investigation. We additionally tried to contact the 157 non-responders by phone. This was successful in 69 patients, of whom 54 (78%) accepted a phone interview, while 15 denied any participation. In total, we thus had data from 155 of 252 patients included in the study (62%). Data on the hospital stay were taken from COVID-DB-project [
      • Budweiser S.
      • et al.
      Patients' treatment limitations as predictive factor for mortality in COVID-19: results from hospitalized patients of a hotspot region for SARS-CoV-2 infections.
      ,
      • Budweiser S.
      • et al.
      Comparison of the first and second waves of hospitalized patients with SARS-CoV-2.
      ]. Written informed consent was obtained from all participants attending the inpatient assessment, whereas verbal informed consent was obtained from those contacted via phone. Both approaches were approved by the Ethics Committee of the University of Regensburg.

      2.3 Assessments at the study visit

      2.3.1 Symptoms, physical examination and medical history

      In a structured manner, patients were asked for symptoms that had either newly occurred or deteriorated since discharge from the hospital in comparison to the state prior to COVID-19. The list comprised 27 symptoms selected in accordance with the current literature on PACS that were available at the time of the study [
      • Mandal S.
      • et al.
      Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19.
      ,
      • Petersen M.S.
      • et al.
      Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients.
      ] (see supplemental Table S1). The telephone interviews comprised the 9 symptoms that had turned out to be most frequent in the patients undergoing inpatient investigation. The burden from comorbidities was summarized in the Charlson Comorbidity Index (CCI) based on 20 diseases excluding the patient's age [
      • Charlson M.E.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ], as this was carried as explicit predictor. The physical examination comprised a complete physical examination according to the standards of Internal Medicine and included the assessment of blood pressure, heart rate and oxygen saturation (SpO2) by pulse oximetry at rest. Data on COVID-19 were taken from previous work [
      • Budweiser S.
      • et al.
      Patients' treatment limitations as predictive factor for mortality in COVID-19: results from hospitalized patients of a hotspot region for SARS-CoV-2 infections.
      ,
      • Budweiser S.
      • et al.
      Comparison of the first and second waves of hospitalized patients with SARS-CoV-2.
      ]. The analysis of chest computer tomography (CT) scans was performed by an experienced radiologist following guidelines [
      • Salehi S.
      • et al.
      Coronavirus disease 2019 (COVID-19) imaging reporting and data system (COVID-RADS) and common lexicon: a proposal based on the imaging data of 37 studies.
      ].

      2.3.2 Functional and laboratory measures

      Spirometry and bodyplethysmography (Vyaire, Höchberg, Germany) were performed by experienced personnel. We evaluated forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio FEV1/FVC to characterize airway obstruction, moreover residual volume (RV), total lung capacity (TLC) and the ratio RV/TLC to quantify lung hyperinflation or restrictive disorders. Spirometric reference values and the respective LLN (lower limit of normal, 5th percentile) were those of the Global Lung Function Initiative [
      • Quanjer P.H.
      • et al.
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
      ]. For bodyplethysmography, corresponding values including the ULN (upper limit of normal) for RV and RV/TLC, and the LLN for TLC were taken from the European Community for Coal and Steel (ECSC) [
      • Quanjer P.H.
      • et al.
      Lung volumes and forced ventilatory flows.
      ].
      Physical capacity was assessed by a 6 min walk test performed according to the guidelines of the American Thoracic Society (ATS) [
      A.T.S. Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories
      ATS statement: guidelines for the six-minute walk test.
      ] by asking patients to walk as fast as possible on a course of 30 m length. The resulting 6 min walk distance (6-MWD) was expressed in relation to reference and LLN values [
      • Enright P.L.
      • et al.
      Reference equations for the six-minute walk in healthy adults.
      ].
      Routine laboratory parameters were obtained from a venous blood sample, including the levels of hemoglobin (Hb), d-dimers, creatinine, gamma-glutamyltransferase (GGT) and C-reactive protein (CRP). The estimated glomerular filtration rate (eGFR) was determined from creatinine according to the CKD-EPI-formula [
      • Levey A.S.
      • et al.
      Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions.
      ]. Reference values were those used in the local medical laboratory.

      2.3.3 Questionnaires

      To assess and quantify symptoms of depression, the Patient Health Questionnaire for Depression (PHQ-9-D) was chosen. It comprises 9 items rated from 0 to 3 each, resulting in a maximum score of 27 [
      • Kroenke K.
      • et al.
      The PHQ-9: validity of a brief depression severity measure.
      ,
      • Spitzer R.L.
      • et al.
      Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of mental disorders. Patient health questionnaire.
      ]. To categorize the results regarding potential major depression, a cut-off value of ≥ 7 was chosen, as this had been shown to yield high sensitivity with still satisfactory specificity [
      • Hartung T.J.
      • et al.
      The hospital anxiety and depression scale (HADS) and the 9-item patient health questionnaire (PHQ-9) as screening instruments for depression in patients with cancer.
      ]. We additionally evaluated the clinically more common cut-off of ≥ 10 for major depression requiring at least a score of 2 in the first two questions.
      HrQoL was determined by the St. George's Respiratory Questionnaire (SGRQ). It was chosen because it was initially assumed that impairments were mainly related to respiratory factors. Nonetheless, the questionnaire also contains general questions, for example on activity, and covers a broad range of impairments [
      • Jones P.W.
      • et al.
      A self-complete measure of health status for chronic airflow limitation. The St. George's respiratory questionnaire.
      ]. It comprises 73 items that can be summarized in a total score or three sub-scores (symptoms, activity, impact), ranging from 0 (no limitation) to 100 (maximum limitation).
      Previous data suggested that PACS represents a complex situation potentially involving psycho-social factors that are known to contribute to persistent symptoms in general, even more so after severe somatic disease. This was addressed via the SOMS-2 J (Screening for Somatoform Disorders) questionnaire comprising 68 items [
      • Rief W.H.
      • et al.
      SOMS-das screening für somatoforme störungen. manual zum fragebogen.
      ]. It asks for the presence of somatic symptoms that are a burden in daily life and for which a physician could not identify an objective cause. For the present study, the SOMS-2 J general somatization index, the International Classification of Disease (ICD-10) somatization disorder (SD) index and the ICD-10 somatoform autonomous disorder (SAD) index were calculated. The SOMS-2 J general somatization index summarizes all 53 symptom items, while the SD index and the SAD index summarize the symptoms relevant for the respective diagnosis (F45) according to the ICD-10 and use additional plausibility criteria [
      • Rief W.H.
      • et al.
      SOMS-das screening für somatoforme störungen. manual zum fragebogen.
      ].

      3. Data analysis

      Numeric data are given as median values and quartiles, if suitable with ranges, or as numbers and percentages. Comparisons between groups of patients were performed by the Mann-Whitney U-test, correlation analyses by the Spearman rank correlation coefficient. To reveal independent predictors for key symptoms, binary logistic regression analyses were employed. We used the inclusion of predictors. These were selected according to the results of univariate analyses and pathophysiological plausibility, and we checked for predictors potentially hidden by collinearity by additional stepwise selection procedures. All analyses were performed using the software IBM SPSS (Version 26.0.0.0, Armonk, NY, US). p-values <0.05 were assumed as statistically significant, and these values are given explicitly in the tables.

      4. Results

      4.1 Demographic data of the clinically examined patients

      Basic demographic characteristics and data on the hospital stay during COVID-19 of the 101 patients are given in Table 1A stratified according to sex. This stratification was chosen, as sex had turned out as major determinant of PACS in previous studies [
      • Qu G.
      • et al.
      Health-related quality of life of COVID-19 patients after discharge: a multicenter follow-up study.
      ,
      • Peghin M.
      • et al.
      Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients.
      ,
      • Todt B.C.
      • et al.
      Clinical outcomes and quality of life of COVID-19 survivors: a follow-up of 3 months post hospital discharge.
      ,
      • Xiong Q.
      • et al.
      Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-Centre longitudinal study.
      ,
      • Aparisi A.
      • et al.
      Exercise ventilatory inefficiency in post-COVID-19 syndrome: insights from a prospective evaluation.
      ,
      • Sudre C.H.
      • et al.
      Attributes and predictors of long COVID.
      ]. The median age was 60 (IQR 51–66; range 28–69) years, 58% of patients were male, 35% had a history of smoking, and 76% at least one comorbidity. The median CCI was 0 (0, 7), whereby 61% of patients had a CCI of 0. A previous diagnosis of an obstructive lung disease (either asthma or chronic obstructive pulmonary disease) was present in 10 patients, and none was on long-term oxygen therapy. The median length of the hospital stay was 8 (5, 10; range 2–111) days, 20% of patients had ICU treatment, and 20% participated in an inpatient rehabilitation program after discharge. The time of follow-up was 308 (309, 346; range 226–393) days after admission to the hospital. Table 1A demonstrates significant differences between men and women regarding smoking history and the length of the hospital stay.
      Table 1APatients‘ characteristics grouped by sex.
      All (n = 101)Men (n = 59)Women (n = 42)
      Age (years)60.0 [50.8; 66.0]61.0 [52.5; 66.0]58.0 [49.5; 62.5]
      Smoking history (yes)35 (35%)28 (48%) **7 (17%)
      Follow-up time (days)308 [309; 346]308 [309; 342]311 [309; 350]
      Hospital stay (days)8.0 [5.0; 10.3]8.0 [6.0; 11.5] *7.0 [3.5; 10.5]
      Intensive Care Unit20 (19.8%)14 (23.7%)6 (14.3%)
      Intubation (yes)9 (9%)8 (14%)1 (1%)
      Rehabilitation (yes)20 (20%)12 (20%)8 (19%)
      Any Comorbidity (yes)77 (76%)45 (76%)32 (76%)
      Charlson Score (without age)0 [0; 7]0 [0; 1]0 [0; 1]
      Obstructive lung disease (yes)10 (10%)5 (9%)5 (12%)
      Systemic hypertension (yes)41 (41%)28 (48%)13 (31%)
      Left heart failure (yes)12 (12%)9 (9%)3 (7%)
      Coronary heart disease/MI (yes)16 (16%)12 (20%)4 (10%)
      Diabetes (yes)12 (12%)8 (14%)4 (10%)
      Baseline characteristics of the 101 follow-up participants including characteristics of their hospital stay due to COVID-19. Median values and quartiles (in brackets) are given. MI = history of myocardial infarction. Data are stratified for men and women in order to illustrate the differences. Statistical comparisons were based on the Mann-Whitney U test or Fisher's Exact test. *p < 0.05, ** p < 0.01.

      4.2 Physical examination and functional status

      The physical examination did not reveal pathological results except for one patient with signs of aortic valve stenosis, which was considered not to be related to COVID-19. Data are given in Table 1B including the subgroups of men and women. SpO2 showed a small but statistically significant difference between the two groups, while the statistically significant difference for diastolic blood pressure values depicted the expected dependency on sex. Data from spirometry and bodyplethysmography could be obtained in all 101 patients, whereby 21% showed abnormal findings (<LLN or >ULN, respectively) in at least one of the lung function measures FEV1, FEV1/FVC, FVC, TLC, or RV/TLC. 6-MWD was available in 99 patients, since two used wheelchairs. Laboratory values (Hb, erythrocytes, leucocytes, thrombocytes, eGFR, d-dimers, GGT) were mostly in the normal range, and the majority of clinical and functional measures showed differences between men and women as expected.
      Table 1BFunctional values grouped by sex.
      All (n = 101)Men (n = 59)Women (n = 42)
      Vital parameters
      RRsys (mmHg)130.0 [110.0; 140.0]130.0 [120.0; 140.0]12.00 [110.0; 132.5]
      RRdia (mmHg)80.0 [72.3; 90.0]80.0 [80.0; 90.0] *80.0 [70.0; 80.0]
      Heart rate (1/s)70.0 [64.0; 75.0]70.0 [63.0; 74.5]70.0 [64.5; 76.5]
      BMI (kg/m2)27.5 [25.0; 30.9]27.8 [24.9; 30.8]26.8 [24.1; 31.2]
      SpO2 (%)97.0 [96.8; 98.0]97.0 [96.0; 97.5]97.0 [97.0; 99.0] *
      Lung function/physical capacity
      FEV1 (%predicted)91.6 [82.8; 102.6]91.1 [82.7; 101.1]92.29 [82.9; 104.1]
      FEV1<LLN (no.)14 (14%)8 (14%)6 (14%)
      FEV1/FVC (%)76.9 [71.8; 81.4]76.0 [71.5; 80.09]78.5 [73.1; 84.2]
      FEV1/FVC<LLN (no.)5 (5%)4 (7%)1 (2%)
      FVC (%predicted)94.5 [81.9; 101.6]94.5 [82.9; 100.3]93.78 [79.9; 101.8]
      FVC<LLN (no.)13 (13%)8 (14%)5 (12%)
      TLC (%predicted)109.5 [102.5; 121.7]105.2 [98.6; 121.1]111.6 [107.3; 122.1] *
      TLC<LLN (no.)6 (6%)4 (7%)2 (5%)
      RV/TLC (%predicted)44.1 [105.7; 126.5]43.0 [105.6; 126.0]47.3 [108.3; 129.3]
      RV/TLC>ULN (no.)26 (26%)10 (17%)16 (38%) *
      6-MWD (%predicted) (n = 99)101.9 [88.2; 110.9]101.9 [90.6; 106.2]101.9 [88.1; 114.7]
      6-MWD<LLN (no.)5 (5%)5 (9%)0 (0%)
      Laboratory values
      Hemoglobin (g/dl) (n = 98)14.7 [13. 6; 15.6]15.3 [14.6; 16.2] ***13.7 [12.8; 14.1]
      Leucocytes (x109/l) (n = 98)6.27 [5.38; 7.26]6.19 [5.27; 7.24]6.38 [5.49; 7.66]
      Thrombocytes (Gpt/l) (n = 98)245.5 [212.3; 285.3]231.5 [185.5; 270.0]257.0 [229.0; 298.5] **
      gGT (U/l) (n = 98)30.0 [17.8; 40.5]35.0 [26.0; 51.0] ***21.5 [13.5; 29.0]
      eGFR (ml/min) (n = 98)78.5 [69.0; 99.0]77.0 [69.0; 91.0]82.5 [69.0; 102.0]
      CRP (mg/l) (n = 98)0.16 [0.07; 0.37]0.13 [0.07; 0.27]0.18 [0.07; 0.46]
      D-dimers (μg/l) (n = 56)75.5 [0.0; 186.3]0.0 [0.0; 190.5]154.0 [0.0; 179.5]
      Results of physiological assessments in the 101 follow-up participants expressed as percent predicted, except for FEV1/FVC and SpO2. SpO2 = oxygen saturation from pulse oximetry, FEV1 = forced expiratory volume in 1 s, FVC = forced vital capacity, TLC = total lung capacity, RV = residual volume, 6-MWD = 6 min walk distance, LLN = lower limit of normal, ULN = upper limit of normal. Data are stratified for men and women in order to illustrate the differences. Statistical comparisons were based on the Mann-Whitney U-test or Fisher's Exact test. *p < 0.05, ** p < 0.01, *** p < 0.001.

      4.3 Symptoms

      Upon follow-up, only 10% of patients reported no symptoms (see Table S1), while 51% reported 1–4 symptoms (of 26 symptoms asked) and 39% more than 4 symptoms. The most frequent symptoms were fatigue (49%), shortness of breath (49%), hair loss (41%) and cognitive impairment (39%). Data are shown in Fig. 1 stratified according to sex. Regarding the number of symptoms, women reported more symptoms than men (median 5 versus 3; p = 0.002). The results of the telephone interview can be found in the Supplement (Table S4).
      Fig. 1
      Fig. 1Frequency of symptoms (absolute numbers) in the 101 participants of the follow-up visit. Due to the fact that the total number was n = 101, the numerical values of percentages are virtually the same. Data are given separately for males (blue) and females (red).

      4.4 Mental health, health related quality of life and somatization

      The respective data are given in Table 1C stratified according to sex. In the PHQ-9-D questionnaire, 20 patients (20%) had a score of ≥ 7, indicating hints for major depression, and 5 patients reported signs of a major depression (score ≥ 10). A previous diagnosis of depression was known in only 3 of the 20 patients, and in 6 of all 101 patients asked, while it was known only in 1 of the 5 patients with signs of a major depression. Women had a higher median PHQ-9-D score than men (p = 0.002) and a higher risk of suspicious values ≥ 7 (7% of men versus 38% of women; p < 0.001).
      Table 1CQuestionnaire results grouped by sex.
      All (n = 101)Men (n = 59)Women (n = 42)
      PHQ-9-D Score3.0 [1.0; 6.3]2.0 [0.0; 2.0]5.0 [3.0; 12.0] **
      SGRQ Activity Score18.4 [6.0; 43.1]12.17 [0.0; 29.3]24.32 [15.6; 56.9] *
      SGRQ Impact Score3.6 [0.0; 18.7]0.0 [0.0; 5.6]10.2 [0.0; 25.1] **
      SGRQ Total Score12.2 [1.9; 25.7]5.7 [1.7; 15.6]16.7 [7.7; 34.4] *
      SOMS-2 J general somatization index3.0 [0.0; 8.0]2.0 [0.0; 5.0]4.5 [0.0; 12.3]
      SOMS-2 J SD index0.0 [0.0; 0.0]0.0 [0.0; 0.0]0.0 [0.0; 0.0]
      SOMS-2 J SAD index0.0 [0.0; 2.0]0.0 [0.0; 1.0]0.5 [0.0; 3.3] *
      Results of questionnaires in the 101 follow-up participants. Data are stratified for men and women in order to illustrate the differences. Statistical comparisons were based on the Mann-Whitney U-test. *p < 0.05, ** p < 0.01.
      The total score and the sub-scores of the SGRQ questionnaire can also been found in Table 1C. There were significantly higher scores, i.e. lower quality of life, in women compared to men regarding the total score as well as all sub-scores (symptoms, activity, impact, p < 0.05 each).
      Regarding SOMS-2 J, the median (quartiles) of the general somatization index was 3 (0; 8), the SAD index was 0 (0; 2). Formally, with the SD index being 0 in all patients, no patient met the criteria for a somatization disorder according to ICD-10. A summary of symptoms, assessments of mental health and clinical and functional data is given in Fig. 2.
      Fig. 2
      Fig. 2Percentages of patients in the follow-up visit (n = 101) showing specific counts of symptoms (red) or abnormal values according to LLN or ULN for lung function and physical performance (blue). SpO2 = oxygen saturation from pulse oximetry, FEV1 = forced expiratory volume in 1 s, TLC = total lung capacity, 6-MWD = 6 min walk distance, LLN = lower limit of normal. For functional measures, percentages were in the range of 5% that is expected by definition in a normal population, except for FEV1, possibly because of the fact that about 10% of patients had a history of obstructive airway disease.

      4.5 Stratification of characteristics according to symptoms

      Major symptoms at follow-up were shortness of breath, fatigue and cognitive impairment; we omitted hair loss as it might have causes not addressed in the set of available variables. Table S2A–S2C show the same data as Table 1A1C but stratified according to the presence of shortness of breath, fatigue and cognitive impairment. In univariate comparisons (Mann-Whitney U-test) between the groups of patients reporting one of these symptoms or not, women reported shortness of breath and fatigue more frequently than men. There were no statistically significant relationships between the three major symptoms and any functional value. Patients reporting the three selected symptoms scored significantly higher in all scores administered (PHQ-9-D, SGRQ, SOMS-2 J). The results of further comparisons are given as figures below.
      As illustrated in Fig. 3A, 3B and 3C, at follow-up none of the functional measures showed a significant difference between the groups reporting or not reporting shortness of breath, fatigue and cognitive impairment. Fig. 4A, 4B and 4C show the scores of the PHQ-9-D and SGRQ stratified in the same manner. All scores significantly differed between groups defined via shortness of breath, fatigue or cognitive impairment (p < 0.004 each).
      Fig. 3A
      Fig. 3ABox plots of functional measures in percent predicted, or percentages for SpO2 and FEV1/FVC, for the two groups of patients either reporting or not reporting shortness of breath at the follow-up visit. SpO2 = oxygen saturation from pulse oximetry, FEV1 = forced expiratory volume in 1 s, FVC = forced vital capacity, TLC = total lung capacity, RV = residual capacity, 6-MWD = 6 min walk distance. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. In none of the measures there were statistically significant differences between the two groups (Mann-Whitney U-test).
      Fig. 3B
      Fig. 3BBox plots of functional measures in percent predicted, or percentages for SpO2 and FEV1/FVC, for the two groups of patients either reporting or not reporting fatigue at the follow-up visit. SpO2 = oxygen saturation from pulse oximetry, FEV1 = forced expiratory volume in 1 s, FVC = forced vital capacity, TLC = total lung capacity, RV = residual capacity, 6-MWD = 6 min walk distance. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. In none of the measures there were statistically significant differences between the two groups (Mann-Whitney U-test).
      Fig. 3C
      Fig. 3CBox plots of functional measures in percent predicted, or percentages for SpO2 and FEV1/FVC C, for the two groups of patients either reporting or not reporting cognitive impairment at the follow-up visit. SpO2 = oxygen saturation from pulse oximetry, FEV1 = forced expiratory volume in 1 s, FVC = forced vital capacity, TLC = total lung capacity, RV = residual capacity, 6-MWD = 6 min walk distance. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. In none of the measures there were statistically significant differences between the two groups (Mann-Whitney U-test).
      Fig. 4A
      Fig. 4ABox plots of the scores of the PHQ-9-D and SGRQ (total and three sub-scores) for the two groups of patients either reporting or not reporting shortness of breath at the follow-up visit. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. There were statistically significant differences between the two groups (p < 0.05 each, Mann-Whitney U-test) for all of the scores.
      Fig. 4B
      Fig. 4BBox plots of the scores of the PHQ-9-D and SGRQ (total and three sub-scores) for the two groups of patients either reporting or not reporting fatigue at the follow-up visit. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. There were statistically significant differences between the two groups (p < 0.05 each, Mann-Whitney U-test) for all of the scores.
      Fig. 4C
      Fig. 4CBox plots of the scores of the PHQ-9-D and SGRQ (total and three sub-scores) for the two groups of patients either reporting or not reporting cognitive impairment at the follow-up visit. The boxes indicate the quartiles, the horizontal bar the median value, the whiskers the 10- and 90-percentiles, and the circles points outside of these. There were statistically significant differences between the two groups (p < 0.05 each, Mann-Whitney U-test) for all of the scores.

      4.6 Associations with symptoms in multivariate analyses

      As these factors were not necessarily independent of each other and differences might be due to confounding, we performed logistic regression analyses for each of the three symptoms. The predictors included those revealed as potentially relevant in the simple comparisons as well as predictors that could become relevant in multivariate analyses. As covariates we thus included age, sex, smoking status (active vs. non-active), SpO2, BMI, 6-MWD as measure of physical capacity, FEV1 (%predicted) as measure of airway obstruction, RV/TLC (%predicted) as measure of trapped air, the PHQ-9-D score, SGRQ total score, sex-adjusted hemoglobin (by multiplication of the women's Hb value with the ratio of the World Health Organization's mean reference values for men (16 g/dL) and women (14 g/dL)), and the SOMS-2 J SAD index.
      Table S3 shows the Odds Ratios for the three symptoms and the predictors. Shortness of breath was related to BMI, SGRQ and Hb (p < 0.05 each), fatigue was related to PHQ-9-D and SGRQ (p < 0.05 each), and cognitive impairment was related to PHQ-9-D (p < 0.05) but not to the SOMS-2 J SAD index. There was, however, an association with the SOMS-2 J general somatization index, if this was used as predictor instead of the SAD index.

      4.7 Relationship to clinical history during the hospital stay

      A further factor relevant for the symptoms reported at follow-up could be the clinical history experienced during the hospital stay. For this purpose, again logistic regression analyses of the three symptoms were performed, including parameters assessed during the inpatient situation. The predictors comprised ICU treatment, length of hospital stay, invasive ventilation, CCI (without age), age, SpO2 upon admission, renal dysfunction (eGFR< 60 /min), the concentration of lactate dehydrogenase (LDH), and the administration of anti-coagulative therapy or systemic steroids. Shortness of breath was not dependent on any of these covariates (p > 0.05 each). The same was true for fatigue and cognitive impairment. Moreover, lung function values of patients with ICU treatment were not different from the values of patients treated on the normal ward (p > 0.1 for all measures evaluated).
      During the hospital stay, chest CT scans had been obtained in 65 of the 101 patients. In a further logistic regression analysis, the percentage of lung affected by COVID-19 during the hospital stay according to CT imaging was added as predictor to those mentioned above, again for shortness of breath, fatigue and cognitive impairment as outcomes. None of the three symptoms showed a significant relationship to the CT parameter.

      5. Discussion

      The major finding of our study is that 10 months after acute COVID-19 neither the current somatic functional status of the patient nor the characteristics of the previous hospital stay were related to the presence of three major symptoms associated with PACS. To the best of our knowledge, we present the data with the longest follow-up comprising data on both functional and subjective alterations.
      As major symptoms, shortness of breath, fatigue and cognitive impairment were reported by 39 to 49% of patients, and only 10% reported no symptoms at all. This result is consistent with previous findings on reduced self-reported exercise capacity (53.1%), fatigue (41.7%), sleeping problems (32.3%), concentration problems (31.3%) and dyspnea (27.1%) as major symptoms after 12 months, while 23% of patients reported no symptom [
      • Seessle J.
      • et al.
      Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
      ]. However, only 30% of the patients of this previous study were hospitalised, and the median age was slightly smaller (57 vs. 60 years in our cohort).
      We also found the symptom burden not to be related to characteristics of the previous hospital stay, particularly the severity of COVID-19, which goes along with data from shorter follow-up times in previous studies [
      • Riou M.
      • et al.
      Respiratory follow-up after hospitalization for COVID-19: who and when?.
      ,
      • Aparisi A.
      • et al.
      Exercise ventilatory inefficiency in post-COVID-19 syndrome: insights from a prospective evaluation.
      ,
      • Frija-Masson J.
      • et al.
      Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days post-infection.
      ,
      • Garrigues E.
      • et al.
      Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19.
      ,
      • Taylor R.R.
      • et al.
      Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia.
      ]. In some studies, however, a positive correlation between the severity of the COVID-19 disease and the symptom burden at follow-up had been found [
      • Mahmud R.
      • et al.
      Post-COVID-19 syndrome among symptomatic COVID-19 patients: a prospective cohort study in a tertiary care center of Bangladesh.
      ,
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ,
      • Fernandez-de-Las-Penas C.
      • et al.
      Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: a systematic review and meta-analysis.
      ,
      • Peghin M.
      • et al.
      Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients.
      ,
      • Xiong Q.
      • et al.
      Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-Centre longitudinal study.
      ,
      • Zhang S.
      • et al.
      Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors.
      ]. This heterogeneity could be due to different classifications of disease severity or not yet specified subtypes of the virus or the fact that studies employed different tools, such as personal interview, phone interview and online survey. Moreover, in our study the number of patients with invasive ventilation was too low to draw reliable conclusions.
      In the present cohort, lung function as well as physical capacity assessed by 6 min walk test, showed distributions not markedly different from those in normal populations and were not related to the characteristics of the hospital stay, particularly with respect to disease severity. This is consistent with data that shows that 12 months after COVID-19 values of spirometry and bodyplethysmography were <LLN in less than 10% of patients (except for a reduction of TLC in 42%), independently from the severity of the disease during inpatient treatment (WHO guideline severity scale) [
      • Yan X.
      • et al.
      Follow-up study of pulmonary function among COVID-19 survivors 1 year after recovery.
      ,

      World Health Organization (2021), Clinical management of severe acute respiratory infection when COVID-19 disease is suspected: interim guidance, in: who.int, https://www.who.int/publications/i/item/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected, accessed: 11/08/2021.

      ]. When assessed up to 8 months after hospitalization, some studies reported a significant relationship between the current functional impairment and the previous severity of the disease [
      • Raman B.
      • et al.
      Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
      ,
      • Guler S.A.
      • et al.
      Pulmonary function and radiological features four months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
      ,
      • Smet J.
      • et al.
      Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection.
      ,
      • Huang C.
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ,
      • Riou M.
      • et al.
      Respiratory follow-up after hospitalization for COVID-19: who and when?.
      ,
      • Strumiliene E.
      • et al.
      Follow-up analysis of pulmonary function, exercise capacity, radiological changes, and quality of life two months after recovery from SARS-CoV-2 pneumonia.
      ,
      • Zhang S.
      • et al.
      Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors.
      ,
      • Debeaumont D.
      • et al.
      Cardiopulmonary exercise testing to assess persistent symptoms at 6 months in people with COVID-19 who survived hospitalization-a pilot study.
      ], while others did not [
      • Gautam N.
      • et al.
      Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection.
      ,
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ,
      • Frija-Masson J.
      • et al.
      Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days post-infection.
      ,
      • Lerum T.V.
      • et al.
      Dyspnoea, lung function and CT findings 3 months after hospital admission for COVID-19.
      ]. The situation is complicated by a potential interplay between persistent symptoms and functional alterations that could be promoted by changes in behavior, for example regarding physical capacity or anxiety and depression. This probably renders associations increasingly difficult to detect after a longer time-lag from the acute disease, suggesting to a multi-dimensional etiology.
      We furthermore observed a lack of correlation between functional status and symptom burden, in line with previous findings obtained after 75 days or 3 and 6 months [
      • Arnold D.T.
      • et al.
      Patient outcomes after hospitalization with COVID-19 and implications for follow-up: results from a prospective UK cohort.
      ,
      • Aparisi A.
      • et al.
      Exercise ventilatory inefficiency in post-COVID-19 syndrome: insights from a prospective evaluation.
      ,
      • Townsend L.
      • et al.
      Persistent poor health after COVID-19 is not associated with respiratory complications or initial disease severity.
      ]. Other investigators, however, found that patients with a higher symptom burden had more impaired lung function after 2.5 or 3–6 months [
      • Smet J.
      • et al.
      Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection.
      ,
      • Fortini A.
      • et al.
      COVID-19: persistence of symptoms and lung alterations after 3–6 months from hospital discharge.
      ]. The lack of association in our study is illustrated in the supplemental Fig. S1A and S1B. Patients reporting either shortness of breath or fatigue were distributed over the middle part of the scatter plot, although one might have expected that, for example, patients with fatigue or shortness of breath showed a lower 6-MWD at a given FEV1.
      A worsened quality of life is a fairly consistent finding for PACS [
      • Gautam N.
      • et al.
      Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection.
      ,
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ,
      • Havervall S.
      • et al.
      Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers.
      ,
      • Qu G.
      • et al.
      Health-related quality of life of COVID-19 patients after discharge: a multicenter follow-up study.
      ,
      • Todt B.C.
      • et al.
      Clinical outcomes and quality of life of COVID-19 survivors: a follow-up of 3 months post hospital discharge.
      ,
      • Gianella P.
      • et al.
      Clinical, radiological and functional outcomes in patients with SARS-CoV-2 pneumonia: a prospective observational study.
      ,
      • Rass V.
      • et al.
      Neurological outcome and quality of life 3 months after COVID-19: a prospective observational cohort study.
      ]. In the absence of reference values for the SGRQ we could not define an overall worsened HrQoL, but data were consistent regarding their correlation with shortness of breath and fatigue, suggesting that we asked for important factors underlying the overall impairment in quality of life. Regarding fatigue and cognitive impairment, a similar tendency was observed for the PHQ-9-D as a score for depression. The PHQ-9-D is sensitive to impairments from respiratory disease in patients with COPD [
      • von Siemens S.M.
      • et al.
      Effect of COPD severity and comorbidities on the result of the PHQ-9 tool for the diagnosis of depression: results from the COSYCONET cohort study.
      ] but in our study population the percentage of patients with a history of such disease was small and lung function normal or close to normal.
      Thus, it is likely that we measured the PHQ-9-D unbiased and that the scores indeed indicated depression. As the PHQ-9-D is not subject to gender bias [
      • Thibodeau M.
      • et al.
      The PHQ-9 assesses depression similarly in men and women from the general population.
      ], the higher prevalence of post-COVID-19 depression in women in our cohort appeared to be a valid result. The fact that HrQoL was lower and the prevalence of depression higher than in a control group never tested positive for SARS-CoV-2 [
      • Logue J.K.
      • et al.
      Sequelae in adults at 6 months after COVID-19 infection.
      ,
      • Raman B.
      • et al.
      Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
      ], suggests that the deterioration of mental health is not simply due to the impact of the pandemic on the whole population's mental health [
      • Bauerle A.
      • et al.
      Increased generalized anxiety, depression and distress during the COVID-19 pandemic: a cross-sectional study in Germany.
      ], but that PACS itself bears a greater risk for psychological suffering [
      • Mary-Krause M.
      • et al.
      Impact of COVID-19-like symptoms on occurrence of anxiety/depression during lockdown among the French general population.
      ].
      The SOMS-2 J general index was related to cognitive impairment. This is remarkable, as by design the SOMS-2 J aims to assess symptoms that are not sufficiently explained by organic dysfunction and for which a physician could not identify an objective cause. In the current, complicated situation, one might expect that patients are inclined to attribute symptoms to somatic deteriorations associated with COVID-19, leading to a lower sensitivity of SOMS-2 J. Our findings suggest the potential relevance of psycho-social factors and somatization in addition to somatic factors.

      5.1 Limitations and strengths

      The present study focused on hospitalized patients and did not comprise patients without hospital admission. We had pre-COVID values (via cooperation with general practitioners) in only 17 patients, and no statistically valid, unbiased comparison was possible due to this low number. Moreover, the differences regarding laboratory parameters obtained during the hospital stay were trivial as they only indicated the end of the acute disease. Therefore, we had to perform a cross-sectional analysis. Moreover, there was no matched control group without previous COVID-19 that would have allowed to estimate the distribution of symptoms and functional measures for comparison. This could have been relevant, as depression scores, for example, might also have been affected in non-COVID patients, for example in relation to the lock-down [
      • Augustin M.
      • et al.
      Post-COVID syndrome in non-hospitalized patients with COVID-19: a longitudinal prospective cohort study.
      ,
      • Andersen A.J.
      • et al.
      Symptoms of anxiety/depression during the COVID-19 pandemic and associated lockdown in the community: longitudinal data from the TEMPO cohort in France.
      ]. On the other hand, at least for lung function measures, the percentages of potentially abnormal values were in the 5 percent range expected from the definition of the LLN or ULN. Due to organizational factors, we could not include the assessment of CO diffusing capacity of the lung, which might have been a marker of vascular alterations [
      • van den Borst B.
      • et al.
      Comprehensive health assessment three months after recovery from acute COVID-19.
      ,
      • Provencher S.
      • et al.
      COVID-19 and the pulmonary vasculature.
      ,
      • Heckman E.J.
      • et al.
      Pulmonary function tests for diagnosing lung disease.
      ]. The results of the phone interviews (see Supplement) did not suggest a major bias in the group of subjects studied in the hospital, particularly not the selection of less symptomatic patients. A strength of the study is that we had detailed information on the COVID-19 related hospital stay and that we aimed to analyze and confirm the symptoms by using three standard questionnaires.

      6. Conclusions

      Our findings indicate that 10 months after discharge from a COVID-19 set off inpatient treatment, the prevalence of symptoms was high, especially that of shortness of breath, fatigue and cognitive impairment. Symptoms and scores of depression and HrQoL showed gender-dependent differences and a consistent relationship to each other, but could not be attributed to alterations in lung function or physical capacity at the time of the follow-up, or to major characteristics of the hospital stay. The associations between shortness of breath and lower hemoglobin concentration at the follow-up, and between fatigue or cognitive impairment and hints for depression, especially in women, might be helpful in the clinical assessment of post-COVID-19 patients but the results also suggest to consider alternative etiologies including psychosocial factors.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      None.

      Acknowledgments

      We are grateful to all patients who participated in the follow-up and phone calls. We also thank the staff engaged in the coordination of the follow-up appointments (Annika Rotter, Roswitha Schmid, Christine Ehrl, Claudia Scharnagl, Veronika Ruml), the staff in the lung function laboratory (Sonja Silbernagl, Cornelia Dick), as well as Jens Deerberg-Wittram MD, CEO of RoMed, and Max v. Holleben, business administration manager Klinikum Rosenheim, for providing the technical and organizational environment needed for the study. Moreover, we thank Sevki Baş, Hedwig Grella, Ayşenur Kaya, Anja Krams, Julia Reiser, Sophie Gast, Antje Parstorfer, Sabine Leidl, Katarina Vlajic, Bardha Krivaqa and Katharina Thaler, who were involved in the updates of the database COVID-DB.

      Appendix. Supplementary materials

      References

      1. Robert Koch Institut (2021), COVID-19: Fallzahlen in deutschland und weltweit, in: rki.de, 11/08/2021, https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Fallzahlen.html, accessed: 11/08/2021.

      2. European Centre for disease prevention and control (2021), COVID-19 situation update for the EU/EEA, as of 10 August 2021, in: ecdc.europa.eu, 10/08/2021, https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea, accessed: 08/08/2021.

        • Richardson S.
        • et al.
        Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area.
        JAMA. 2020; 323: 2052-2059https://doi.org/10.1001/jama.2020.6775
        • Huang C.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
        China Lancet. 2020; 395: 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
        • Guan W.J.
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720https://doi.org/10.1056/NEJMoa2002032
        • Chen N.
        • et al.
        Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
        Lancet. 2020; 395: 507-513https://doi.org/10.1016/S0140-6736(20)30211-7
        • Wiersinga W.J.
        • et al.
        Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.
        JAMA. 2020; 324: 782-793https://doi.org/10.1001/jama.2020.12839
        • Wang D.
        • et al.
        Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan.
        China JAMA. 2020; 323: 1061-1069https://doi.org/10.1001/jama.2020.1585
        • Budweiser S.
        • et al.
        Patients' treatment limitations as predictive factor for mortality in COVID-19: results from hospitalized patients of a hotspot region for SARS-CoV-2 infections.
        Respir Res. 2021; 22: 168https://doi.org/10.1186/s12931-021-01756-2
        • Dorjee K.
        • et al.
        Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: a comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients.
        PLoS ONE. 2020; 15e0243191https://doi.org/10.1371/journal.pone.0243191
        • Zhou F.
        • et al.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        Lancet. 2020; 395: 1054-1062https://doi.org/10.1016/S0140-6736(20)30566-3
        • Boari G.E.M.
        • et al.
        Short-term consequences of SARS-CoV-2-related pneumonia: a follow up study.
        High Blood Press Cardiovasc Prev. 2021; https://doi.org/10.1007/s40292-021-00454-w
        • Carvalho-Schneider C.
        • et al.
        Follow-up of adults with noncritical COVID-19 two months after symptom onset.
        Clin Microbiol Infect. 2021; 27: 258-263https://doi.org/10.1016/j.cmi.2020.09.052
        • Logue J.K.
        • et al.
        Sequelae in adults at 6 months after COVID-19 infection.
        JAMA Netw Open. 2021; 4e210830https://doi.org/10.1001/jamanetworkopen.2021.0830
        • Mahmud R.
        • et al.
        Post-COVID-19 syndrome among symptomatic COVID-19 patients: a prospective cohort study in a tertiary care center of Bangladesh.
        PLoS ONE. 2021; 16e0249644https://doi.org/10.1371/journal.pone.0249644
        • Nehme M.
        • et al.
        Prevalence of symptoms more than seven months after diagnosis of symptomatic COVID-19 in an outpatient setting.
        Ann Intern Med. 2021; https://doi.org/10.7326/M21-0878
        • Vaes A.W.
        • et al.
        Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members.
        ERJ Open Res. 2021; 7https://doi.org/10.1183/23120541.00141-2021
        • Carfi A.
        • et al.
        Persistent symptoms in patients after acute COVID-19.
        JAMA. 2020; 324: 603-605https://doi.org/10.1001/jama.2020.12603
        • Augustin M.
        • et al.
        Post-COVID syndrome in non-hospitalized patients with COVID-19: a longitudinal prospective cohort study.
        Lancet Reg Health Eur,. 2021; 6100122https://doi.org/10.1016/j.lanepe.2021.100122
        • Kuehn B.M.
        Most patients hospitalized with COVID-19 have lasting symptoms.
        JAMA. 2021; 325: 1031https://doi.org/10.1001/jama.2021.2974
        • Nasserie T.
        • et al.
        Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review.
        JAMA Netw Open. 2021; 4e2111417https://doi.org/10.1001/jamanetworkopen.2021.11417
        • Writing Committee for the Comebac Study Group
        Four-month clinical status of a cohort of patients after hospitalization for COVID-19.
        JAMA. 2021; 325: 1525-1534https://doi.org/10.1001/jama.2021.3331
      3. Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19. Lledó, G., Sellares J., Brotons C., Sans M., Díez, J., Blanco J., Bassat Q., Sarukhan A., Campins M., Guerri R., Miró J.M., de Sanjose, S. (2021), Post-Acute COVID Syndrome (PACS): definition, impact and management, in: isglobal.org, http://hdl.handle.net/2445/178471, accessed: 11/10/2021.

        • Gautam N.
        • et al.
        Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection.
        Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab341
        • Raman B.
        • et al.
        Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
        EClinicalMedicine. 2021; 31100683https://doi.org/10.1016/j.eclinm.2020.100683
        • van den Borst B.
        • et al.
        Comprehensive health assessment three months after recovery from acute COVID-19.
        Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa1750
        • Bellan M.
        • et al.
        Respiratory and psychophysical sequelae among patients with COVID-19 four months after hospital discharge.
        JAMA Netw Open. 2021; 4e2036142https://doi.org/10.1001/jamanetworkopen.2020.36142
        • Ekbom E.
        • et al.
        Impaired diffusing capacity for carbon monoxide is common in critically ill COVID-19 patients at four months post-discharge.
        Respir Med. 2021; 182106394https://doi.org/10.1016/j.rmed.2021.106394
        • Guler S.A.
        • et al.
        Pulmonary function and radiological features four months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
        Eur Respir J. 2021; https://doi.org/10.1183/13993003.03690-2020
        • Sibila O.
        • et al.
        Lung function sequelae in COVID-19 patients 3 months after hospital discharge.
        Arch Bronconeumol. 2021; 57: 59-61https://doi.org/10.1016/j.arbres.2021.01.036
        • Smet J.
        • et al.
        Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection.
        Respir Med. 2021; 176106276https://doi.org/10.1016/j.rmed.2020.106276
        • Havervall S.
        • et al.
        Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers.
        JAMA. 2021; 325: 2015-2016https://doi.org/10.1001/jama.2021.5612
        • Huang C.
        • et al.
        6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
        Lancet. 2021; 397: 220-232https://doi.org/10.1016/S0140-6736(20)32656-8
        • Abdallah S.J.
        • et al.
        Symptoms, pulmonary function and functional capacity four months after COVID-19.
        Ann Am Thorac Soc. 2021; https://doi.org/10.1513/AnnalsATS.202012-1489RL
        • Fernandez-de-Las-Penas C.
        • et al.
        Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: a systematic review and meta-analysis.
        Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.06.009
        • Riou M.
        • et al.
        Respiratory follow-up after hospitalization for COVID-19: who and when?.
        Eur J Clin Invest. 2021; : e13603https://doi.org/10.1111/eci.13603
        • Strumiliene E.
        • et al.
        Follow-up analysis of pulmonary function, exercise capacity, radiological changes, and quality of life two months after recovery from SARS-CoV-2 pneumonia.
        Medicina. 2021; 57 (Kaunas)https://doi.org/10.3390/medicina57060568
      4. National Institue for Health and Care Excellence (2021), COVID-19 rapid guideline: managing the long-term effects of COVID-19, in: NICE Guidance, https://www.nice.org.uk/guidance/ng188, accessed: 11/08/2021.

        • Arnold D.T.
        • et al.
        Patient outcomes after hospitalization with COVID-19 and implications for follow-up: results from a prospective UK cohort.
        Thorax. 2020; https://doi.org/10.1136/thoraxjnl-2020-216086
        • Yan X.
        • et al.
        Follow-up study of pulmonary function among COVID-19 survivors 1 year after recovery.
        J Infect. 2021; https://doi.org/10.1016/j.jinf.2021.05.034
        • Seessle J.
        • et al.
        Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
        Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab611
        • Budweiser S.
        • et al.
        Comparison of the first and second waves of hospitalized patients with SARS-CoV-2.
        Dtsch Arztebl Int. 2021; 118: 326-327https://doi.org/10.3238/arztebl.m2021.0215
        • Mandal S.
        • et al.
        Long-COVID': a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19.
        Thorax. 2020; https://doi.org/10.1136/thoraxjnl-2020-215818
        • Petersen M.S.
        • et al.
        Long COVID in the Faroe Islands - a longitudinal study among non-hospitalized patients.
        Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa1792
        • Charlson M.E.
        • et al.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chron Dis. 1987; 40: 373-383https://doi.org/10.1016/0021-9681(87)90171-8
        • Salehi S.
        • et al.
        Coronavirus disease 2019 (COVID-19) imaging reporting and data system (COVID-RADS) and common lexicon: a proposal based on the imaging data of 37 studies.
        Eur Radiol. 2020; 30: 4930-4942https://doi.org/10.1007/s00330-020-06863-0
        • Quanjer P.H.
        • et al.
        Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
        Eur Respir J. 2012; 40: 1324-1343https://doi.org/10.1183/09031936.00080312
        • Quanjer P.H.
        • et al.
        Lung volumes and forced ventilatory flows.
        Eur Respir J. 1993; 6: 5-40https://doi.org/10.1183/09041950.005s1693
        • A.T.S. Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories
        ATS statement: guidelines for the six-minute walk test.
        Am J Respir Crit Care Med. 2002; 166: 111-117https://doi.org/10.1164/ajrccm.166.1.at1102
        • Enright P.L.
        • et al.
        Reference equations for the six-minute walk in healthy adults.
        Am J Respir Crit Care Med. 1998; 158: 1384-1387https://doi.org/10.1164/ajrccm.158.5.9710086
        • Levey A.S.
        • et al.
        Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions.
        Am J Kidney Dis. 2010; 55: 622-627https://doi.org/10.1053/j.ajkd.2010.02.337
        • Kroenke K.
        • et al.
        The PHQ-9: validity of a brief depression severity measure.
        J Gen Intern Med. 2001; 16: 606-613https://doi.org/10.1046/j.1525-1497.2001.016009606.x
        • Spitzer R.L.
        • et al.
        Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of mental disorders. Patient health questionnaire.
        JAMA. 1999; 282: 1737-1744https://doi.org/10.1001/jama.282.18.1737
        • Hartung T.J.
        • et al.
        The hospital anxiety and depression scale (HADS) and the 9-item patient health questionnaire (PHQ-9) as screening instruments for depression in patients with cancer.
        Cancer. 2017; 123: 4236-4243https://doi.org/10.1002/cncr.30846
        • Jones P.W.
        • et al.
        A self-complete measure of health status for chronic airflow limitation. The St. George's respiratory questionnaire.
        Am Rev Respir Dis. 1992; 145: 1321-1327https://doi.org/10.1164/ajrccm/145.6.1321
        • Rief W.H.
        • et al.
        SOMS-das screening für somatoforme störungen. manual zum fragebogen.
        Huber, Bern1997
        • Qu G.
        • et al.
        Health-related quality of life of COVID-19 patients after discharge: a multicenter follow-up study.
        J Clin Nurs. 2021; 30: 1742-1750https://doi.org/10.1111/jocn.15733
        • Peghin M.
        • et al.
        Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients.
        Clin Microbiol Infect. 2021; https://doi.org/10.1016/j.cmi.2021.05.033
        • Todt B.C.
        • et al.
        Clinical outcomes and quality of life of COVID-19 survivors: a follow-up of 3 months post hospital discharge.
        Respir Med. 2021; 184106453https://doi.org/10.1016/j.rmed.2021.106453
        • Xiong Q.
        • et al.
        Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-Centre longitudinal study.
        Clin Microbiol Infect. 2021; 27: 89-95https://doi.org/10.1016/j.cmi.2020.09.023
        • Aparisi A.
        • et al.
        Exercise ventilatory inefficiency in post-COVID-19 syndrome: insights from a prospective evaluation.
        J Clin Med. 2021; 10https://doi.org/10.3390/jcm10122591
        • Sudre C.H.
        • et al.
        Attributes and predictors of long COVID.
        Nat Med. 2021; 27: 626-631https://doi.org/10.1038/s41591-021-01292-y
        • Frija-Masson J.
        • et al.
        Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days post-infection.
        Eur Respir J. 2020; 56https://doi.org/10.1183/13993003.01754-2020
        • Garrigues E.
        • et al.
        Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19.
        J Infect. 2020; 81: e4-e6https://doi.org/10.1016/j.jinf.2020.08.029
        • Taylor R.R.
        • et al.
        Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia.
        Clin Med (Lond). 2021; https://doi.org/10.7861/clinmed.2021-0037
        • Zhang S.
        • et al.
        Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors.
        Sci Rep. 2021; 11: 13854https://doi.org/10.1038/s41598-021-93191-y
      5. World Health Organization (2021), Clinical management of severe acute respiratory infection when COVID-19 disease is suspected: interim guidance, in: who.int, https://www.who.int/publications/i/item/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected, accessed: 11/08/2021.

        • Debeaumont D.
        • et al.
        Cardiopulmonary exercise testing to assess persistent symptoms at 6 months in people with COVID-19 who survived hospitalization-a pilot study.
        Phys Ther. 2021; https://doi.org/10.1093/ptj/pzab099
        • Lerum T.V.
        • et al.
        Dyspnoea, lung function and CT findings 3 months after hospital admission for COVID-19.
        Eur Respir J, 2021. 2021; 57https://doi.org/10.1183/13993003.03448-2020
        • Townsend L.
        • et al.
        Persistent poor health after COVID-19 is not associated with respiratory complications or initial disease severity.
        Ann Am Thorac Soc. 2021; 18: 997-1003https://doi.org/10.1513/AnnalsATS.202009-1175OC
        • Fortini A.
        • et al.
        COVID-19: persistence of symptoms and lung alterations after 3–6 months from hospital discharge.
        Infection. 2021; https://doi.org/10.1007/s15010-021-01638-1
        • Gianella P.
        • et al.
        Clinical, radiological and functional outcomes in patients with SARS-CoV-2 pneumonia: a prospective observational study.
        BMC Pulm Med. 2021; 21: 136https://doi.org/10.1186/s12890-021-01509-3
        • Rass V.
        • et al.
        Neurological outcome and quality of life 3 months after COVID-19: a prospective observational cohort study.
        Eur J Neurol. 2021; https://doi.org/10.1111/ene.14803
        • von Siemens S.M.
        • et al.
        Effect of COPD severity and comorbidities on the result of the PHQ-9 tool for the diagnosis of depression: results from the COSYCONET cohort study.
        Respir Res. 2019; 20: 30https://doi.org/10.1186/s12931-019-0997-y
        • Thibodeau M.
        • et al.
        The PHQ-9 assesses depression similarly in men and women from the general population.
        Pers Individ Difer. 2014; 56: 149-153https://doi.org/10.1016/j.paid.2013.08.039
        • Bauerle A.
        • et al.
        Increased generalized anxiety, depression and distress during the COVID-19 pandemic: a cross-sectional study in Germany.
        J Public Health (Oxf). 2020; 42: 672-678https://doi.org/10.1093/pubmed/fdaa106
        • Mary-Krause M.
        • et al.
        Impact of COVID-19-like symptoms on occurrence of anxiety/depression during lockdown among the French general population.
        PLoS ONE. 2021; 16e0255158https://doi.org/10.1371/journal.pone.0255158
        • Andersen A.J.
        • et al.
        Symptoms of anxiety/depression during the COVID-19 pandemic and associated lockdown in the community: longitudinal data from the TEMPO cohort in France.
        BMC Psychiatry. 2021; 21: 381https://doi.org/10.1186/s12888-021-03383-z
        • Provencher S.
        • et al.
        COVID-19 and the pulmonary vasculature.
        Pulm Circ. 2020; 102045894020933088https://doi.org/10.1177/2045894020933088
        • Heckman E.J.
        • et al.
        Pulmonary function tests for diagnosing lung disease.
        JAMA. 2015; 313: 2278-2279https://doi.org/10.1001/jama.2015.4466