key: cord-0945000-vwno8bkz authors: Darcis, Gilles; Bouquegneau, Antoine; Maes, Nathalie; thys, Marie; Henket, Monique; Labye, Florence; Rousseau, Anne-Françoise; Canivet, Perrine; Desir, Colin; Calmes, Doriane; Schils, Raphael; De Worm, Sophie; Léonard, Philippe; Meunier, Paul; Moutschen, Michel; Louis, Renaud; Guiot, Julien title: Long-term clinical follow up of patients suffering from moderate to severe COVID-19 infection: A monocentric prospective observational cohort study date: 2021-07-14 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.07.016 sha: 39516f876afce79952217b539a441194e3335833 doc_id: 945000 cord_uid: vwno8bkz OBJECTIVES: Various symptoms and considerable organ dysfunction persist following SARS-CoV-2 infection. Uncertainty remains about the potential mid- and long-term health sequelae. We prospectively studied patients hospitalized for COVID-19 in Liège University Hospital, Belgium, to determine the persistent consequences of Coronavirus disease 2019 (COVID-19). METHODS: We prospectively recruited patients admitted at the University hospital of Liège for moderate to severe confirmed COVID-19, who were discharged between March 2 and October 1, 2020. Follow-up at 3 and 6 months after hospital discharge included demographic and clinical data, biological data, pulmonary function tests (PFT) and chest HRCT scan. RESULTS: 199 individuals were included in the analysis. Most patients received oxygen supplementation (80.4%). Six months after discharge, 47% and 32% of patients still presented exertional dyspnea and fatigue. PFT at three months revealed a reduced DLCO value (71.6 ± 18.6 %) that significantly increased at six months (p<0.0001). Chest CT showed a high prevalence (in 68.9 % of the cohort) of persisting abnormalities, mostly ground glass opacities. The duration of hospitalization, the admission in ICU or mechanical ventilation were not associated with the persistence of symptoms at 3 months after discharge. CONCLUSION: The prevalence of persisting symptoms following hospitalization for COVID-19 is high and stable up to six months after discharge. However, biological, functional and iconographic abnormalities significantly improved overtime. In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) was detected in Wuhan, China, and identified as the etiological agent of coronavirus disease 2019 . Clinical manifestations range from the absence of symptoms to acute respiratory distress syndrome (ARDS) and sometimes multi-organ failure (1) (2) (3) (4) . For most patients, the infection is mild with low-grade fever and cough, but 15% of patients experience respiratory impairment, combined with diffuse alveolar damage (DAD), pulmonary (hyper)inflammatory infiltrates and microvascular thrombosis associated to elevated levels of inflammatory markers, and require hospital care (3, 5) . Apart from respiratory symptoms, multiple organs can be affected. These disorders include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury (AKI), gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications (6) (7) (8) (9) (10) . AKI in hospitalized patients is high with a prevalence from ≈20% to ≈80% according to the definition used for AKI and the type of hospitalization (usual versus intensive care units). AKI was also associated with death (11) (12) (13) (14) . Until now few and discrepant results are available regarding the evolution of patients with AKI and or proteinuria (15) (16) (17) . More recently, data have emerged that patients persistently endure symptoms related to COVID-19 after the acute phase of infection. Terminology found in the literature mostly refers to "post-COVID conditions", "long COVID", "post-COVID syndrome" or "Post-acute COVID-19" (18) (19) (20) . The National Institute for Health and Care Excellence (NICE) defines long COVID as "signs and symptoms that develop during or after an infection consistent with COVID-19 which continue for more than 12 weeks and are not explained by an alternative diagnosis" (20) . The incidence, natural history and aetiology of these symptoms is presently indeterminate and may vary depending on numerous factors including viral, individual or treatment features. A growing number of studies highlighted that a noteworthy proportion of patients who have suffered from SARS-CoV-2 infection present a "post-COVID syndrome" (21) . Learning more about the whole range of short-and long-term health effects associated with COVID-19 became a key priority. Tools constructed from patients' lived experiences would provide validated and reliable instruments for monitoring the symptoms and impact of "post-COVID syndrome (22 They identified that fatigue or muscle weakness, sleep difficulties, and anxiety or depression were common, even at 6 months after symptom onset. More severely ill patients had increased risk of pulmonary diffusion abnormality, fatigue or muscle weakness, and anxiety or depression. They also showed that lung function was altered with a reduced diffusion capacity and long-term imaging lung abnormalities mainly represented by ground glass opacities (GGO) and interstitial lung abnormalities (27, 28) . More recently, Ayoubkhani et al. quantified rates of organ specific dysfunction in individuals with COVID-19 after discharge from hospital compared with a matched control group from the general population (19) . Mean follow-up in the last study was 140 days (18) . Admission to hospital for COVID-19 was associated with an increased risk of readmission and death after discharge. Rates of multiorgan dysfunction after discharge were raised in individuals with COVID-19 compared with those in the matched control group, suggesting extrapulmonary pathophysiology. Long-term complications after coronavirus disease 2019 (COVID-19) are thus associated with severity but not limited to hospitalized patients (29) . A Danish population-based cohort study revealed that the absolute risk All these data point out that the toll of COVID-19 extends well beyond hospitalization. Studies aimed at determining long-term pathophysiology across organ systems are deeply needed. Here we prospectively studied patients hospitalized for COVID-19 in our center to determine the durable consequences of COVID-19 and to characterize risk factors associated with long-term COVID-associated symptoms. We prospectively recruited patients admitted at the University hospital of Liège for moderate to severe confirmed COVID-19, who were discharged between March 2 and October 1, 2020. Inclusion criteria were: (1) age ≥16, (2) confirmed SARS-CoV-2 infection and (3) hospitalization at the University hospital of Liège, Belgium. We excluded all patients who died before the first follow-up visit, those for whom no recommended follow-up was available and those who declined to participate. All discharged patients met uniform discharge criteria according to the clinical standard of care. The following variables were considered at patient admission: age, weight, height, body mass index (BMI), history of hypertension (based on medical records and/or the presence of antihypertensive medications at admission), history of diabetes (based on medical records and/or the presence of specific therapy at admission), active smoking, and history of chronic kidney disease (CKD) (based on medical records, not on biological data). Biological data of interest were considered at the closest time of discharge (maximum 72h before discharge). All biological data were generated from one single laboratory (Unilab, CHU de Liège) accredited for ISO 15189 Guideline. The following variables were collected: C-reactive protein (CRP), procalcitonin, serum creatinine, lactate dehydrogenase (LDH), albumin, sodium, potassium, total calcium, bicarbonates concentrations (Abbott Alinity instrument), leucocytes, lymphocytes, platelet counts, hemoglobin (Sysmex SE-9000 Hematology analyzer), and D-Dimer (Innovance D-Dimer kit on the Siemens CS5100 automate). AKI was defined by the Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria (33) . The KDIGO criteria for AKI were applied using only serum creatinine variations. Baseline serum creatinine value was defined by the most recent value found in the centralized electronic medical records of the CHU Liège preceding the current admission. Whenever data were not available, we used as baseline value the initial serum creatinine level measured at the time of admission. Estimated Glomerular Filtration Rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) (34) . Renal data on thirty patients of this cohort have already been published (16) . We performed lung function tests in the routine respiratory laboratory of Liège University Hospital. The forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured in accordance with the recommendations of the European Respiratory Society (ERS) (35) . The results were expressed in milliliter and percent predicted. The Tiffeneau index or FEV1 / FVC was expressed in percent. The total lung capacity (TLC) was measured by body plethysmography according to European Respiratory Society (ERS) recommendations. The diffusion capacity of CO (DLCO) and the report DLCO/AV were measured by the singlebreath carbon monoxide gas transfer method and expressed as percent predicted (Sensor Medics 2400 He / CO Analyzer System, Bilthoven, Netherlands). We also evaluated the evolution between pre-and post-COVID19 PFT when available. All CT images used in the study were acquired on one of five multidetector CT scanners (Siemens Edge Plus, GE Revolution CT, GE Brights peed) available in University hospital of Liège. Since CT images were prospectively collected based on the standard of care, no standardized scan protocol was available over the complete dataset. Two thoracic radiologists performed CT scanner analysis (PC: 3 years of experience, CD: 6 years of experience). Results were summarized using means and standard deviations (SD) or median and interquartile ranges (IQR) for quantitative variables. Qualitative variables were presented as frequency tables (number and percent). Chi-squared test, or Fisher exact when appropriated, were used to compare proportions, non-parametric Kruskal-Wallis test was used to compare quantitative variables. Linear or logistic regressions models were used to analyse the impact of Results were considered significant at the 5% critical level (p<0.05). Missing data were not replaced and calculations were always done on the maximum number of data available. Data analysis was carried out using SAS (version 9.4 for Windows). R (version 3.6.1) packages were used for the figures. 199 individuals were included in the analysis (Table S1 ). The demographic, clinical and treatment characteristics of the patients are given in Table S1 and S2. Mean age was 60.5 ± 13.9 years old. 63.3% were men. Mean BMI was 28.6kg/m 2 (Table S1 ). The percentages of comorbidities were high with 44.4% of hypertension, 36.2% of diabetes and 36.4% of obesity. 20.6% had a chronic pulmonary disease. Median duration of hospitalization was 9 days (Table S2 ). Most patients received oxygen supplementation (80.4%; Table S2 ). 26.1% were hospitalized in ICU. 16 .6% had endotracheal intubation. More than 80% were treated with hydroxychloroquine and the huge majority (90.4%) received antibiotics as well (Table S2) . Persistence of symptoms was systematically analyzed. Figure 1 represents the symptoms at 1 month, 3 months or 6 months after discharge. The most frequent symptoms were exertional dyspnea and fatigue followed by cough and chest pain ( Figure 1 and Table S3 ). Shortness of breath was present in 53% of individuals after 1 month and remained highly prevalent at 3 (41%) and 6 months (47%). Fatigue was frequent 1 month after discharge. Surprisingly, the prevalence of fatigue even increased at 3 months (41%). A high proportion of individuals still complained about fatigue 6 months after discharge (32%). Dry cough was common at 1 month (12%). The proportion of individuals presenting dry cough remained high at 3 months and 6 months (11% and 9% respectively). The prevalence of chest pain decreased from 10% to 5% from 1 month to 6 months after discharge. By contrast, we observed a slight increase in the proportion of patients presenting memory impairment overtime. Altogether, the proportion of individuals presenting symptoms after discharge was high and remained elevated at 6 months. The most prevalent symptoms at 1 month, 3 months and 6 months were shortness of breath and fatigue. The evolution of biological data is presented in Table 1 . The level of hemoglobin significantly increased from discharge to month 1 and from month 1 to month 3 (p<0.0001). 37.5% had anemia at discharge. This number drops down to 15.5% at month 3. The percentage of lymphocyte significantly increased from discharge to month 1 (p<0.0001). The level of D-Dimer decreased significantly from discharge to month 1 (p=0.001) and further diminished from month 1 to month 3 (p<0.0001). Median CRP value significantly decreased after discharge and reached normal value at month 1 (p<0.0001). The eGFR was not different at discharge and at 1 month ( In the overall population, we evaluated 156 patients of which 128 were not presenting any chronic lung disease based on the medical history. Out of the 28 patients of the population suffering from chronic lung disease, 36% were suffering from chronic obstructive pulmonary disease (COPD). Interestingly, the total patient population exhibited a low DLCO value (71.6 ± 18.6 %) ( Table 2) . FEV 1 as well as FVC were in the normal range values (90.8 ± 20.8% and 88.6% ± 18.2 respectively). Some patients were evaluated with PFT at both 3 months and 6 months after discharge. Reassuringly, they exhibited a significant improvement on several parameters including FEV1, FVC and DLCO ( Figure S4 ). We had the chance to evaluate the evolution between pre-and post-COVID19 PFT. The median reassessment between two PFT (first before COVID-19 infection, second at follow-up) was of 22 months ± 51. Data are represented in Table S5 . We identified that patients presented a significant FVC and DLCO decline after having suffered from COVID-19 infection. The median FVC was reduced from 87.3 ± 18.9 % to 81.6 ± 19.7 % of predicted values (pred.) (p<0.05). The DLCO value was also significantly reduced from 65.4 ± 26.0 to 58.0 ± 21.1 % pred. We evaluated CT-scan evolution over the time at 3 months (94 days (76; 114)) for 149 patients. Comparing to CT-scan performed at admission to hospital, the main persistent pattern was GGO (68.9 % of the cohort) with thin condensations (68.2%), condensations (46.6%) and crazy paving (6.8%). The CT-scan reevaluation showed that most of the images were improved with a significant reduction of the GGO (p<0.0001), pleural effusion (p<0.05), organizing pneumonia (p<0.05), condensations (p<0.0001), crazy paving and condensations (p<0.0001; p<0.0001 respectively). We did not find any significant differences between the two CT scans concerning the honeycombing, reticular pattern and bronchiectasis. As expected, the quantifications of lung involvement identified a substantial decline in the COVID-19 lesions from a mean value of 32.4 ± 21.4 % to 10.4 ± 14.9 % at 3 months of follow up. We correlated persistence of symptomatology with clinical and demographic features (Table S6 ) and with selected biological data (haemoglobin, D-dimer), pulmonary function tests (DLCO) and chest CT scan (GGO) (table S7). Unfortunately, we were not able to determine a typical clinical or biological profile of patients at risk of presenting long-term symptoms. In particular, the duration of hospitalization, the admission in ICU or any mechanical ventilation were not associated with the persistence of symptoms at 3 months after discharge. We observed that more patients (56.6%) with a decreased DLCO had persistent symptoms compared to those with normal DLCO value (31.8%), although p value was at the limit of statistical relevance (p 0.051) (Table S7 ). For some individuals, COVID-19 can cause symptoms that last weeks or months after the infection has gone. Post-COVID conditions are being seen in a growing number of patients reporting a constellation of symptoms after SARS-CoV-2 infection that are persistent, debilitating, and have yet to be fully explained by known or measurable mechanisms (36) . Pioneering studies showed that COVID-19 survivors often suffered from fatigue or muscle weakness, sleep difficulties, and anxiety or depression, up to 6 months after infection (26, 37) . In addition, individuals discharged from hospital after COVID-19 have increased rates of multiorgan dysfunction compared with the expected risk in the general population (19) . The prevalence of post-COVID conditions seems associated with severity (30), although a recent report suggested that it is common in young home-isolated adults with mild COVID-19 as well (31) . Augustin et al. also observed the ongoing presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in nonhospitalised patients at four-and seven-months post-infection (38) . We confirmed the very high prevalence of extreme tiredness and shortness of breath up to 6 months after discharge in patients hospitalized for COVID-19. The prevalence of anosmia and ageusia was low in our study, compared to other recent reports (38) . Surprisingly, the frequencies of those symptoms remained high and stable overtime, indicating that a longer follow up is needed to determine their duration. A better understanding of the causes of symptoms persistence is necessary to provide answers and solutions to this crucial concern as well as to design prevention strategies. The severity of the persistent symptoms was not correlated with pulmonary functional tests nor CT-scan images. Interestingly, PFT reassessment did not find any significant decrease in lung volumes, but an isolated DLCO reduction. Of note, patients having benefited from previous PFT evaluation were suffering from a Our study suffers from several limitations, mostly the limited number of participants and the absence of control group of non COVID-19 patients. Loss to follow-up may also be non-random; thus, the proportion of patients who had adverse outcomes may be biased. Nevertheless, our study confirmed the very high prevalence of persisting symptoms following hospitalization for COVID-19, and revealed a worrying stability of post-COVID symptoms overtime. We also found high percentages of biological, functional and iconographic abnormalities several months after discharge. In contrast with symptomatology, these objective parameters improved overtime. 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Lancet Reg Health -Eur High-dimensional characterization of post-acute sequalae of COVID-19 Postacute COVID-19 syndrome Assessing Brain Capillaries in Coronavirus Disease Decreasing Incidence of Acute Kidney Injury in Patients with COVID-19 Critical Illness FEV1: forced expired vital capacity in 1 sec, FVC: forced vital capacity, DLCO: Diffusion lung capacity for CO, AV: alveolar ventilation. TLC: total lung capacity, FRC: functional residual capacity, RV: residual volume We thank all participants. The authors declare no competing interests.