Discharge from the Emergency Department and Early Hospital Revaluation in Patients with COVID-19 Pneumonia: an Observational Study

Background: Health National Systems world-wide are facing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We purpose an outpatient management for patients affected by SARS-CoV-2 related pneumonia at risk of progression, after discharge from Emergency Department (ED). Methods: This was a single-center prospective observational study. We enrolled patients with confirmed SARS-CoV-2 pneumonia, without hypoxemic respiratory failure, and at least one of the following: age ≥ 65 or presence of one or more comorbidities or pneumonia involvement > 25% on high resolution computed tomography (HRCT). The ambulatorial visit was performed after at least 48 hours, then patients could be discharged, admitted for hospitalization, or deferred for a further visit. As a control, we evaluated a historical cohort of patients hospitalized with comparable clinical and radiological features. Results: A total of 84 patients were enrolled (51 M, mean age 62.8 y). Two-thirds of patients had at least one comorbidity and 41.6% had a lung involvement > 25% at HRCT;the mean duration of symptoms was 8 ± 3 days and the mean PaO2/FiO2 ratio 357.5 ± 38.6. At the end of the follow-up period, 69 patients had been discharged and 15 hospitalized (mean stay 6 days). Older age and higher NEWS2 were significant predictors of hospitalization at the first follow-up visit. One hospitalized patient died of septic shock. In the control group, the mean hospital stay was 8 days. Conclusions: Adopting a “discharge and early revaluation” strategy appear to be safe and feasible. This approach may help to optimize hospital resources during the SARS-CoV-2 pandemic.

one comorbidity and 41.6% had a lung involvement > 25% at HRCT; the mean duration of symptoms was 8 ± 3 days and the mean PaO2/FiO2 ratio 357.5 ± 38.6. At the end of the follow-up period, 69 patients had been discharged and 15 hospitalized (mean stay 6 days). Older age and higher NEWS2 were signi cant predictors of hospitalization at the rst follow-up visit. One hospitalized patient died of septic shock. In the control group, the mean hospital stay was 8 days.
Conclusions Adopting a "discharge and early revaluation" strategy appear to be safe and feasible. This approach may help to optimize hospital resources during the SARS-CoV-2 pandemic.

Background
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been rst identi ed in December 2019 in China [1], where it caused the rst cluster of cases that have rapidly diffused worldwide, leading to a pandemic. Italy is one of the most affected countries with more than 2.7 million cases and a case fatality rate of 3.4% [2].
The Italian National Health System, like most countries, has struggled to withstand the epidemic wave, especially due to the lack of hospital beds, both for ordinary and intensive care.
In a large epidemiological study, only 19% of patients with SARS-CoV-2 infection developed severe or critical illness and pneumonia with hypoxemic respiratory failure is the more frequent complication [3].
Several risk scores adopting clinical, radiological and laboratory markers of progression of the disease [4,5] that could help in the management of patient affected by Coronavirus 19 disease (COVID-19) have been proposed; however, their real-life applicability is limited, as they must be integrated into a more complex clinical judgment. Indeed, one of the crucial decisions is the discharge from the Emergency Department (ED). In a retrospective cohort of low-risk patients (median age 38 and 61% without comorbidities) with COVID19-like symptoms discharged from ED, the readmission rate was 4% after a median of 5 days [6]. In a multicentre study enrolling only con rmed COVID-19 patients, about 5% of patients discharged from ED was readmitted, and then hospitalized, within 72 hours and 8.2% within seven days; the major predictors of readmission were the presence of hypoxia, fever and age > 60 years [7].
A useful solution for the optimization of resources may be to treat and follow-up these patients as outpatient. Two Spanish recent studies reported similar experiences [8,9]. Teigell Muñoz et al We consider that a goal should be to identify at their rst access to ED symptomatic patients with mild-tomoderate COVID-19 pneumonia and reserving them a fast-track access to hospital care, if needed. In this prospective study aims to evaluate the feasibility and safety of our new protocol in patients with SARS-CoV-2 related pneumonia discharged from the ED at risk of progression.

Study design, setting and selection of population
The study population was a cohort of patients admitted and discharged within a few hours from the Emergency Department of Azienda Ospedaliera Ospedali Riuniti Marche Nord (Pesaro), Italy and reevaluated in our COVID-19 Early Medical Revaluation Ambulatory. All the patients were older than 18 and gave informed consent. The inclusion criteria were: 1) con rmed SARS-CoV-2 infection by RT-PCR nasopharyngeal swab; 2) age ≥ 65 or presence of at least one comorbidity including hypertension, chronic obstructive pulmonary disease (COPD), chronic heart failure, obesity (BMI > 30), active neoplasia or semiquantitative pneumonia involvement > 25% on HRCT; 3) radiological evidence of interstitial pneumonia at HRCT with semiquantitative extension ≤ 50% [8]; 4) absence of functional respiratory failure de ned by the presence of both PaO2/FiO2 ≥ 300 and no desaturation at quick walking test (QWT) [9]. The patients who did not meet all the inclusion criteria were excluded.
As a control group, we collected clinical data of a historical cohort of patients admitted to the same hospital from March 10 to December 31, 2020 for COVID-19 pneumonia. Controls were matched at admission to ED for age, sex, number of comorbidities, evidence of pneumonia at HRCT and absence of respiratory failure (considered as PaO2/FiO2 ratio > 300).
The study was performed according to the ethical guidelines of the Declaration of Helsinki (seventh revision). The report is according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement for observational studies.

Interventions and measurements
Upon discharge, clinicians gave a pulse oximeter and a personal diary to measure and report three times daily i) body temperature, ii) peripheral oxygen saturation (SpO2) at rest and iii) after a QWT. The ambulatorial visit was performed after at least 48 hours after discharge and included: complete physical examination, personal diary check, lung ultrasound [10], arterial blood gas test and quick walking test.
After the visit, patients could be discharged, admitted for hospitalization, or deferred for a further visit. The last follow-up of all discharged patients was a phone call made 30 days after the index admission.

Data analysis
Continuous variables were summarized using mean ± standard deviation (SD) or median and interquartile range (IQR) if the data were parametric or nonparametric, respectively. Categorical data were summarized as absolute numbers and percentages. The results were tested for normality by Kolmogorov-Smirnov's test. Student's t-test or nonparametric Mann-Whitney U test were used to compare continuous variables in subgroups of patients, as appropriate. Chi square test was used to compare categorical variables. A logistic regression model was performed to identify variables associated with hospitalization. A p value <0.05 was considered signi cant. All statistical analyses were performed with the STATA Software.

Characteristics of study subjects
From November 15th, 2020 to January 10th, 2021, 84 patients were enrolled (51 M, mean age 62.8 ± 12.0 years). Table 1 summarizes the baseline characteristics of the cohort. Most patients had one or more comorbidities (22.6% were obese, 23.8% had diabetes, 32.1% hypertension, 8.3% COPD). At the 30-day follow-up call, all but one patients were alive. The deceased patient was a 84-year-old woman that had to be admitted after the second visit because of hypoxemic respiratory failure. After a hospitalization that lasted 12 days (6 in the Intensive Care Unit and 6 in the Sub-intensive Care Unit), she was discharged home. Two days later she was referred to ED for fever, chills, myalgias and shortness of breath. The investigations showed the presence of Enterococcus Faecium in the urine and Acinetobacter Baumannii in the lower respiratory tract. She died of septic shock after 36 hours.
A total of 15/84 (17.8%) patients had to be admitted by the end of the follow-up window. The mean duration of hospitalization was 6.1 ± 2.5 days. All but 3 institutionalized patients (one still receiving low ow oxygen supplementation) were at home at the time of the phone call. The 66 patients that could answer were also asked to rate the ambulatory service on a 10-point scale, with 10 representing the best possible. Overall, they rated the service with a mean of 9.1 ± 1.5 points. Table 2 summarizes the comparisons between patients that have been hospitalized and patients that were managed home, considering the variables at the index admission and at the rst follow-up visit. Overall, there were no differences between the two groups at the index admission except for age (higher for the hospitalized group). Conversely, considering only patients that attended the rst follow-up visit (n = 78), the group that had been hospitalized showed higher mean NEWS2, lower peripheral oxygen saturation at rest and after a walking test, lower PaO2/FiO2 ratio and, more importantly, their diary was more likely to be positive for warning signs while at home.  We next compared the group of patients that have been managed with the Early Discharge and Re-Evaluation protocol and a historical cohort of patients that were admitted to the ED and hospitalized, marched for age, sex, number of comorbidities, evidence of pneumonia at HRCT and absence of respiratory failure (considered as PaO2/FiO2 ratio > 300). The cohorts were comparable for all other variables (data not shown). Although the mean duration of hospitalization was not different between groups (6.2 ± 5.5 vs 8.8 ± 5.2 days), in our cohort only 15/84 (17.8%) patients were hospitalized, compared to the totality of the 63 patients of the historical cohort.

Discussion
Discharging patients with SARS-CoV-2 pneumonia and without hypoxia and managing them in an ambulatorial service appears to be safe and feasible.
Of the 84 enrolled patients, all completed the follow-up period. Only one died of septic shock due to a nosocomial infection; hospitalization was needed for the progressive development of hypoxia detected in a control visit. This cohort of patients was representative of those with SARS-CoV-2 related pneumonia with low-to-moderate risk for progression of the disease [4,11]: 60.7% of them were male, the median age was 62.8 years, with 1 or more comorbidities and 41.7% of them had a lung involvement higher the 25% (but lower than 50%) at HRCT score. Fever was reported by almost all patients (96.4%), cough by more than a half (58.3%) and shortness of breath by a third of them (34.5%).
COVID-19 has a triphasic course: the early disease (I), the pulmonary (IIa without and IIb with hypoxia) and the hyperin ammation phases [12]. With the ambulatorial strategy, we tried to revaluate patients between stage IIa and IIb. In fact, our patients complained of symptoms attributable to SARS-CoV-2 infection from 8.0 ± 3.0 days and the mean duration of the ambulatorial management was 4.6 ± 2.7 days.
At the index admission, the respiratory status was satisfactory: all patients were eupnoeic, with a negative QWT and values of PaO2/FiO2 ratio at the lower boundaries for the need of oxygen supplementation. Older age and higher NEWS2 appear to be the most important predictors of hospitalization. However, of the 10 patients that had been admitted by the end of the rst scheduled follow-up, only 2 had a NEWS2 score ≥ 2 at the index admission, whereas all the 4 patients that presented to the rst visit with a NEWS2 score ≥ 2 were hospitalized. A small prospective Norwegian study claimed that the NEWS2 score predicted severe disease and in-hospital mortality better than the other risk score evaluated [13], while in a larger multicentric cohort, the model of 'NEWS2 + age' alone had poor-to-moderate discrimination for severe COVID-19 at 14 days (AUC 0.7), that improves with the integration of other blood and physical parameters [14]. With these limitations, this is the rst study to assess the utility of a longitudinal evaluation of NEWS2 score for outpatients with COVID-19.
Importantly, a high proportion of patients lled out the diary: it suggests satisfactory training during the enrolment, good performance status and/or a correct engagement of the caregiver. This tool proved to be useful and helped physicians during the follow-up visit to decide how to manage the patient: in our cohort, 85.7% of patients hospitalized after a control visit had warning signs (persistent fever > 38.5°C or pulse oximetry lower than 92% at rest or lower than 90% after a QWT), versus the 11.3% that were not hospitalized. For COVID-19 patients, the presence of a caregiver or social support is crucial due to the risk of progression; in our cohort, the lack of home assistance represented the reason for hospitalization in 2 out of 15 patients.
Unsurprisingly, there was no difference between the patients managed home and those hospitalized with regard to lung involvement at HRCT. Although radiological abnormalities have prognostic relevance in patients with extensive involvement [5,15], in the Diamond Princess Ship study half of asymptomatic patients had pathologic ndings at HRCT [16], suggesting a limited speci city of this technique. Thus, HRCT extension alone may not be a good predictor of worse outcomes in patients presenting at the ED without respiratory failure. In this context, we used lung ultrasound, that is a safe and reproducible tool for the longitudinal evaluation of the severity of pneumonia [17], as described.
During a pandemic, the optimization of resources is crucial. Although we were able to provide only an indirect comparison with a cohort of comparable patients, adopting a "discharge and early revaluation" strategy may have spared many hundreds of hospitalization-days, considering that without the ambulatorial management most, if not all, of the enrolled patients would have been hospitalized. This is also more important because, to date, no therapies have proved to be effective for SARS-CoV-2-related pneumonia patients without respiratory failure [18], even if hospitalized.

Limitations
The study was observational and conducted in a single center with a small cohort of patients, so data should not be generalizable especially regarding organizational aspects and territorial management (our hospital was the hub center for COVID -19). The inclusion criteria were established with a multiparametric evaluation that may have determined selection and information bias. There were no absolute indications for the hospitalization in the control visit but it was left to the medical judgment. The control group was searched in a historical cohort to match low-risk patients that were managed as in-patient, but this determined a selection of patients and an incomplete matching of data.

Conclusions
Our study demonstrates that COVID-19 patients without respiratory failure can be safely managed with a "discharge and early revaluation" approach directly from the ED staff. This translates into similar outcomes for the patients but with a signi cant saving of resources for the National Health System.
Further studies are needed to assess the best management strategy for low-to-moderate risk COVID-19 patients.

Declarations
Ethics approval and consent to participate: The local ethics committee waived approval of the study given our outpatient service was ongoing for the pandemic; all the patients gave written informed consent Consent for publication: It was obtained and collected from all the patients Figure 1 The ow-chart summarizes the management course of the enrolled patients: admission, revaluation or discharge. ED: Emergency Department.