Three–month outpatient follow-up of discharged COVID – 19 patients: a single center cross – sectional study

T. Aloè¹, L. Benedetti ^2,3, S. Garbarino¹¹, E. Tagliabue¹, A. Torricella⁵, C. Campi¹¹ , M. Piana⁴, M.  Grosso¹, S.G. Grisanti³, C. Sepulcri⁶, F. Cosini⁷, F. Baldi⁶, D.Giacobbe⁶, A. Sulli⁹, D.Ferone⁸, M. Bassetti⁶, L. Castellan⁵, M. Amore⁹ and E. Barisione¹
 

1. Interventional Pulmonology Unit, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy

2. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy

3. Division of Neurology, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy

4. LISCOMP, Department of Mathematical Sciences, University of Genoa and CNR - SPIN Genoa, Italy

5. Department of Radiology, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, University of Genoa, Italy

6. Infectious Diseases Unit, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, university of Genoa, Italy

7. Allergy and Respiratory Diseases, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, University of Genoa, Italy

8. Endocrinology Unit, Department of Internal Medicine, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, University of Genoa, Italy

9. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, Genoa, Italy

10. Research Laboratories and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS AOU San Martino, Genova, Italy.

11. LISCOMP, Department of Mathematical Sciences, University of Genoa, Genoa, Italy

Corresponding Author: Dr. T. Aloè, Interventional Pulmonology Unit, Policlinic San Martino University Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy.

Copy Right: © 2021 Dr. T. Aloè. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  

Received Date: August 05, 2021

Published date: September 01, 2021

Abstract

Background:
Despite the growing literature describing the clinical and radiologic progression of COVID-19 and the course of its acute phase, little is known about the post-acute patients' condition and, since COVID-19 is a new disease, about the possible long-term health consequences.

Purpose:
The objective of this paper is to describe the clinical characteristics of COVID-19 survivors at three-month follow-up after the acute phase and identify potential risk factors associated with persistent abnormalities.

Materials and Methods:
Between July and November 2020, for this single center cross – sectional study 148 patients (85 [57%] men; mean age, 63 range 31- 85 years) were enrolled. In this cohort the severity of COVID 19 acute course was mild for 20% of patient; moderate for 33%; mild – severe for 22%; severe for 25%. The average length of hospital stay was 26 days (range 3 – 111). The most commonly recovery complication was overlapping infection (18%), followed by thrombotic events (9% pulmonary, 8% other district), hematoma (6%), kidney failure (4%) and cardiac impairment (4%). Patients’ post COVID-19 evaluation was performed averagely 12 weeks after the acute phase (range 10 – 15 weeks) through standardized sets of questionnaires (core components included demographic data, body mass index comorbidities, acute phase COVID 19 course and data about post COVID 19 manifestations) and clinical investigations. Chest radiological study, pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 minutes walking test laboratory analysis, echocardiogram and, if necessary, a specialist assessment were collected. Multivariable logistic regression was used to evaluate the association between demographic data, clinical data, hospitalization, and long-term health consequences.

Results:
Analysis revealed that at the three months evaluation a large percentage (67%) of subjects still suffered from several multiorgan symptoms. The most common persistent symptoms were fatigue, effort dyspnoea followed by hair loss and psychological impairment. Pulmonary radiological and functional studies showed persistent abnormalities in 54% and 28% respectively, although these percentages fall to 30% if we consider severe radiological impairment (> 5%) and to 3% for severe decreased pulmonary diffusion capacity for carbon monoxide. 6-minute walk test resulted pathological for desaturation in 14% of cases. Multivariable analysis identified an higher number of onset symptom during acute phase as independent predictors for many persistent symptoms at 3 months: fatigue (odds ratio [OR]: 1.08, 95%CI:1.02-1.14, p=0.006), dyspnoea (odds ratio: 1.05, 95%CI:1.01-1.09, p=0.02), hair loss (odds ratio: 1.01, 95%CI:1.00-1.02, p=0.03) and psychological impairment (odds ratio: 1.05, 95%CI:1.01- 1.09, p=0.02). In addition, the model showed that developed neurological (odds ratio: 1.16, 95%CI:0.91-1.45, p=0.01) or infective (odds ratio: 0.99, 95%CI:0.83-1.18, p=0.01) complications during hospitalization were risk factors for persistent neurological symptoms.

Conclusions:
The results of this single center cross-sectional study imply that COVID-19 may result in a long-lasting syndrome, with residual symptoms (fatigue, dyspnoea, hair loss and psychological impairment) associated with a high number of onset symptoms during the disease acute phase. Since the SARS CoV2 infection causes an elevated cytokine release and immune-cell hyperactivation, immune dysregulation and multisystem inflammatory syndrome could be involved in this persistence of post infection symptoms. Our analysis showed that developed neurological or infective complications during hospitalization were risk factors for persistent neurological symptoms. This result can be explained by the fact that, during acute phase, there are different mechanisms by which SARS-Cov-2 may enter and damage the nervous system (direct infection injury, blood circulation pathway, neuronal pathway, immune mediated injury, hypoxic injury). Further, critical illness polyneuropathy (CIP) is a frequent condition in critically ill patients that recognized sepsis among the most significant risk factor.Finally, in our opinion management of COVID-19 survivors should be optimized through a multidisciplinary approach and, although further studies result necessary, optimise the management during acute phase in order to prevent complications could reduce long term sequela.

Introduction

At the end of 2019 a novel coronavirus (SARS CoV2) arose in Wuhan China and caused a significant global medical issue, with a growing number of cumulative confirmed cases (1,2). The clinical spectrum of the SARS CoV2 infection (COVID-19 from now on) ranges from mild respiratory symptoms to severe multiorgan disease (3). The occurrence of such a wide spectrum of diagnostic and clinical events is probably the main lesson learnt from the first wave of the COVID-19 contagion, as extensively described and discussed in an impressive amount of recently published scientific literature (4–10). However, with the progression of the pandemic, several evidences, often of multi- organ character, are emerging about clinical symptoms and complications that may persist for several months after hospitalization. These evidences show that COVID-19 survivors often present persistent health issues that include cough and breathing difficulties, enduring fatigue, and issues that can be associated to post-traumatic stress disorders.

According to the NICE guidelines on long COVID-19 the two definitions of post-acute COVID-19 include ongoing symptomatic COVID-19 (symptoms between 4 and 12 weeks after the start of acute symptoms) and post-COVID-19 syndrome (symptoms for more than 12 weeks after the start of acute disease) (11). In the last few months, several observational studies contributed to a better refinement of these definitions, thus allowing a more sophisticated characterization of long COVID-19 (12–14). However, very few papers so far have been published about the identification of descriptors of the acute COVID-19 phase that may significantly impact on post disease manifestations.

In particular, a very recent study has been conducted on a population of around 4,000 individuals who utilized a specifically designed app in order to self-report their long COVID-19 symptoms. This analysis pointed out a statistically significant correlation between the number of symptoms in the acute phase with typical long COVID-19 manifestations. Using more detailed information acquired from standardized questionnaires and clinical investigation, the present study confirms this correlation, and, further, proves that neurological and infective complications during hospitalization are risk factors for neurological complications at 12 weeks after the acute phase.

Methods
Population overview

The present observational, cross sectional study was conducted at the IRCCS Ospedale Policlinico San Martino in Genoa (Italy), from July 2020 to November 2020. Patients were referred to the post COVID-19 evaluation either by their general physician or directly, in case they were discharged from a COVID-19 hospital unit from March 2020 to July 2020. The service delivery model followed established clinical criteria as for traditional outpatient programs. Therefore, patients with active neoplastic disease and patients with severe comorbidities (such as psychotic disorder, dementia or who were unable to move freely due to concomitant osteoarthropathy disease) not allowing outpatient medical examination were excluded from the study. The study involved 148 subjects with previous SARS CoV 2 infection, 63 (43%) of them being females and 85 (57%) males. Median age was 62 years (range 31 – 85). Complete demographic, baseline characteristics and comorbidities data are reported in Table 1.

COVID-19 diagnosis and acute phase

Acute phase was defined as the time between symptom onset and hospital discharge.

The severity of the COVID 19 acute phase course was divided into four categories: the first group included the mild cases, not requiring oxygen supplemental; the second group included the moderate cases, receiving oxygen therapy; the third group included the mild-severe cases, requiring continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) support; the fourth group included the severe cases, requiring orotracheal intubation and intensive care unit (ICU) admission.

COVID-19 diagnosis was made by relying on laboratory assessment, either by molecular assays on nasopharyngeal swab (92%) or by molecular assays on bronchoalveolar lavage (1%) or in case of patients with clinical and radiological lesions strongly suggestive for SARS CoV2 infection (7%). Severity of COVID 19 course was mild for 20% of patient; moderate for 33%; mild – severe for 22%; severe for 25%. The average length of hospital stay was 26 days (range 3 – 111); 14% of patients had never been hospitalized but had received home care treatments. The most common recovery complication was overlapping infection (18%), followed by thrombotic events (9% pulmonary, 8% other district), hematoma (6%) (mainly iliopsoas muscle was involved – probably due to enoxaparin treatment), kidney failure (4%), and cardiac impairment (4%) (15,16). At hospital discharge, 4% of patients needed to continue supplemental oxygen therapy, but none of them had chronic respiratory failure in their personal anamnesis. Principal characteristics about acute phase course are reported in Table 2.

Data collection

For each patient, the cross-sectional post-discharge evaluation was performed averagely 12 weeks after acute phase of COVID 19 (range 10 – 15 weeks) via standardized sets of questionnaires and investigations. The core components included patients' assessment via standard questionnaire to evaluate demographic data (age, gender, smoking), body mass index (BMI) comorbidities, acute phase COVID-19 course (onset symptoms, severity of the disease, therapy, complications, duration of the hospitalization, hospitalization time and time interval for having two subsequent COVID 19 swabs with negative result) and data about post COVID-19 manifestations (residual symptoms such as fatigue, dyspnoea, hair loss, neurological symptoms, chest pain). Dyspnoea was investigated by means of the Medical Research Council (mMRC) questionnaire. The mMRC scale is a validated self-reported questionnaire to characterize the level of dyspnoea with physical activity in which higher scores correspond with increased dyspnoea.

At follow up program intake, patients underwent a full medical assessment including full pulmonary function tests, 6-minute walking test, either a high-resolution computed tomography (CT) or an X ray of the chest, laboratory analysis, echocardiogram and, if necessary, a specialist assessment (cardiological, neurological, psychiatric, etc).

Imaging evaluation at three months was performed with high resolution CT or contrast-enhanced CT. High resolution CT (HRCT) was performed on a multidetector 16 row CT scanner with volumetric acquisition during a single full inspiration; 1,25 mm contiguous thin slices were reconstructed with standard and high-resolution filters for evaluation. Patients complicated by pulmonary thromboembolism during the acute phase or by abdominal haematoma were evaluated by contrast-enhanced CT scan in order to evaluate pulmonary reperfusion or hematoma evolution.

When available, the chest CT images performed during the hospital stay and the follow – up images were compared. The CT features were evaluated by one experienced radiologist and one pneumologist. A Six-Minute-Walk Test (6MWT) was performed during outpatient first assessment, considering as pathological an arterial oxygen saturation value below 90%. Those patients who presented physical contraindications to the 6MWT were excluded. Spirometry and lung volumes were measured with the subject sitting in whole – body plethysmograph. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC ratio, total lung capacity (TLC), standard diffusion lung capacity for carbon monoxide (DLCO) were determined following standard procedures and compared with available predicted values (17,18).

Since acute phase of COVID-19 is considered as a multiorgan disease, laboratory tests were performed at tree months revaluation in order to exclude persistent systemic infection or treatment related to other acute exacerbation of chronic disease. Blood tests included blood count, kidney, liver and thyroid functions, ions, LDH, PCR, B-type natriuretic peptide, glycated haemoglobins, d-dimer.

Blood gas analysis was performed to measure the levels of oxygen and carbon dioxide concentrations in the blood and to evaluate persistency of respiratory insufficiency.

Regression analysis

We performed a multivariate logistic linear regression analysis to investigate the impact of both demographic and clinical data, and COVID-19 severity and hospitalization, on the post COVID-19 symptoms at three months follow-up. We considered:

• Whether the variable we defined to account for the severity of COVID-19 during the acute phase (four stages: mild, moderate, mild-severe, severe) could be considered as a valid and robust measure of the severity of acute COVID-19. To do so, we performed a linear regression analysis predicting such variable from demographic and clinical data; specifically: sex, BMI, age, smoking habit and number of comorbidities at onset.

• The impact of both demographic and clinical data, and COVID-19 severity and hospitalization, on the post COVID- 19 symptoms at three months. Specifically, we built a linear regression model to predict the five most common symptoms (fatigue, anxiety, hair loss, dyspnoea, neurological impairment) from a set of variables including both demographic and clinical (sex, BMI, age, smoking habit, number of comorbidities at onset), and COVID-19 severity and hospitalization (number of COVID-19 symptoms at inset, thoracic X-ray scan severity, severity of COVID-19 at onset, cardiological complications, infective complications, TEP complications, neurological complications).

Results

Major post COVID 19 clinical manifestations

Analysis of post COVID 19 manifestations revealed that at the three months revaluation a large percentage of subjects still suffered from several multiorgan symptoms. In our cohort, only 33% of patients evaluated at three months from post-acute phase claimed no residual symptoms. It is worth mentioning that some patients reported hair loss as the only symptom (18.9%). As shown in Table 3, the most common reported symptoms were fatigue and dyspnoea followed by hair loss and phycological impact. Approximately 80% of the subjects who reported symptoms, reported persistence of one or two symptoms, while only few of them (18%) reported more than two symptoms. Complete overview of symptoms is provided in Table 3.

The most common symptom was fatigue (29%), defined by impaired exercise tolerance, reduced capacity and/or impaired memory and concentration.

The second most common symptom was dyspnoea (24%). Most people affected by this symptom (99%) reported its manifestation in case of physical effort (mMRC < grade 5). Among other symptoms, hair loss was reported by 28 patients (23/28 females and 5/28 males). Begin of effluvium was noted in hospitalized patients, either during hospitalization or close to the discharge date. None of subjects claiming hair loss reported other associated symptoms as scalp itchiness, skin desquamation or hair loss in other body areas. The examination detected diffuse non-scarring hair loss in all the study subjects.

Approximately 14% of patients enrolled in study reported persistence of moderate to severe anxiety symptoms, or depressive symptoms, at three-month follow-up, whereas a lower percent of cases (< 1%) experienced symptoms corresponding to post traumatic stress disorder (PTSD). Moreover, 14% of these patients reported chronic history of psychiatric disease.

One of the most common neurological symptoms is hyposmia/anosmia, often associated to taste impairment (19). Among patients included in our study, 18% reported smell and/or taste impairment as onset symptoms and 39% of these patients complained persistence of these alterations. Interestingly, a significant number of patients who recovered smell/taste reported a transient period when smell and/or taste were altered (parosmia/dysgeusia, i.e. things do not smell/taste like they used to) before full recovery. The most common scent reported were burnt, coffee or mold taste, often associated with salty or bitter taste.

Furthermore, a few percentages (10%) of our patients reported other persistent neurological symptoms: the most common were headache and dizziness, followed by impairment of cranial or peripheral nerves.

At least, approximately 40% of population in study reported cognitive disturbances, especially memory disorders and attention deficit.

Only a small proportion of patients reported persistent myalgia and arthralgia (5%). Arthralgia is a common symptom that occurs in patients during acute phase of COVID-19. However, to date information on rheumatic and inflammatory manifestations (such as arthritis) are scarce in literature. Patients included in this study reported sudden onset of polyarticular pain after initial illness phase. At three months revaluation shoulder and hand joints were mainly affected; no patient reported rheumatic diseases in their medical history.

Specialist evaluations at three months

Radiology and pulmonary function

In our cohort, approximately 54% of cases showed radiological abnormalities consistent with extended ground glass area (GGOs), consolidation or fibrosis, whereas the remaining cases had complete resolution of the initial alterations, limited GGOs area, or only residual fibrous stripes. The main residual lesions were ground glass area (46%), fibrotic stripes (31%) (in this group 36% showed bronchiectasis). Only in a minimal percentage of cases (<1%) residual CT pattern showed consolidation (Figure 1)

Exams performed in this study were compared to an acute phase radiological study when available; all exams showed an improvement in imaging findings including reduction in number and size, or even resolution, of GGOs, decrease in the consolidation density with gradual reduction in the density and transition to ground glass opacity and, finally, in a few percentage (<5%) of cases resolution of fibrosis displayed by the previous test. (20).

At three month evaluation a contrast enhanced CT scan were performed in patients (9%) complicated by pulmonary embolism during acute phase of COVID-19. All exams showed complete resolution of massive or micro thromboembolism.

Pulmonary functional tests

In our cohort after three months from acute phase, 28% of patients had decreased pulmonary diffusion capacity for carbon monoxide, 25% mild grade, 3% moderate – severe grade (scale according to ERS/ATS DLCO standards). Approximately 85% of patients had a normal total lung capacity; in the rest of population, we observed 13% of mild restrictive ventilatory deficit (scale according to ERS standard. Airflow obstruction was present in less than 1% of our population and these patients had chronic obstructive lung pathology in their medical history.

Six-Minute-Walk-Test

A total of 135 out of 148 patients completed the test and few patients (9%) were excluded due to their physical condition. The median distance covered during the examination was 455 m (range 220 – 580 m), an abnormal desaturation during physical exercise was present in 14% of cases.

All patients with 6MWT abnormalities presented an altered functional pulmonary test and/or persistent lesions at the imaging. (14)

Blood test

Blood tests included blood count, kidney, liver and thyroid functions, ions, LDH, PCR, B-type natriuretic peptide, glycated haemoglobins, d-dimer. Results showed no significant persistent abnormalities, except for three patients who developed renal failure during acute phase of illness which was still present at three-month control.

The majority of patients refused the blood gas analysis and for this reason only 50 arterial blood draws were collected; in available samples no abnormalities were recorded. In our cohort, six patients were discharged with the recommendation of long-term oxygen therapy and at three-month revaluation only one patient needed a prolonged prescription for oxygen due to persistent desaturation during physical exercise.

Echocardiogram

A small percentage (4%) of survived patients in study cohort, during hospital recovery, presented cardiovascular complications. At three-month evaluation, results showed approximately 3% of persistent pericardial effusion in the major cases with no associated constrictive physiology. In only two cases, moderate grade of pericardial effusion persisted. Both patients developed viral myocarditis during acute phase of COVID-19. During the post-acute phase, no other effects of SARS-CoV-2 infection on the heart were identified in the study population, except for one case of pulmonary hypertension associated with interstitial lung disease.

Statistical results

We performed a multivariate linear logistic regression analysis to investigate the impact of both demographic and clinical data, and COVID 19 severity and hospitalization, on the post COVID-19 symptoms at three months. We found that:

• Both sex (M) and BMI showed significant correlation with the variable we defined to account for the severity of COVID 19 (sex: p=0.003; BMI: p=0.0003), which agrees with recent results and guarantees that such variable is a valid measure of COVID-19 severity. (1)

• Significant statistical correlation between number of symptoms of COVID 19 acute phase and persistent fatigue (odds ratio [OR]: 1.08, 95% CI:1.02-1.14, p=0.006), effort dyspnoea (OR: 1.05, 95%CI:1.01-1.09, p=0.02), hair loss (OR: 1.01, 95% CI:1.00-1.02, p=0.03) and psychological impairment    (OR:1.05,95%CI:1.01-1.09,p=0.02).  In addition, the model showed that developed neurological (OR: 1.16,95%CI:0.91-1.45,p=0.01) or infective  (OR:0.99,95%CI:0.83-1.18, p=0.01) complications  during.

hospitalization were risk factors for persistent neurological symptoms. No other significant statistical correlation was found considering other variables analysed (demographic data, comorbidities, severity course of the acute phase). Illustration of these results is reported in Figure 2.