key: cord-0774604-6mxxqntb
authors: Mumoli, Nicola; Bonaventura, Aldo; Colombo, Alessandra; Vecchié, Alessandra; Cei, Marco; Vitale, José; Pavan, Luca; Mazzone, Antonino; Dentali, Francesco
title: Lung function and symptoms in post-COVID-19 patients: a single-center experience
date: 2021-08-10
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2021.08.002
sha: 0c8126579bc8fcbe56e01936dbe49a6581cc4b3e
doc_id: 774604
cord_uid: 6mxxqntb

Objective To address the lack of information about clinical sequelae of coronavirus disease 2019 (COVID-19). Patients and Methods Previously hospitalized COVID-19 patients who were attending the outpatient clinic for post-COVID-19 patients (ASST Ovest Milanese, Magenta, Italy) were included in this retrospective study. They underwent blood draw for complete blood count, C-reactive protein (CRP), ferritin, D-dimer, and arterial blood gas analysis (ABG) and chest high-resolution computed tomography (HRCT) scan. The primary endpoint was the assessment of blood gas exchanges after 3 months. Other endpoints included the assessment of symptoms and chest HRCT scan abnormalities and changes in inflammatory biomarkers after 3 months from hospital admission. Results Eighty-eight patients (men 73.9%) were included. Admission arterial ABG analysis showed hypoxia and hypocapnia and a PaO2/FiO2 of 271.4 (238-304.7) mmHg, that greatly improved after 3 months (426.19 [395.24-461.90] mmHg, P<.001). A 40% of patients was still hypocapnic after 3 months. Inflammatory biomarkers dramatically improved after 3 months from hospitalization. Fever, resting dyspnea, and cough were common at hospital admission and improved after 3 months, when dyspnea on exertion and arthralgias arose. On chest HRCT scan, more than half of individuals still presented interstitial involvement. Positive correlations between the interstitial pattern at 3 months and dyspnea on admission were found. CRP at admission was positively associated with the presence of interstitial involvement at follow-up. The persistence of cough was associated with presence of bronchiectasis and consolidation on follow-up chest HRCT scan. Conclusion While inflammatory biomarker levels normalized after 3 months, signs of lung damage persist for a longer period. These findings support the need for implementing post-COVID-19 outpatient clinics to closely follow-up COVID-19 patients after hospitalization.

Over the past months, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been responsible for the coronavirus disease 2019 in a huge number of patients all over the world [1] [2] [3] . Typical symptoms reported among COVID-19 patients, either hospitalized or not, were fever, dyspnea, cough, weakness, headache, nausea, diarrhea, and vomiting 4 . While most patients had no or few symptoms, a portion of them requires hospitalization and eventually develops acute respiratory distress syndrome (ARDS), potentially fatal 5 .

A wealth of evidence is now available about pathophysiology, clinical characteristics, and complications of the acute phase of COVID-19 4 , but less is known about long-term consequences and few reports have been published to date. In the early recovery stage (i.e. 30 days), abnormal findings on pulmonary function tests (PFTs) and chest computed tomography (CT) scan were found in more than half of COVID-19 6 . Another report described that most patients who recovered from COVID-19 had no signs of lung damage after 4 weeks from hospital discharge 7 . Carfi et al. reported that after a mean of 60 days from the onset of the first COVID-19 symptom, only 13% of patients were symptom-free, while more than one third was still experiencing 1 or 2 symptoms and more than a half at least 3 symptoms, but none of them was had fever or any other symptom of acute illness 8 . In a study who followed patients after 90 days, clinical sequelae were commonly encountered, including fatigue, arthralgia, post-activity polypnea, resting tachycardia, psychosocial symptoms, and alopecia 9 .

Since no report has been published that assessed blood gas exchanges in patients who recovered from COVID-19, the aim of our study was to evaluate whether oxygen and carbon dioxide levels were restored in post-COVID-19 patients attending our dedicated outpatient clinic in a COVID-19 hub in Lombardy (Italy).

Due to the large spread of SARS-CoV-2 and its potential long-term impact on lungs, an outpatient clinic for post-COVID-19 patients was implemented at Magenta Hospital (Azienda Socio Sanitaria Territoriale Ovest Milanese; Magenta, Milan, Lombardy, Italy).

Admission to this outpatient clinic was primarily dedicated to all adult patients (≥ 18 years) who had been hospitalized for SARS-CoV-2 pneumonia (laboratory real-time-polymerase chain reaction [RT-PCR] SARS-CoV-2 positivity and chest X-ray or CT scan suggestive for interstitial pneumonia along with typical symptoms) and with the following characteristics during hospital admission: (i) respiratory failure defined by arterial partial pressure of oxygen (PaO2) <60 mmHg in ambient air and/or resting peripheral capillary oxygen saturation (SpO2) <93% in ambient air and/or ratio of PaO2 to fractional inspired oxygen (PaO2/FiO2), i.e. Horowitz Index, <300 mmHg 10 ; (ii) continuous positive airway pressure (CPAP) for at least 72 h; (iii) interstitial involvement >40% on chest X-ray or CT scan; (iv) length of hospital stay >7 days; (v) evidence of venous thromboembolism, either pulmonary or peripheral, during hospital stay. All patients were treated with antibiotics, glucocorticoids (methylprednisolone 0.1-1.5 mg/kg for at least 7 days, then tapered) and oxygen therapy, while a portion of them were also treated with darunavir/ritonavir, lopinavir/ritonavir, hydroxychloroquine, and tocilizumab according to contemporary evidence about therapeutics.

After 3 months from hospital discharge, patients were admitted to the outpatient clinic and underwent the following evaluations in order to comprehensively assess the clinical status and any residual lung damage following COVID-19: blood draw for complete blood count, C-reactive protein (CRP), ferritin, and D-dimer, among others; arterial blood gas (ABG) analysis; chest high-resolution CT (HRCT) scan. HRCT scans were then reviewed by a trained radiologist in order to assess for interstitial involvement (such as ground-glass opacities [GGOs] and fibrosis) and consolidation.

J o u r n a l P r e -p r o o f From May 25 st to August 31 st 2020, 88 patients were consecutively considered for the present analysis. All clinical, laboratory, and radiologic information was included in a locked database, that was accessible only to researchers involved in the study.

The ethical approval for this study and the need for written informed consent was not required due to the retrospective nature of the study and the ethical considerations of this research were conformed to the Declaration of Helsinki. The study was carried out and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies 11 .

Data on main comorbidities were collected, such as hypertension, diabetes mellitus, obesity, cardiovascular disease (CVD), respiratory and metabolic diseases, and cancer.

CVD includes coronary artery disease, atrial fibrillation, heart failure, and venous thromboembolism. Respiratory disease includes chronic obstructive pulmonary disease and asthma. Metabolic disease includes hyperlipidemia and hypothyroidism.

Fever was defined for a body temperature >37.5 °C. Dyspnea on exertion (DOE) was defined based on patient's description of dyspnea for usually well tolerated activities, e.g. climbing stairs.

The primary endpoint of the study was the evaluation of persistently abnormal blood 

Eighty-eight patients were included in this study, with a large prevalence of males (n=65, 73.9%) and with a mean age of 62.7 years ( (Figure 1) . A portion of patients (n=35, 39.8%) was persistently hypocapnic (PaCO2 <35 mmHg), but no significant difference in demographic or clinical characteristics was found when compared with normocapnic patients. Table 2 summarizes all these findings in more detail.

With regard to inflammatory biomarkers, all patients showed a dramatic decrease of CRP, ferritin, and D-dimer levels after 3 months compared with those assessed at the time of hospitalization (P<.001 for all, Figure 2A-C) . Detailed findings are included in Table 2 .

Fever (n=77, 90.6%), dyspnea at rest (n=48, 56.5%), and cough (n=49, 57.6%) were the most common symptoms at the time of hospital admission. Following 3 months from hospital discharge, DOE (n=42, 49.4%) and arthralgias (n=6, 7.1%) were the symptoms that patients complain most frequently about (Figure 3) . Dyspnea at rest, cough, and fatigue were persistent in a number of patients, although to a lesser extent compared with the time of hospital admission, (Figure 3) . No sex-related nor comorbidity-related differences with regard to symptom presentation was found, except for resting dyspnea at the time of hospital admission that was found more frequently in males than in females (63.5% [n=40] vs. 36.5%

[n=8], P=.04).

Chest HRCT scan findings at 3 months J o u r n a l P r e -p r o o f After 3 months, one-third of patients showed a normal CT scan without any abnormalities (Figure 4) . More than half of patients still presented interstitial involvement (n=42, 54.5%), including GGOs (n=23, 29.5%) and fibrosis (n=13, 16.9%) (Figure 4) . No sex-related difference was observed.

Whether chest HRCT findings after 3 months may have any correlation with symptoms and/or inflammatory biomarkers is not known. We found positive correlations between the interstitial pattern, including GGO, at 3 months and dyspnea on admission (Table 3) . Moreover, CRP levels at admission were positively associated with the presence of interstitial involvement at follow-up. The presence of bronchiectasis positively correlated with the presence of cough, after 3 months from COVID-19. The strongest correlation was found for the persistence of cough after 3 months in those patients with persisting consolidation on follow-up chest HRCT scan ( Table 3) .

In the present study, the short-term (3 months) impact of COVID-19 on hospitalized patients has been assessed. We took into consideration different aspects, either subjective (symptoms complained by patients) and objective (chest HRCT findings and circulating inflammatory biomarkers). Apart from the persistence of some symptoms (fatigue, arthralgias, and cough), the presence of DOE, and persistent lung damages still found on 3-month chest CT scan, the most interesting finding is that 40% of patients are still hypocapnic after 3 months, while hypoxia completely resolved.

An abnormal lung function measured through PFTs has been recorded in COVID-19 patients. In particular, an impaired diffusion capacity of carbon monoxide is very frequent along with restrictive ventilatory defects at the time of hospital discharge and both are likely to be associated with severity disease 12 . Although we did not perform any PFT, we assessed ABG after 3 months and found a mild, persisting hypocapnia while hypoxia completely J o u r n a l P r e -p r o o f normalized. This finding is interesting and may underline the residual, lasting impairment of the alveolar-capillary barrier following SARS-CoV-2 infection causing a ventilation/perfusion ratio (V/Q) mismatch. In fact, in SARS-CoV-2 infection the primary cause of arterial hypoxemia is a V/Q mismatch meaning that there is pulmonary arterial blood flow in nonventilated alveoli. This concept is also summarized as 'happy hypoxemia'i.e. a severe hypoxemia coupled by a relatively mild respiratory discomfort reported by COVID-19 patients 13 . COVID-19 patients usually present with hypoxemia-driven tachypnea and hyperpnea, that determine respiratory alkalosis and hypocapnia followed by a leftward shift of the sigmoid shaped oxyhemoglobin dissociation curve 13, 14 . In addition, COVID-19 is known to damage the endothelium and is now also referred to as an endotheliopathy [15] [16] [17] .

As a result, the pulmonary capillary endothelium may activate an inflammatory response through the expression of cytokines and adhesion molecules, that sustains the abnormal inflammatory response to the virus and increases the risk for thrombosis, either in small and large vessels 18, 19 . All these events, taken together, might leave some type of scar tissues during the recovery phase and therefore explain why hypocapnia is still present 3 months months, and found that survivors to COVID-19 complained about fatigue, weakness, sleep disorders, anxiety, and depression 23 . They also analyzed chest CT findings between hospital stay and after 6 months describing GGO as the most common pattern at follow-up, while other findings were completely resolved 23 . This is in line with what we found on HRCT performed after 3 months, where GGO was frequently encountered along with interstitial involvement. These radiologic findings are often described at the same time patients have a respiratory deterioration and are coupled with lymphocytopenia and increased D-dimer levels 24 . Fibrosis is another abnormality that can be observed as early as 7-10 days after symptom onset in up to one-third of patients with COVID-19 25, 26 . Indeed, almost 20% of our patients showed evidence of fibrosis on HRCT scan at the time of follow-up that may arise from the healing process of lung inflammation when scar tissues replace the pulmonary cellular cells. Whether fibrosis in post-COVID-19 patients is prognostically benign or not is still controversial as it might represent either a bridge toward a stabilization of the disease 27 or the primum movens toward a frank interstitial disease 27, 28 . This aspect definitively needs future studies to be fully elucidated.

Interestingly, in our cohort CRP levels at admission positively correlated with interstitial involvement. So that, patients with higher inflammatory burden during COVID-19 pneumonia may be more at risk to develop pulmonary sequelae. With this regard, a doseresponse effect of CRP towards adverse outcomes in COVID-19 patients has been recently demonstrated 29 . A median CRP value >108 mg/L was associated with a 3-fold increased risk of death and critical illness and a 2-fold higher risk of venous thromboembolism and acute kidney injury. The greatest risk for adverse outcomes was found in those patients showing increased levels of both CRP and D-dimer, further supporting the strong relationship between inflammation and thrombosis 16 .

Our study has, however, some strengths and some limitations. The major strength of our paper deals with the enrollment of a number of patients, who have been adequately assessed for respiratory function. In particular, the availability of ABG analysis allows for a prompt evaluation of gas exchanges 3 months after COVID-19. One limitation is the absence of PFTs, that might enrich the explanation about the persisting hypocapnia through the demonstration of a decreased lung diffusion capacity for carbon monoxide (DLCO), as already shown in COVID-19 patients at the time of discharge 12 . In addition, the retrospective nature and the limited number of patients recruited at a single center prevent from any definitive conclusions, but support the need for a more in depth follow-up evaluation in COVID-19 patients in the long-term.

In conclusion, COVID-19 patients who recovered from acute SARS-CoV-2 infection present some clinical sequelae. In particular, a substantial portion of them still has a residual hypocapnia after 3 months. They also show persisting abnormal findings on chest HRCT scan, especially interstitial involvement, GGO, and fibrosis. While inflammatory biomarker levels completely normalized, signs of lung damage, e.g. hypocapnia and radiologic abnormalities on CT scan, are still there suggesting that SARS-CoV-2 stigma persist for a longer period. These findings should push the medical community to carefully evaluate COVID-19 patients, especially those who experienced a moderate-to-severe disease, in the short-and long-term to catch any early sign of respiratory failure that may arise months or 

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PaO2/FiO2 e , mmHg