key: cord-0983678-lqdejjx7
authors: Guglielmetti, Lorenzo; Kontsevaya, Irina; Leoni, Maria Cristina; Ferrante, Patrizia; Fronti, Elisa; Gerna, Laura; Valdatta, Caterina; Donisi, Alessandra; Faggi, Alberto; Paolillo, Franco; Ratti, Giovanna; Ruggieri, Alessandro; Scotti, Marta; Sacchini, Daria; Taliani, Gloria; Codeluppi, Mauro
title: Severe COVID-19 pneumonia in Piacenza, Italy – a cohort study of the first pandemic wave
date: 2020-12-09
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2020.11.012
sha: a4321bae08a68b2d26adbdc725405b4a2211417b
doc_id: 983678
cord_uid: lqdejjx7

Background Piacenza is the closest city to the first coronavirus disease 2019 (COVID-19) cluster in Italy and has the highest national COVID-19 death rates per population. The objective of this study is to present characteristics and outcomes of patients admitted to medical departments of the Hospital of Piacenza during the first wave of the epidemic. Methods A total of 218 patients with confirmed or suspect COVID-19 and severe pneumonia were included from February 21st to May 15th, 2020. Routinely-collected clinical and laboratory data were retrospectively retrieved from electronic medical files. A Cox proportional-hazards model was fit to assess the association of treatment and other variables with death. Results Median age of patients was 68 years; 150 patients (69%) had comorbidities, mainly hypertension (107, 49%). Overall, 185 (85%) patients had acute respiratory distress syndrome (ARDS) on admission, including 103 (47%) with moderate or severe ARDS. Chest computed tomography scan showed bilateral disease in 201 (98%) and extensive lung involvement in 79 (50%) patients. Most patients received antiviral treatment (187, 86%) and corticosteroids (134, 61%). All patients received respiratory support and 64 (29%) were admitted to intensive care unit. As of June 30th, 100 patients (46%) died, 109 patients (50%) were discharged, and 9 patients (4%) were still hospitalized. In multivariable Cox analysis, age above 65 years, having more than one comorbidity, severe ARDS, low platelet counts, and high LDH levels at admission were associated with mortality, while having diarrhea at admission was associated with survival. The use of antivirals or corticosteroids was not associated with survival. Conclusions Overall case fatality rates were high and associated with comorbidities, extensive lung involvement, ARDS at admission, and advanced age. The use of antivirals was not associated with increased survival.

There is no specific funding to declare for this study. The work of the corresponding author ( LG) in the Hospital of Piacenza was supported by the Italian Society of Infectious and Tropical Diseases (SIMIT).

Authors have no competing interests to disclose.

The study was approved by the local Ethics Committee (Area Vasta Emilia Nord). Requirement for informed consent was waived by the Ethics Committee.

Data may be made available by contacting directly the corresponding author.

LG made a substantial contribution to the conception and design of the work, to the acquisition, analysis and interpretation of data for the work, performed statistical analysis, wrote the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. COVID-19 is thought to have a favorable clinical course in most patients. However, in some cases, it may lead to severe pneumonia and eventually to acute respiratory distress syndrome (ARDS). [1] To date, there is no established antiviral treatment for COVID-19. Many drugs are currently under investigation, while several are being employed in off-label use, and others are available via compassionate use or expanded access programs.

As of October 31 st , 2020, 45 667 780 cases of COVID-19 and 1 189 499 deaths have been reported worldwide, [2] with 594 472 cases and 37 781 deaths having occurred in Italy. [3] Italy, the first Western country reporting sustained COVID-19 transmission, has been disproportionately affected by the epidemic. [4] [5] [6] In areas of Northern Italy surrounding the first COVID-19 cluster in the town of Codogno, public healthcare systems have been overwhelmed by the abrupt caseload increase. [7] Limited availability of ventilatory support in intensive care units (ICUs) of many hospitals prompted the need to implement forms of patient triage. After the first months of the epidemic, the province of Piacenza, the closest to the initial cluster, had the highest COVID-19 death rates per population in the country. [8] In the Piacenza Hospital, the first proven case was reported on February 21 st , 2020. [9] As ICU capacity was quickly exhausted by COVID-19 patients, non-ICU medical departments, and in particular the Infectious Diseases Unit, had to admit increasing numbers of critically-ill patients who needed advanced respiratory support.

Multiple case series of COVID-19 patients have been published, mostly from China and the United States. [10] [11] [12] [13] [14] [15] [16] [17] [18] However, descriptions of the characteristics of patients in Italy are less J o u r n a l P r e -p r o o f common, excluding studies from the ICU setting. [19, 20] Moreover, there is a need to characterize management and outcomes of severe cases admitted to non-ICU wards.

In this study, we present the characteristics of patients with severe COVID-19 pneumonia who were admitted to four medical departments of the Hospital of Piacenza during the first epidemic wave of the outbreak, aiming to describe treatment, case fatality rates, and factors associated with mortality.

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

Consecutive patients admitted to four non-ICU medical departments (Infectious Diseases, Emergency Medicine, and two COVID-19 Units created during the epidemic) of the "Guglielmo da Saliceto" Hospital in Piacenza between February 21 st , 2020, and May 15 th , 2020, were included in this single-center, retrospective, observational study. Inclusion criteria for the study were the following: 1) confirmed COVID-19 cases with positive Sars-CoV-2 polymerase-chain-reaction (PCR) test, or suspect COVID-19 cases with highly suggestive radiologic evidence on chest high-resolution computed tomography (HRCT), in the absence of an alternative diagnosis, and 2) severe COVID-19 pneumonia. Children (<18 years old) were not included. The study was approved by the local Ethics Committee (Area Vasta Emilia Nord).

Requirement for informed consent was waived by the Ethics Committee.

Confirmed and suspect COVID-19 cases, and cases with severe COVID-19 pneumonia were defined according to WHO criteria. [21, 22] COVID-19 cases were confirmed using reverse transcriptase real-time PCR on nasopharyngeal swab specimen. HRCT scans were routinely performed at hospital admission to diagnose pulmonary COVID-19 and to assess the extent of lung involvement. HRCT scans were read by expert radiologists, who assessed optically the proportion of lung parenchyma involved by viral pneumonia (i.e. interstitial involvement, ground-glass opacities, crazy-paving pattern, etc.), as described previously. [23] Blood tests (including blood gas testing) were performed at the Clinical Laboratory of the Piacenza Hospital. Results from samples collected on admission or on the following day were considered as baseline results and included in the analysis.

Routinely-collected data were retrieved retrospectively from electronic medical files, crosschecked and collated in an anonymized database. Collected data included demographic and clinical characteristics of patients, laboratory and radiologic examinations, treatment and oxygen support received, and outcomes. Treatment data were only available for the period of hospital stay at the medical departments, but not during the stay in the ICU. Data collection was completed and data were locked on June 30 th , 2020.

Results of continuous data were reported as median and interquartile range (IQR), while categorical data were reported as counts and proportions. Missing data were not imputed.

Survival analysis was performed to describe the time from hospitalization to death and Kaplan-Meier curves were estimated for probability of survival after hospitalization, overall J o u r n a l P r e -p r o o f and by various strata. Tests between strata were done by the log-rank test. The association of explanatory variables (patient characteristics, symptoms, comorbidities, laboratory and radiologic exams, and treatments) with death was analyzed using a multivariate Cox proportional hazards model. Variables were initially included into the multivariate Cox proportional hazards model if they predicted the outcome at a p-value ≤ 0.20 in univariate analysis and if they fulfilled the proportional hazards assumption; a stepwise backwards hierarchical approach was applied for variable selection in the multivariable model. Hazard ratios (HRs) were reported with standard errors and 95%-confidence intervals (CI). No routine imputation of missing explanatory variables was done.

Statistical analysis was performed using Stata software version 15.0 (StataCorp).

There is no specific funding to declare for this study. The work of the corresponding author (LG) in the Piacenza Hospital was supported by the Italian Society of Infectious and Tropical Diseases (SIMIT).

Overall, 245 proven or suspect COVID-19 cases were admitted to the four non-ICU medical departments of the Piacenza Hospital during the study period, out of which 218 had severe COVID-19 pneumonia and were included in the study.

Baseline clinical characteristics are shown in Table 1 (8) Onco-hematologic cancer 10 (5) Chronic kidney disease 20 (9) Chronic liver disease 3 (2) HIV infection 2 (1)

None 68 (31) One 59 (27) More than one 91 (42) Total number, median (IQR) 1 (0-4) IQR = interquartile range; BMI = body mass index; COPD = chronic obstructive pulmonary disease; HIV = human immunodeficiency virus.

As shown in Table 2 Overall, 68 (31%) died in the ward and 33 (15%) in ICU. Figure 1 shows Kaplan-Meier curves for mortality, overall and stratified by age (log-rank, p<0.0001), extension of lung parenchyma affected by pneumonia at chest HRCT scan (log-rank, p<0.0001), and PaO2/FiO2 ratio on admission (log-rank, p<0.0001). One hundred-nine patients (50%) were discharged to a rehabilitation facility or sent home. Among these patients, median duration of hospitalization was 18 days (IQR, 11-27 days). Four patients (2%) were still in ICU and 5 patients (2%) were still in a non-ICU ward. Figure 2 J o u r n a l P r e -p r o o f

We hereby report high case fatality rates in patients affected by severe COVID-19 pneumonia who were hospitalized in non-ICU wards in Italy, despite the frequent use of antiviral drugs and access to non-invasive ventilation support.

In our study, 79% of patients were male, similarly to what has been described for ICU patients in Italy. [20] Overall, 85% of patients in our study had ARDS on admission, including 47% with moderate or severe ARDS. These rates of ARDS, much higher than in previous studies with a similar setting, [10, 17, 18, 24] are more comparable to ICU cohorts, [11, 12, 16, 20, 25] and may account for the high mortality observed in our study (Figure 1d ). The median time from onset of symptoms to hospitalization was 7 days, suggesting that our patients developed severe illness in a short time. Median age was 68 years, which is higher compared to studies from Italy, [20] China, [10, 13, 15, 24, 25] Singapore, [26] and the United States, [11, 12, 14] and to surveillance data from Italy. [3] In addition, 69% of patients had at least one comorbidity, which is consistent with data from an ICU-based study from Italy, [20] higher than in studies from China, [10, 13, 17, 18] although notably lower than in a cohort from the United States. [14] As in previous reports, the most common comorbidities were cardiovascular and metabolic diseases. Therefore, our observation confirms that older age ( Figure 1b) and comorbidities are associated with poor outcomes. [16] [17] [18] 24, 27, 28] Another relevant finding was that, among patients who underwent HRCT on admission, half had 50% or more of lung parenchyma affected and 98% had bilateral disease. It has been shown that the score of pulmonary involvement is associated with ICU admission/death [23] and the results from our study support this conclusion, as well as the routine use of HRCT to assess the extension of pulmonary COVID-19 at hospital admission (Figure 1c ). On clinical grounds, almost all patients J o u r n a l P r e -p r o o f had fever, often associated with respiratory symptoms, while gastrointestinal symptoms were present in a minority of patients. This is in line with previous reports. [10, 12, 24, 26] On admission, most patients had reduced lymphocyte counts and an increase in laboratory markers linked to inflammation, such as lactate dehydrogenase, ferritin, C-reactive protein, D-dimer, and interleukin-6. These findings are consistent with previous studies indicating the decrease of antiviral immune response and the trigger of the cytokine storm. [10, 13, 14, 24, 28] The vast majority of patients included in the study received at least one antiviral and most of them a combination of two, usually hydroxychloroquine and a boosted protease inhibitor (lopinavir/ritonavir or darunavir/cobicistat). In addition, 61% of patients were treated with corticosteroids. These high rates of treatment were based on local guidelines [29] and understandable in light of the clinical severity at presentation. To date, however, the evidence backing the efficacy of these drugs is limited. In two randomized controlled trials, lopinavir/ritonavir failed to show efficacy compared to standard-of-care. [30, 31] The in vivo activity of hydroxychloroquine against COVID-19, despite high expectations, has not been confirmed in a large randomized, controlled clinical trial. [32] In our study, the use of these antivirals, often administered in combination, was not associated with increased survival, reinforcing the strong reserves on the efficacy of these drugs for treatment of severe COVID-19 pneumonia. [33] Corticosteroids are currently a mainstay of treatment of severe COVID-19 pneumonia: while no benefit had been found in the treatment of other coronaviruses, [34] multiple randomized, controlled trials have shown that corticosteroids improve survival rates in patients who need oxygen support for COVID-19. [35] More promising agents like remdesivir [36] and tocilizumab [37] were prescribed to small numbers of patients and could not be assessed in this study. In our study, corticosteroid use was associated with survival, but this finding did not reach statistical significance. This may be partially explained by the J o u r n a l P r e -p r o o f heterogeneous timing of start and duration of treatment with corticosteroids in our cohort,

and by the small sample size.

The main finding from our study is an overall case fatality rate of 46%, similar to rates reported for ICU patients [11, 12, 16, 20, 25] and much higher than those reported in studies from non-ICU wards. [10, [13] [14] [15] 24, 26] Mortality rates are often difficult to compare between these two groups of studies, also because indications for intensive care and mechanical ventilation may change greatly among different settings. [38] Indeed, most of our patients have characteristics that would have made them likely eligible for ICU directly at the triage level, had there not been a request overload due to the epidemic wave. Most deaths occurred quickly, half in the first 7 days of hospitalization and the majority within the first 28 days (Figure 1a) . There are multiple possible explanations for the high case fatality rate we observed. Above all, the characteristics of patients in our study are similar to those of ICU cohorts: high rates of comorbidities, extensive lung involvement, high proportion of ARDS at admission, and advanced age -all factors associated with mortality. As a matter of fact, during the peak of the epidemic in Piacenza Hospital, COVID-19 patients who needed ventilatory support were often allocated to non-ICU wards, like the Infectious Diseases or Emergency Medicine Units, which acted as a de facto sub-intensive care ward. This study describes the first wave of the epidemic, including the peak of COVID-19 admissions, and it is remarkable how non-ICU wards were quickly transformed to cope with the emergency, indicating a virtuous learning curve. Indeed, a high proportion of patients in our case series died without being admitted to the ICU, similarly to what has been reported previously in China, [39] likely reflecting the lack of ICU resources. Finally, it has been postulated that high pollution levels in the area may have increased fatality rates in Northern Italy [40] -an element which deserves future research.

This study has multiple limitations. As described above, the specific epidemic circumstances and patient selection must be taken into account. These findings may therefore not be representative of the overall characteristics and outcomes of COVID-19 cases in Piacenza and of severe COVID-19 pneumonia in general. In addition, 4% of patients were still hospitalized, without a final outcome, at data lock. Finally, the retrospective nature of the study explains the high rates of missing information for some laboratory tests.

In conclusion, this study describes the features of patients with severe COVID-19 pneumonia, their outcomes, and factors associated with mortality. These results warn about the consequences of hospital admission of large fluxes of patients that may overwhelm the healthcare system, despite swift response and optimal use of available resources. It seems therefore paramount to implement adequate prevention policies, while optimizing hospital preparedness, and increasing the capacities of medical and ICU wards for the management of future pandemic waves. Our results also highlight the dire need for an effective antiviral treatment for COVID-19 pneumonia. Hopefully, forthcoming randomized controlled clinical trials (NCT04315948, NCT04330690) will allow identifying promising treatment options.

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

Novel coronavirus: where we are and what we know

Situation update worldwide, as of 31 October2020

Integrated surveillance of COVID-19 in Italy

COVID-19 in Italy -Passing through bitter waters

SARS-CoV-2 and Europe: timing of containment measures for outbreak control

On the death of 100 + Italian doctors from COVID-19

Adaptations and Lessons in the Province of Bergamo

COVID-19 in Italy: An app for a province-based analysis

Covid-19: The role of palliative care had to be adapted to manage this "ultra-emergency

Clinical Characteristics of Coronavirus Disease 2019 in China

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

Covid-19 in Critically Ill Patients in the Seattle Region -Case Series

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Clinical Course and Outcomes of 344 Intensive Care Patients with COVID-19

Clinical characteristics of 145 patients with corona virus disease 2019 (COVID-19

Clinical characteristics of 194 cases of COVID-19 in Huanggang and Taian

Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response

Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy

Global surveillance for COVID-19 caused by human infection with COVID-19 virus. Interim guidance

Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance

Well-aerated Lung on Admitting Chest CT to Predict Adverse Outcome in COVID-19 Pneumonia

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Lombardy Section Italian Society Infectious And Tropical Diseases -. Vademecum for the treatment of people with COVID-19

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial

SARS-CoV-2: First Do No Harm

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial

Mechanical Ventilation in COVID-19: Interpreting the Current Epidemiology

Clinical Characteristics of Patients Who Died of Coronavirus Disease 2019 in China

SARS-Cov-2 RNA Found on Particulate Matter of Bergamo in Northern Italy: First Preliminary Evidence. Infectious Diseases (except HIV/AIDS)

The authors are grateful to the health care workers of the Infectious Diseases Unit, EmergencyMedicine department, and the other COVID-19 departments, of the "Guglielmo da Saliceto" Hospital in Piacenza, Italy, and to all the patients who were included in the study.