key: cord-0862250-0pkd4k6l
authors: Meije, Y.; Duarte-Borges, A.; Sanz, X.; Clemente, M.; A, Ribera; Ortega, L.; González-Pérez, R.; Cid, R.; Pareja, J.; Cantero, I.; Ariño, M.; Sagués, T.; LLaberia, J.; Ayestarán, A.; Fernández-Hidalgo, N.; Candás-Estébanez, B.
title: Long-term outcomes of patients following hospitalization for COVID-19: a prospective observational study
date: 2021-04-23
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.04.002
sha: 97cef12582fde7dbe78936c72d932cae90945a48
doc_id: 862250
cord_uid: 0pkd4k6l

OBJECTIVES: Few data regarding follow-up of patients after COVID-19 discharge are available. We aim to describe the long-term outcomes of survivors of hospitalization for COVID-19 followed up first at an outpatient facility and subsequently by telephone. METHODS: Observational prospective study conducted at a tertiary general hospital. Clinical and radiological progression was assessed and data recorded on a standardized reporting form. Patients were divided into three groups according to PaO2/FiO2 at hospitalization: PaO2/FiO2 > 300, PaO2/FiO2 300-200 and PaO2/FiO2 < 200. A logistic multivariate regression model was performed to identify factors associated with persistence of symptoms. RESULTS: Facility follow-up: 302 patients were enrolled. Median follow-up was 45 days after discharge; 78% (228/294) of patients had COVID-19-related symptoms (53% asthenia, 56% respiratory symptoms) and 40% (122/302) had residual pulmonary radiographic lesions. PaO2/FiO2 <200 was an independent predictor of persistent dyspnea; OR = 1.87 (1.38 to 2.52), (p <0.0001). PaO2/FiO2 >300 was associated with resolution of chest radiographic lesions; OR = 0.56 (0.42 to 0.74), (p <0.0001). Fifty per cent of patients required specific medical follow-up after the first consultation and were transferred to another physician. Telephone follow-up: 294 patients were contacted after a median time follow-up of 7 months. Fifty per cent of patients (147/294) still presented symptoms and 49% (145/294) psychological disorders. Asthenia was identified in 27% (78/294) and dyspnea in 10% (28/294) of patients independently of PaO2/FiO2. CONCLUSIONS: COVID-19 patients require long term follow-up due to persistence of symptoms; patients with low PaO2/FiO2 during the acute illness require special attention.

Coronavirus infectious disease 2019 (COVID-19) represents a major global medical challenge [1] . A great deal of information has emerged about the epidemiology of acute COVID-19, its clinical features and predictive factors for patients during hospital admission [2, 3] , but at present very little is known about the subsequent course of COVID-19 survivors after hospital discharge [4] . In fact, the great majority of COVID-19 studies in the literature are either retrospective or report only short-term follow-up [5] [6] [7] . Data have been published on the long-term clinical outcomes of patients following hospitalization in the Asian setting [8] , but to our knowledge no descriptions are as yet available in a European population.

To optimize clinical care, it is imperative to understand the natural history of SARS-CoV-2 infection, including the evolution of recovering patients, and to determine predictors that may be useful in longer term clinical management. Since the beginning of the pandemic, our group has been aware of the need for a specific follow-up facility for patients after discharge from our tertiary care hospital. The identification of possible sequelae is crucial in order to address the individual requirements of each patient.

The present study aims to describe the mid/long-term outcomes of survivors of COVID-19 discharged from our hospital and who were subsequently followed up both at the outpatient facility visit and by telephone.

The main aim was to systematically characterize the evolution of survivors of COVID-19 admitted to our hospital, in terms of the development and persistence of symptoms, the development of new clinical sequelae, immune status, and chest radiography findings. The secondary objective was to identify conditions that were associated with the persistence of clinical symptoms or radiological disease.

This observational prospective study was conducted at the Hospital de Barcelona-SCIAS, a 250-bed cooperative non-profit private tertiary care general hospital in Barcelona, Spain.

Patients who were discharged after COVID-19 hospitalization were selected for follow-up, divided into two subcohorts: in the first, all those seen at face-to-face facility visits, and in the second, those who were also followed up by telephone.

The patients were divided into three groups according to their worst PaO2/FiO2 during hospitalization:

PaO2/FiO2 > 300, PaO2/FiO2 300-200 and PaO2/FiO2 < 200. PaO2/FiO2 has been used by other investigators to study patient outcomes based on a standardized measure of lung injury [9] . PaO2/FiO2 was calculated according to arterial gasometry values. Those patients in whom arterial gasometry was not performed, PaO2 was replaced by oxygen saturation in accordance with the Severinghaus-Ellis equation [10] .

Patients at admission: Patients aged > 15 years who had been discharged following hospitalization for COVID-19 between 1 March and 31 May 2020 were included. Patients were identified in the electronic hospital database due to a specific coding for COVID-19. 40-50) later, in chronological order, and were scheduled for an outpatient clinic appointment in the following

week. All patients who attended the facility were included (Figure 1 ).

Procedures in the outpatient facility (face-to-face assessment applied in all patients) were as follows:

J o u r n a l P r e -p r o o f a) A standard follow-up protocol checklist of symptoms and adverse events, including psychological manifestations was administered to prospectively record the variables at the facility (see web-only   Supplementary Table S1 ).

b) Medical histories were reviewed and a physical examination performed. c) Laboratory testing, chest x-ray and SARS-CoV-2 serological testing were performed. d) Ten internal medicine and family medicine physicians with experience in the management of hospitalized COVID-19 patients were enrolled in the follow-up.

Telephone follow-up: All patients seen at the outpatient facility were contacted 7 months (range 6.5 to 7.3)

after discharge by phone. A second follow-up was conducted. All patients who agreed to the telephone interview were included.

Procedures in the phone follow-up were as follows:

a)

The same follow-up protocol checklist of clinical manifestations and adverse events performed to report the variables at the facility was used to record the persistence of symptoms in the telephone interview (see web-only Supplementary Table S1).

b) Data related to demographic characteristics or patient comorbidities that were missing in the previous data collection were obtained from the patient.

c) The same initial eight internal medicine physicians from the COVID-19 hospital team conducted the telephone interview.

All patients gave informed consent prior to participation in the study. The research protocol was approved by the hospital's institutional review board (identification code: HdB-COVIDFOLLOW-2020/04)

COVID-19 diagnosed patients included both confirmed and probable cases. Confirmed cases met clinical criteria (acute respiratory syndrome), radiological criteria, and positive PCR for SARS-CoV-2. Probable cases were those with clinical criteria (acute respiratory syndrome), radiological criteria with negative or inconclusive PCR for SARS-CoV-2 result, in accordance with the protocol in force in Spain [11] , and were diagnosed with COVID-19 by two independent clinicians in the absence of an alternative cause of pneumonia.

J o u r n a l P r e -p r o o f

The Rockwood score was used as a global clinical measure of frailty in elderly people [12] . The MuLBSTA score was used for the risk stratification of hospitalized patients; values >12 were perceived as high risk [13] .

See all variables and definitions in web-only Supplementary Table S1 . The Hospital protocol is described in web-only Supplementary Figure S1 .

The presence of 2019-nCoV in nasal and pharyngeal respiratory swabs was identified by RNA extraction followed by reverse transcription polymerase chain reaction (RT-PCR) through the identification of SARS-CoV-2 RNA (three specific regions: E gene, RdRP gene and N gene), (AllPlex 2019-nCoV Assay, Seegene).

Descriptive analysis: Quantitative results of variables were expressed as means and standard deviations (SD) or medians and interquartile ranges (IQR), and categorical variables were reported as absolute numbers and percentages. To detect significant differences between groups, the χ2 test or Fisher's exact test for categorical variables were used, as appropriate.

The purpose of the model was to identify risk factors related to outcomes using logistic multivariate analysis. First, a logistic bivariate regression analysis was conducted in order to identify variables associated with the most severe persistent symptoms or residual lesions (any of the following: dyspnea, asthenia and pathological x-ray findings; dependent variables). We included variables associated with the dependent variable in the bivariate analysis (p<0.1) and pre-defined variables that were clinically relevant. Once the significant variables (independent variables) were identified, a logistic multivariate regression model was performed. The variables included in the final model were selected by an automatic backward stepwise procedure. Interactions between variables were considered based on the ones that could be related clinically (r>0.4 were eliminated). A two-sided α of less than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics for Windows v.25 (SPSS Inc., Chicago, IL) and Analyse-it Software, Ltd. for Windows v.3.

The results were reported in accordance with the Strobe statement (See web-only Supplementary Table S2 ).

From 1 March 2020 to 31 May 2020, 562 patients were admitted to the hospital with suspected diagnosis of COVID-19; of these, the diagnosis was confirmed in 542. Of the 461 patients eventually discharged, 302

were enrolled in the final outpatient follow-up cohort. The remaining 159 patients were excluded for various reasons explained in Figure 1 . Two hundred and ninety-four patients were included in the final telephone cohort.

The demographic and clinical characteristics of the study cohort (302 patients) are described in Table 1 .

Median hospital stay was eight days (IQR 5-12). Sixty-eight (22.5%) patients were PCR-SARS-CoV2

negative. Median hospital stay was eight days (IQR 5-12). The comparison of the characteristics and outcomes of patients according to PCR+/-for SARS-CoV-2, and according to the inclusion and exclusion criteria of the cohort, is detailed in Supplementary Table S3 and S4.

The median time of follow-up after discharge was 45 days (IQR 43-47). were IgG positive (Table 1) .

The median time from discharge to telephone contact was seven months (IQR 6-7.4). of patients, including dyspnea, anosmia or dysgeusia. In terms of the evolution of symptoms, diarrhea and migraine rapidly decreased over the course of follow-up, while others such as anosmia and dysgeusia decreased slowly over time. All symptoms are described Table 2 . (See web-only Supplementary Figure S2 "Proportion of patients presenting each of the symptoms studied over time")

Patient clinical outcomes and radiology outcomes related to PaO2/FiO2: A significant relationship was observed between persistent dyspnea and lower PaO2/FiO2 at medium-term follow-up (p<0.0001) ( Table 3) .

However, in the long-term follow-up (7 months) the trend was maintained, but was no longer statistically significant. Asthenia occurred in all periods regardless of PaO2/FiO2 (Table 4 ). however, little is known about long-term clinical outcomes in COVID-19 patients [16] . In survivors of SARS and MERS, lung function abnormalities, psychological impairment and reduced exercise capacity were reported to be common [17] . A recent study of COVID-19 patients in Italy showed persistence of symptoms after recovery, with only 12.6% patients completely free of any COVID-19-related symptoms at two-month follow-up [6] . Other studies have found that 64% of patients had no symptoms three months after discharge and that 76% had no symptoms six months after discharge [8, 18] . Our study, with a considerably longer time span, reported symptoms in 50% of patients at seven months of follow-up.

We assessed the symptoms over seven months following discharge. The most frequent limiting symptoms were asthenia (over 50% at 1.5 months, and still present in more than 26% at 7 months) and respiratory symptoms, especially dyspnea (30% at 1.5 months and still above 9% at 7 months). Other authors have reported dyspnea in 30% of patients and asthenia in 40% at two months of follow-up [7] . In our study, more than 40% of patients had residual pulmonary lesions 1.5 months after discharge. Similarly, other studies found that around 35% of patients had persistent pulmonary abnormalities after four weeks [19] , and persistent pulmonary infiltrates in up to 90% using chest-computed tomographic imaging [5] .

The present observational study found that patients with lower PaO2/FiO2 values had a higher risk of persistence of dyspnea (OR 1.9), and that a higher PaO2/FiO2 was associated with resolution of x-ray lesions (OR 0.6) at an average of 1.5 months after discharge. Similarly, a recent study showed that patients J o u r n a l P r e -p r o o f with more severe illness during their hospital stay presented a higher level of dyspnea and abnormal chest imaging manifestations after six months of follow-up [8] . In another study, residual signs suggesting pulmonary fibrosis were found most frequently in a subgroup of critical COVID-19 patients [5] . Comparisons between ward and ICU patients did not reveal statistically significant differences regarding symptoms at three months of follow-up [20] or between severe or non-severe patients at one month of follow-up [21] .

The presence of limiting symptoms such as asthenia or neurological sequelae was not negligible in our study. Social monitoring programs for recovering patients may help improve health, physiological status and physical activity, and the provision of counselling and psychological support to these patients is also

important.

This study has several limitations. First, as it is a single-center study it is not possible to extrapolate the results to other settings. Second, the follow-up period covered the first seven months after the discharge; a longer follow-up might benefit the analysis of longer-term outcomes, and indeed our intention is to continue monitoring these patients and record further data after 12 months. Despite these limitations, the study's prospective design aided data collection; additionally, the fact that all recovered patients come from a center with a specific, updated COVID-19 treatment protocol meant that there were few deviations in the regular management of patients, and allows the comparison of clinical outcomes in a uniform cohort.

To our knowledge, this is the first study to describe long-term follow-up of a large number of COVID-19

survivors after hospitalization. We found that a worse PaO2/FiO2 is associated with persistence of dyspnea for at least 45 days of follow-up, and that dyspnea, asthenia and psychological disorders persist in many patients several months after discharge.

It is important to continue studying the sequelae and prognosis of recovered patients in order to develop guidelines for their multidisciplinary management. Special attention should be paid to patients with J o u r n a l P r e -p r o o f *Re-admitted to hospital: 5 for respiratory insufficiency related to COVID-19, 2 for bacterial pneumonia, 1 for diarrhea, 1 for pulmonary embolism, 1 for ovarian neoplasia, 1 for acute pyelonephritis. **Death after discharge: 7 at home, 3 at hospital (2 due to respiratory insufficiency related to COVID-19, 1 due to cerebral stroke) ***Death: 2 at home, 2 at hospital (1 due to septic shock, 1 due to pancreatic neoplasia) 

Coronavirus disease 2019 Situation Report 51

China: a descriptive study

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Follow-up studies in COVID-19 recovered patients -is it mandatory?

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