key: cord-0797836-q2dd6ts1
authors: Vargas Centanaro, Gianna; Calle Rubio, Myriam; Álvarez-Sala Walther, José Luis; Martinez-Sagasti, Fernando; Albuja Hidalgo, Andrea; Herranz Hernández, Rafael; Rodríguez Hermosa, Juan Luis
title: Long-term outcomes and recovery of patients who survived COVID-19: LUNG INJURY COVID-19 Study
date: 2022-02-25
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac098
sha: 75cd3deab30dab7c43530faf8a177fb4a8b7b7ff
doc_id: 797836
cord_uid: q2dd6ts1

INTRODUCTION: LUNG INJURY COVID-19 (clinicaltrials.gov NCT 21/399-E) is a registry-based prospective observational cohort study to evaluate long-term outcomes and recovery 12 months after SARS-CoV-2 infection according to severity. RESULTS: 305 COVID-19 survivors were included (moderate: 162, severe: 143). 12 months after SARS-CoV-2 infection, there was resolution of respiratory symptoms (37.9% in severe versus 27.3% in moderate pneumonia; p = 0.089). Exertional dyspnea was present (20% in severe vs 18.4% in moderate, p = 0.810). Abnormalities in chest radiology imaging were detected in severe COVID-19 infection versus moderate infection (29% versus 8.8%; p <0.001). Pulmonary function testing (forced spirometry or diffusion) performed at 12 months of mean follow-up according to protocol detected anomalies in 31.4% of patients with severe COVID-19 courses and in 27.7% of moderate patients. Risk factors associated with diffusion impairment at 12 months were age (OR: 1.05, 95% CI: 1.01-1.10, p = 0.008), FEV1% predicted at follow-up (OR: 0.96, 95% CI: 0.93-0.99, p = 0.017) and dyspnea score at follow-up (OR: 3.16, 95% CI: 1.43-6.97, p = 0.004). CT scans performed at 12 months of mean follow-up showed evidence of fibrosis in almost half of patients with severe COVID-19 courses, who underwent CT according to protocol. CONCLUSIONS: At 12 months from infection onset, most patients refer to symptoms, particularly muscle weakness and dyspnea, and almost one third of patients with severe COVID-19 pneumonia had impaired pulmonary diffusion and abnormalities in chest radiology imaging. These results emphasize the importance of a systematic follow-up after severe COVID-19, with appropriate management of pulmonary sequelae.

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

Physicians are observing persisting symptoms and unexpected substantial organ dysfunction after SARS-CoV-2 infection 1 , as previously observed in the severe acute respiratory syndrome (SARS) outbreak 2 .

In previous coronavirus infections, studies concluded that between 20% and 60% of survivors of the global SARS outbreak caused by SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV) experienced persistent physiological impairment and abnormal radiology consistent with pulmonary fibrosis [3] [4] [5] [6] .

The appearance of pulmonary fibrosis correlated with the severity and duration of the acute illness 6, 7 . Drawing on these experiences, respiratory complications are predicted to be an important sequela of COVID-19.

In SARS-CoV-2 infection, several studies have reported lingering radiological and pulmonary diffusion abnormalities in a sizeable proportion of patients up to 3 and 6 months after hospital discharge. More than 70% of patients reported at least one symptom that persisted, and more than 50% of patients presented with residual chest imaging abnormalities 6 months after illness onset 8 . Some reports had data up to three months after onset that indicated one-fifth of the patients displayed a reduced lung diffusing capacity and one-fourth of discharged patients had chest CT scan abnormalities [9] [10] . This is particularly relevant for patients who required mechanical ventilation during their hospital stay 10 . SARS-CoV-2 infection is a new disease and uncertainty remains regarding the possible long-term health sequelae, particularly in survivors of severe disease courses, for whom long-term complications and incomplete recovery after discharge would be expected. The clinical evolution and the recovery is heterogeneous. At short-term follow up, lung parenchymal abnormalities seem to have improved in most cases, while some patients persistently show abnormalities [8] [9] [10] . Potential long-term consequences specifically after severe COVID-19 still need to be investigated. Greater knowledge about the evolution of the disease and its possible complications is necessary for proper planning and optimization of resources.

We initiated LUNG INJURY COVID-19, a registry to assess pulmonary sequelae following moderate or severe COVID-19 infection. This study is designed as a prospective clinical cohort to evaluate long-term outcomes and recovery 12 months after SARS-CoV-2 infection onset according to severity. This study includes adults who survived acute COVID-19 pneumonia and appeared for clinical follow-up after either moderate or severe COVID-19 infection.

This observational cohort study includes consecutive adults aged 18 to 84 years who survived laboratory confirmed SARS-CoV-2 pneumonia and were referred to the follow-up clinic in the Pneumology Department at Hospital Clínico San Carlos in Madrid (Spain) from March 23 to August 20, 2020. Patients were referred from primary or specialized care within clinical practice after suffering a moderate or severe SARS-cov2 infection for follow-up. There were no exclusion criteria, except for patients or families' explicit refusal to participate. M a n u s c r i p t

In this first analysis of our cohort, we report on chronic pulmonary sequelae in patients who had experienced moderate or severe COVID-19 pneumonia, with the goal of improving the current understanding of the heterogeneous COVID-19 trajectories.

Baseline information (demographic data, comorbidities measured by the Charlson index 11 , oxygen saturation in emergency room assessment) and clinical assessments during hospitalization (radiology, laboratory findings, clinical signs and symptoms, severity according to the use of ventilatory support and/or admission to the intensive care unit [ICU]) was retrieved from medical records.

Following the British Thoracic Society Guidance on Respiratory Follow Up of Patients with Diagnosis of COVID-19 Pneumonia 12 , the following procedures were performed: assessment of symptoms and breathlessness, British modified Medical Research Council (mMRC) 13 dyspnea score determination, assessment of oxygen saturation, routine blood examinations and chest X-ray. Pulmonary damage was quantified by adapting the radiographic assessment of lung edema (RALE) score to COVID-19 14 .

If the chest X-ray changes have fully resolved and the patient has made a good recovery, consider discharge. If the chest X-ray has not cleared satisfactorily and/or the patient has ongoing respiratory symptoms, consider pulmonary function testing including spirometry and measurement of carbon monoxide diffusing capacity (DLCO) (Masterscreen, Jaeger, Germany). All procedures were carried out according to American Thoracic Society (ATS) and European

Respiratory Society (ERS) guidelines 15, 16 . Arterial blood gases were obtained when hemoglobin oxygen saturation was below 90% or at the physician's discretion. When there were persistent alterations in the radiography and/or impairment in pulmonary function tests (FVC <80% without FEV1/FVC <70 and/or DLCO <80%), a high-resolution computed tomography (CT) was performed. HRCT scans (Optima CT660, General Electric, USA) were obtained in the supine position during end-inspiration breath-holding. If there was clinical suspicion for pulmonary embolism (PE), additional contrast CTs were performed. The images were classified according to guidance by the Fleischner Society 17 based on the presence of ground-glass opacity (GGO), parenchymal bands, bronchiectasis, irregular lines, and reticular patterns. Images were interpreted by two senior radiologists experienced in chest radiology. All imaging data were analysed in the absence of clinical or laboratory results or pulmonary function test. After independent evaluation, any discrepancias were resolved through discussion and negotiation. Normal radiological pattern was defined as the absence abnormalities.

Patients were stratified into two groups following the WHO Clinical Progression Scale 18 according to severity: 

Between March 23 and August 20, 2020, this registry evaluated 305 patients with pneumonia from SARS-CoV-2 who were treated at Hospital Clínico San Carlos and referred to the follow-up clinic in the Pneumology Department. 67 were not considered for follow-up because they are living outside the area (Figure 1 ). A c c e p t e d M a n u s c r i p t

The assessment of symptoms after more than 10 months since SARS-CoV-2 infection showed resolution in a third of patients in both groups (37.9% in severe versus 27.3% in moderate; p = 0.089). Long-term abnormalities in chest X-ray imaging after SARS-CoV-2 infection were more common in patients with severe Figure 2 . Serum laboratory testing was carried out in 116 patients (42.1%) because they maintained abnormal results from previous visits. More than a third of patients in both groups had elevated Ddimer 500ng/ml; no significant differences were found between both severity groups. Findings in the longterm follow-up are provided in Table 3 .

Ten months after discharge, abnormalities in chest radiology imaging were detected in 47 patients (17.8%).

These patients with abnormalities in the chest X-ray versus normal chest radiology were older (mean [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] ; p <0.001) and greater infection severity than patients with normal chest radiology (72.3% vs 38.2%; p <0.001). Long-term FVC% predicted and DLCO% predicted outcomes at follow-up were significantly less in patients with abnormalities in radiology imaging. Results of the multivariable analysis found that the number of days hospitalized and FVC% predicted at follow-up were associated with long-term abnormalities in chest radiology imaging ( Table 4) . A c c e p t e d M a n u s c r i p t

Ten months after discharge, abnormal D-dimer 500ng/mL was detected in 31% of patients. .020). At follow-up, impaired FEV1% predicted, SpO2 and DLCO% predicted functional data was more common in patients with abnormal D-dimer (Table 6 ).

To our knowledge, this is the first study reporting on long-term outcomes in respiratory follow-up after SARS- Our results showed significant improvement in symptoms between five and ten months after infection onset.

In patients with a severe course of COVID infection, dyspnea ≥2 mMRC was present in 55% of patients at midterm follow-up visits and only in 20% in the long term. This recovery has also been described in SARS. Many patients that recovered from SARS complained of limitation in general physical function and/or shortness of breath in the early rehabilitation phase 20 .

The results of radiological features showed that only 17.8% of patients had chest X-ray abnormalities in the long term, which was more frequent in patients with severe COVID-19 courses (29%) and associated with the number of days hospitalized. The rate of radiological anomalies was 40.2% in our series at an average followup of 5 months, being higher (58.2%) in patients with severe COVID-19 infection. These results indicate that radiological abnormalities caused by SARS-CoV-2 might get better over time. In relation to the abnormalities in chest X-ray after COVID infection, the first reports from discharged patients with SARS-CoV-2 pneumonia showed that 83% of them had chest X-ray alterations a few days after discharge 21, 22 . Data at three months showed that 74.5% had radiological abnormalities 23 . .

In relation to lung function involvement after COVID-19 infection, the first reports from discharged patients with SARS-CoV-2 pneumonia showed that 47% of them had diffusion impairment after one month 22 . Data at three months showed that 24% had reduced DLCO and opacities in the CT scan were present in 25% of patients, without finding differences between patients admitted to the ICU compared to those who were not severe 10 . survivors 25, 26 .

This is the first study to show long-term respiratory outcomes after almost a year. Our cohort confirms that A c c e p t e d M a n u s c r i p t M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 

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The authors thank the investigators Elizabeth Gonzalez Revilla, Roberto Larrosa Barreiro, Celia Pinedo Sierra,