Low mortality from COVID-19 at a nursing facility in France following a combined preventive and active treatment protocol

Introduction

Nursing facilities have been disproportionately affected by COVID-19 both in terms of disease transmission and mortality (1). There are a number of factors that may contribute to heightened levels of transmission in the nursing facility setting, including the high number of physical interactions between residents, staff and visitors, potentially exacerbated by the configuration of the nursing facility, staff shortages, low levels of staff training, and resident ambulation (2). In addition, residents at nursing facilities are a high-risk group due to their advanced age and numerous co-morbidities (3,4). Therefore, implementation of a COVID-19-protocol can be an effective measure to reduce transmission, as well as to decrease mortality.

The protocols implemented across different nursing facilities world-wide to prevent and treat COVID-19, and their effect on the evolution of symptoms, infections, and mortality, have seldom been described (5,6). The authors of this study implemented a protocol for prevention and treatment of COVID-19 at their nursing facility, which consisted of both preventive (administering vitamins and zinc, social distancing, and temperature checks) and active (antibiotics, anticoagulants, and corticosteroids) measures. The efficacy of this protocol at limiting infections and mortality remains unclear, and a detailed assessment could help prepare nursing homes in case of respiratory virus epidemics.

The aim of this study was to retrospectively describe the evolution of symptoms, infections, and mortality at a nursing facility in Val d’Oise (France) that had implemented a protocol for the prevention and treatment of COVID-19. Our null-hypothesis was that the COVID-19 protocol used would result in a comparable mortality rate to other nursing facilities reported in the literature at a similar point in the local profile of the pandemic. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1707).

Methods

The nursing facility was home to 192 residents on 24 January 2020, the day that France officially recorded its first COVID-19 cases (7). Throughout the study period, from 24 January 2020 to 3 July 2020, 133 staff members worked at the nursing facility. A database was created on 21 March 2020 to store all information related to all 192 residents, including the number of new cases, date of onset of any COVID-19 symptoms, type of symptoms, quarantine duration, COVID-19 treatment, and hospital admissions. Resident files were systematically checked to identify any symptoms that had been reported between 24 January and the date of creation of the database. COVID-19 symptoms were divided into common (fever, cough, hypoxemia, asthenia) according to WHO guidelines (8) and less common (vomiting/diarrhoea, abdominal pain, muscle stiffness, aggravated behavioural disorders, thoracic pain, irritated skin rash, headache and meningeal irritation, pain when swallowing, unilateral conjunctivitis, digestive ischemia with rectal bleeding, encephalitis, anosmia or dysgeusia, dry rhinitis, ischemia of the fingers or toes, ischemia of large vessels, petechiae and signs of thrombocytopenia) according to guidelines in place at the nursing facility. Due to the circumstances of the pandemic, any of these symptoms, even in isolation, were taken to be indicative of COVID-19 and were considered a clinical diagnosis of COVID-19 (9-14). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Groupement de Coopération Sanitaire ELSAN (IRB #2020-11-WORCEL-01). Residents (or their guardians) provided informed consent for their data to be used for research and publication purposes.

Pre-existing patient co-morbidities and medical treatments

Patient co-morbidities were recorded, including hypertension, active alcoholism (assessed clinically), pulmonary pathology, cancer, psychosis, obesity (defined as body mass index >30 kg/m²), schizophrenia, stroke, Alzheimers, dementia other than Alzheimers, diabetes, and metabolic pathologies other than diabetes. Pre-existing medical treatments included neuroleptics for patients with psychosis and dementia (both with or without Alzheimers), antihypertensive medication for patients with hypertension, proton pump inhibitors (antacids) for patients with stomach ulcers, and anticoagulants for patients with atrial fibrillation. Additionally, palliative care, such as morphine and/or anxiolytics, was provided for patients at end-of-life stages or with terminal illnesses, to alleviate suffering.

Day-to-day protocol at the nursing facility

At the nursing facility, prior to the implementation of COVID-19 protocols, residents were distributed in single or double (couples) rooms, although they were free to move throughout the facility independently. Residents had daily contact with the nursing facility staff, who entered each room to assist with taking medications and with activities of daily living, such as bathing and dressing. From 12 March 2020, these activities continued, but where possible social distancing measures were implemented to minimize the risk of spread of COVID-19. Meals were served in resident’s rooms, all activities were cancelled, and visitors were not allowed in the facility. Communal spaces were kept open, although residents had to socially distance. Staff started using surgical masks (SSP2), disposable gloves, and disposable gowns that were then replaced by washable gowns. Disinfectant gel was available in every room for staff and residents to use, and surfaces were disinfected every day. Staff and residents had their temperature taken once a day. If staff exhibited any symptoms they were asked to stop working immediately.

COVID-19 testing

All residents and staff were offered reverse transcriptase polymerase chain reaction (RT-PCR) tests (Allplex 2019-nCov assay, Eurobio Scientific, France) to determine whether they were infected, and serology tests (ECLIA, Roche, Switzerland) to determine if they had antibodies. In cases where RT-PCR test outcomes were doubtful, a second RT-PCR test was performed. RT-PCR testing was performed between 21 March 2020 and 24 April 2020, while serology testing was performed between 25 June 2020 and 3 July 2020. Staff with a positive RT-PCR test stopped working immediately, for at least 1 week, and resumed work no earlier than 2 days after symptoms disappeared. Residents with proven or suspected COVID-19 were confined to their rooms for 28 days, although it is important to note that residents were never restrained and doors were left unlocked, which meant that residents with dementia, especially those with Alzheimers, still ambulated the facility.

Protocol for prevention and treatment of COVID-19

A COVID-19 protocol for residents was established on 15 March 2020 and was followed until the end of the study period (3 July 2020). As a prophylactic, all residents were orally administered multivitamin (Bion 3, Merck, NJ, USA) and zinc (60 mg) once a day, and vitamin D3 (100,000 units) once every 15 days. Any resident who exhibited COVID-19 symptoms was administered antibiotics subcutaneously (500 mg of azithromycin on the first day of symptoms, and 250 mg daily for the following 15 days). Any resident who exhibited COVID-19 symptoms or received a positive RT-PCR test was administered anticoagulants subcutaneously (40 mg of enoxaparin was given once a day for 15 days, or twice a day if D-dimers >3,000). Any resident with hypoxemia (<90% oxygen saturation) received oxygen therapy with pure oxygen delivered via a mask. Any resident exhibiting aggravated hypoxemia (<80% oxygen saturation) during the second week after symptoms started were administered corticosteroids orally (60 mg of methylprednisolone once a day for 5 days), always accompanied with double antibiotic therapy (500 mg of azithromycin administered orally on the first day of symptoms and 250 mg daily for the following 15 days, and 1 g of ceftriaxone administered subcutaneously once a day for 15 days). No other COVID-19 treatment was given.

Statistical analysis

The primary outcomes of this study were COVID-19 incidence over the study period of 5.5 months (24 January–3 July) based on the presence of one or more COVID-19 symptoms, based on positive RT-PCR, and based on positive serology, as well as COVID-19 mortality rate. Descriptive statistics were used to summarise the data. Normality was assessed through Shapiro-Wilk tests. Comparisons between deceased and non-deceased residents were performed using Wilcoxon signed rank tests for continuous variables, and Fisher’s exact tests for categorical variables. A new coefficient, named the Zemgor coefficient, was calculated as an indication of hypoxemia. The coefficient was the ratio of haemoglobin (HG) to albumin (AB) at 2 different time points (HG₁/AB₁ – HG₀/AB₀), with the first time point measured before onset of symptoms and the second time point at least 15 days after onset of symptoms; since haemoglobin is dependent on hydration levels, albumin was factored in to correct for this. Univariable linear regression analyses were performed to determine associations of 5 categorical outcomes with 18 independent variables. Multivariable linear regression analyses were performed after backwards selection of independent variables using the Akaike information criterion (AIC) (15). Statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). P values <0.05 were considered statistically significant. Due to the unprecedented nature and lack of prognosis of COVID-19 it was not possible to perform an a priori power analysis.

Results

There were 192 residents, 75 men and 117 women, with a mean age of 80±11 years (range, 52–101 years) on 24 January 2020, of whom 33 were smokers (Table 1). The specific COVID-19 protocol followed throughout the study period resulted in 118 (61%) residents being administered anticoagulants, 98 (51%) antibiotics, 41 (21%) oxygen therapy, and 6 (3%) corticosteroids. All data was collected for all residents, except for the Zemgor coefficient, which was only available for 83 of 192 residents.

Over the study period of 5.5 months (24 January–3 July), a total of 98 residents had clinical signs of COVID-19, since they exhibited at least one COVID-19 symptom. Between 24 January 2020 and RT-PCR testing (21 March 2020–24 April 2020), 91 residents had symptoms, of whom 76 had at least 1 common COVID-19 symptom (Table 2), and 5 died due to COVID-19 while 2 died for reasons unrelated to COVID-19. Two residents refused RT-PCR testing, resulting in 179 RT-PCR tests, of which 63 were positive (Figure 1). At the time of receiving RT-PCR testing, 57 of the 179 residents had symptoms, while 27 had recovered from earlier symptoms and 97 had never exhibited symptoms. Between RT-PCR testing and serology testing (performed between 25 June 2020–3 July 2020) an additional 10 residents died due to COVID-19. Seventeen residents refused serology testing, resulting in 152 serology tests, of which 62 were positive. At the time of receiving serology testing, of those residents receiving serology tests, 7 had symptoms, while 40 more had recovered, and 78 had never exhibited symptoms. On the date of database closure (3 July 2020), there were 166 residents in the nursing facility, of whom 5 still had symptoms, while a total of 73 had recovered and 88 had never exhibited symptoms.

Figure 1 Flowchart describing the study cohort. PCR, polymerase chain reaction; COVID-19, coronavirus disease 2019.

Of the 62 residents with a positive serology test, 39 exhibited symptoms at some point during the study period, with 36 of these patients having common COVID-19 symptoms. Twenty-three of the 62 residents with a positive serology test did not exhibit any symptoms within the study period. For residents with a positive serology test (n=62), the most frequently reported common COVID-19 symptoms were fever (n=29), then coughing (n=20), hypoxemia (n=18), and asthenia (n=17) (Table 3).

There were a total of 15 COVID-19-related deaths along with 11 other deaths (26 total deaths from 192 residents, 14%), and 3 COVID-19-related hospital admissions. It should be noted that the 3 hospital admissions took place early during the pandemic. As the pandemic progressed, hospitals became overwhelmed and patients over 70 years old were refused hospitalization. By comparison, in 2019, the nursing facility reported 18 deaths from 200 residents (9%) across the same dates (24 January 2019 to 3 July 2019).

The Zemgor coefficient was 0.023±0.048 (range, −0.083 to 0.186) for the 83 of 192 residents with HG and AB measurements during the study period. For patients with hypoxemia, the Zemgor coefficient was 0.049±0.053 (range, −0.057 to 0.186) for the 26 of 39 residents with measurements. In comparison, for patients without hypoxemia, the Zemgor coefficient was 0.011±0.041 (range, −0.083 to 0.132) for the 57 of 148 residents with measurements (P=0.001).

Univariable regression analysis revealed that the incidence of common COVID-19 symptoms significantly increased with age [odds ratio (OR), 1.03 per year; P=0.038] and was lower for smokers (OR, 0.30; P=0.008) (Table 4). It also revealed that COVID-19 mortality was higher for men (OR, 3.45; P=0.030) and for residents who had previously experienced a stroke (OR, 4.18; P=0.048). Univariable regression analysis additionally revealed that none of the independent variables analysed had an effect on the incidence of COVID-19 symptoms, the incidence of a positive RT-PCR test or a positive serology test. No multivariable analyses were performed for any of the five outcomes of interest, since backwards selection using the AIC method identified no relevant variables.

RT-PCR tests were performed on all 133 staff members, and 23 were positive. Eight staff members refused serology testing, resulting in 125 tests performed, of which 42 were positive. One staff member was hospitalized for a few days, but there were no deaths amongst staff.

Discussion

The aim of this study was to retrospectively describe the evolution of symptoms, infections, and mortality at a nursing facility in Val d’Oise (France) that had implemented a protocol for the prevention and treatment of COVID-19. Between 24 January and 3 July 2020, the nursing facility recorded a COVID-19 incidence of 51% based on the presence of one or more COVID-19 symptoms, 35% based on positive RT-PCR (amongst residents tested for RT-PCR) and 41% based on positive serology (amongst residents tested for serology), with a COVID-19 mortality rate of 8%, with incidence due to testing at the lower end of the range reported in the literature for nursing facilities (5,6,16-33) (Table 5). The most commonly reported COVID-19 symptoms were fever (36%), cough (21%), dyspnea (21%) and asthenia (19%). Therefore, our null-hypothesis that the COVID-19 protocol used would result in a comparable mortality rate to other nursing facilities was confirmed. Furthermore, the total mortality rate at the nursing facility in the first semester of 2020 (14%) was only 50% higher than in the first semester of 2019 (9%).

A recent systematic review has reported a mean basic reproduction number (R0) of 3.38±1.40 (34) for COVID-19, meaning infection rate within a population without vaccination should peak at 70%. Despite no new symptomatic cases between May 4 and the end of the study on July 3rd, the nursing facility in the current study did not record a 70% infection rate based on either the presence of one or more COVID-19 symptoms or positive serology tests. This could be because of lower infection rates due to the measures implemented at the nursing facility to reduce transmission, however with residents able to ambulate freely across the facility throughout the study period, it may be that other explanations are possible. For example, effective clearance of the virus may need collaborative humoral and cellular immune response (35-37), thus serology testing, which only detects humoral (IgM and IgG antibodies) immunity may not have been sufficient to detect overall COVID-19 immunity (and thus infection levels).

Since the COVID-19 protocol was the same for all residents at the nursing facility, it is difficult to evaluate the effect of each of the different preventive and active measures on the reduced infection and mortality rate. Nonetheless, the administration of vitamin D to all residents may have had an important effect in reducing the risk of infection, as well as in preventing the worsening of symptoms, as suggested by numerous investigations (6,38,39). Furthermore, the administration of anticoagulants to any resident who exhibited COVID-19 symptoms or received a positive RT-PCR test, and of corticosteroids to any whose symptoms persisted over a week, may have also reduced mortality (40-42). Only two papers in the literature were found to describe a specific COVID-19 treatment protocol in nursing facilities (Table 5). Díaz et al. (5) reported on 19 elderly Cuban residents who were included in an expanded access clinical trial to receive itolizumab, an anti-CD6 monoclonal antibody, while Annweiler et al. (6) reported on vitamin D3 supplements taken during or just before COVID-19 by 57 frail, elderly French residents as part of a quasi-experimental study, concluding that vitamin D3 was effective in improving survival amongst this population.

The current study introduced a new coefficient, named the Zemgor coefficient, which is the ratio of haemoglobin to albumin at 2 different time points. A person experiencing hypoxemia will have decreased oxygen levels in their blood, and thus their haemoglobin levels will rise; however, haemoglobin levels can also be affected by hydration, which the Zemgor coefficient corrects for by factoring in albumin levels. The Zemgor coefficient was significantly higher for patients with hypoxemia (0.049±0.05 vs. 0.011±0.041, P=0.001), indicating that it is a promising method for identifying patients with shortness of breath. Since haemoglobin and albumin levels are easy to measure, the Zemgor coefficient could be used to monitor the health of patients, as well as to detect new respiratory viruses, such as coronaviruses, in the future.

Linear regression analyses revealed that the incidence of common COVID-19 symptoms increased with age, which has been seen elsewhere in the literature to affect infection and mortality rates (10,43-45). In addition, smokers had a significantly lower incidence of common COVID-19 symptoms, although age was likely a confounding factor, since the 33 residents that were smokers had a mean age of 69±10 years (range, 52–92), while the 159 residents that were non-smokers had a mean age of 82±10 years (range, 59–100); as such the authors believe this finding should be disregarded. Finally, mortality related to COVID-19 was higher for men than women, a risk factor for which there were no observable confounders, and no current consensus in the literature (10,43,45,46).

This study has several limitations. First, since the COVID-19 protocol was the same for all residents at the nursing facility, in an effort to minimize mortality, it is difficult to evaluate the effect of each of the different preventive and active measures on the reduced infection and mortality rate. Second, RT-PCR testing was only performed once on each resident, unless the test results were doubtful, in which case a second RT-PCR test was performed; ideally, testing should have been performed every few weeks, or when a resident was exhibiting symptoms, although this was not possible due to the limited number of tests available. Third, it has been suggested that instances of COVID-19 may not be detectable in the respiratory system while they are detectable in the digestive system (47-49), meaning fecal testing would be required to detect infection. Fourth, the less common COVID-19 symptoms were identified by clinicians as best they could at the time; since the end of the study period, these less common symptoms have been reported in the literature as indicative of COVID-19 (9-14). Fifth, data was available to calculate the Zemgor coefficient for only 83 of the 192 residents. Sixth, this study is limited by sampling bias, since most of the residents at this particular nursing home had dementia. This population is not representative of the general public, thus further studies are necessary before generalising the implementation of such protocol for the prevention and treatment of epidemic respiratory viruses.

Conclusions

The protocol used during the COVID-19 pandemic at this nursing facility in Val d’Oise (France), consisting in both preventive (administering vitamins and zinc, social distancing, and temperature checks) and active (antibiotics, anticoagulants, and corticosteroids) measures, resulted in a COVID-19 incidence of 51% based on the presence of one or more COVID-19 symptoms, 35% based on positive RT-PCR and 41% based on positive serology, with a COVID-19 mortality rate of 8% (13% amongst men and 4% amongst women), all of which are at the lower end of the range reported in other nursing facilities.

Acknowledgments

The authors would like to acknowledge the COVID-19 team at Residence Médicalisée Zemgor and Clinique Conti ELSAN for their efforts during this pandemic. The authors are grateful to Mo Saffarini for his assistance with manuscript preparation, and Shahnaz Klouche for her assistance with project coordination.

Funding: This work was supported by ELSAN, which provided funding for manuscript preparation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1707

Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-1707

Peer Review File: Available at https://dx.doi.org/10.21037/apm-21-1707

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1707). ELSAN provided funding for manuscript preparation. SRP is an employee of ReSurg SA. PS received consultancy fees from ReSurg SA. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Groupement de Coopération Sanitaire ELSAN (IRB #2020-11-WORCEL-01). Residents (or their guardians) provided informed consent for their data to be used for research and publication purposes.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Thompson DC, Barbu MG, Beiu C, et al. The Impact of COVID-19 Pandemic on Long-Term Care Facilities Worldwide: An Overview on International Issues. Biomed Res Int 2020;2020:8870249 [Crossref] [PubMed]
2. Brown KA, Jones A, Daneman N, et al. Association Between Nursing Home Crowding and COVID-19 Infection and Mortality in Ontario, Canada. JAMA Intern Med 2021;181:229-36. [Crossref] [PubMed]
3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. [Crossref] [PubMed]
4. Parohan M, Yaghoubi S, Seraji A, et al. Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies. Aging Male 2020;23:1416-24. [Crossref] [PubMed]
5. Díaz Y, Ramos-Suzarte M, Martín Y, et al. Use of a Humanized Anti-CD6 Monoclonal Antibody (Itolizumab) in Elderly Patients with Moderate COVID-19. Gerontology 2020;66:553-61. [Crossref] [PubMed]
6. Annweiler C, Hanotte B, Grandin de l'Eprevier C, et al. Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol 2020;204:105771 [Crossref] [PubMed]
7. World Health Organization. Listings of WHO’s response to COVID-19. 2020. Available online: https://www.who.int/news/item/29-06-2020-covidtimeline. Accessed 04/01/2021 2021.
8. World Health Organization. Coronavirus. In: Symptoms. 2020. Available online: https://www.who.int/health-topics/coronavirus#tab=tab_3. Accessed 04/01/2021 2021.
9. Carrillo-Larco RM, Altez-Fernandez C. Anosmia and dysgeusia in COVID-19: A systematic review. Wellcome Open Res 2020;5:94. [Crossref] [PubMed]
10. Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel Coronavirus Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis. J Clin Med 2020;9:941. [Crossref] [PubMed]
11. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 2020;34:e212-3. [Crossref] [PubMed]
12. Wong SH, Lui RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol Hepatol 2020;35:744-8. [Crossref] [PubMed]
13. Wu P, Duan F, Luo C, et al. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol 2020;138:575-8. [Crossref] [PubMed]
14. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun 2020;87:18-22. [Crossref] [PubMed]
15. Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control 1974;19:716-23. [Crossref]
16. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med 2020;382:2081-90. [Crossref] [PubMed]
17. Belmin J, Um-Din N, Donadio C, et al. Coronavirus Disease 2019 Outcomes in French Nursing Homes That Implemented Staff Confinement With Residents. JAMA Netw Open 2020;3:e2017533 [Crossref] [PubMed]
18. Blain H, Rolland Y, Tuaillon E, et al. Efficacy of a Test-Retest Strategy in Residents and Health Care Personnel of a Nursing Home Facing a COVID-19 Outbreak. J Am Med Dir Assoc 2020;21:933-6. [Crossref] [PubMed]
19. Borras-Bermejo B, Martínez-Gómez X, San Miguel MG, et al. Asymptomatic SARS-CoV-2 Infection in Nursing Homes, Barcelona, Spain, April 2020. Emerg Infect Dis 2020; [Crossref] [PubMed]
20. Dora AV, Winnett A, Fulcher JA, et al. Using Serologic Testing to Assess the Effectiveness of Outbreak Control Efforts, Serial Polymerase Chain Reaction Testing, and Cohorting of Positive Severe Acute Respiratory Syndrome Coronavirus 2 Patients in a Skilled Nursing Facility. Clin Infect Dis 2021;73:545-8. [Crossref] [PubMed]
21. Escobar DJ, Lanzi M, Saberi P, et al. Mitigation of a Coronavirus Disease 2019 Outbreak in a Nursing Home Through Serial Testing of Residents and Staff. Clin Infect Dis 2021;72:e394-e396. [Crossref] [PubMed]
22. Graham NSN, Junghans C, Downes R, et al. SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes. J Infect 2020;81:411-9. [Crossref] [PubMed]
23. Kennelly SP, Dyer AH, Noonan C, et al. Asymptomatic carriage rates and case fatality of SARS-CoV-2 infection in residents and staff in Irish nursing homes. Age Ageing 2021;50:49-54. [Crossref] [PubMed]
24. Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility - King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020;69:377-81. [Crossref] [PubMed]
25. Klein A, Edler C, Fitzek A, et al. The first COVID-19 hotspot in a retirement home in Hamburg. Rechtsmedizin (Berl) 2020;1-7. doi:10.1007/s00194-020-00404-110.1007/s00194-020-00404-1
26. McConeghy KW, White E, Panagiotou OA, et al. Temperature Screening for SARS-CoV-2 in Nursing Homes: Evidence from Two National Cohorts. J Am Geriatr Soc 2020;68:2716-20. [Crossref] [PubMed]
27. McMichael TM, Currie DW, Clark S, et al. Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington. N Engl J Med 2020;382:2005-11. [Crossref] [PubMed]
28. Roxby AC, Greninger AL, Hatfield KM, et al. Outbreak Investigation of COVID-19 Among Residents and Staff of an Independent and Assisted Living Community for Older Adults in Seattle, Washington. JAMA Intern Med 2020;180:1101-5. [Crossref] [PubMed]
29. Sacco G, Foucault G, Briere O, et al. COVID-19 in seniors: Findings and lessons from mass screening in a nursing home. Maturitas 2020;141:46-52. [Crossref] [PubMed]
30. Song R, Kim HS, Yoo SJ, et al. COVID-19 in Nursing Facilities: Experience in Republic of Korea. Osong Public Health Res Perspect 2020;11:164-9. [Crossref] [PubMed]
31. White EM, Kosar CM, Feifer RA, et al. Variation in SARS-CoV-2 Prevalence in U.S. Skilled Nursing Facilities. J Am Geriatr Soc 2020;68:2167-73. [Crossref] [PubMed]
32. Dora AV, Winnett A, Jatt LP, et al. Universal and Serial Laboratory Testing for SARS-CoV-2 at a Long-Term Care Skilled Nursing Facility for Veterans - Los Angeles, California, 2020. MMWR Morb Mortal Wkly Rep 2020;69:651-5. [Crossref] [PubMed]
33. Montoya A, Jenq G, Mills JP, et al. Partnering with Local Hospitals and Public Health to Manage COVID-19 Outbreaks in Nursing Homes. J Am Geriatr Soc 2021;69:30-6. [Crossref] [PubMed]
34. Alimohamadi Y, Taghdir M, Sepandi M. Estimate of the Basic Reproduction Number for COVID-19: A Systematic Review and Meta-analysis. J Prev Med Public Health 2020;53:151-7. [Crossref] [PubMed]
35. Ni L, Ye F, Cheng ML, et al. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity 2020;52:971-977.e3. [Crossref] [PubMed]
36. Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: Current State of the Science. Immunity 2020;52:910-41. [Crossref] [PubMed]
37. Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020;584:457-62. [Crossref] [PubMed]
38. Annweiler G, Corvaisier M, Gautier J, et al. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 2020;12:3377. [Crossref] [PubMed]
39. Daneshkhah A, Agrawal V, Eshein A, et al. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res 2020;32:2141-58. [Crossref] [PubMed]
40. Kamel AM, Sobhy M, Magdy N, et al. Anticoagulation outcomes in hospitalized Covid-19 patients: A systematic review and meta-analysis of case-control and cohort studies. Rev Med Virol 2021;31:e2180 [Crossref] [PubMed]
41. Kim MS, An MH, Kim WJ, et al. Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis. PLoS Med 2020;17:e1003501 [Crossref] [PubMed]
42. van Paassen J, Vos JS, Hoekstra EM, et al. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care 2020;24:696. [Crossref] [PubMed]
43. Pijls BG, Jolani S, Atherley A, et al. Demographic risk factors for COVID-19 infection, severity, ICU admission and death: a meta-analysis of 59 studies. BMJ Open 2021;11:e044640 [Crossref] [PubMed]
44. Matsushita K, Ding N, Kou M, et al. The Relationship of COVID-19 Severity with Cardiovascular Disease and Its Traditional Risk Factors: A Systematic Review and Meta-Analysis. Glob Heart 2020;15:64. [Crossref] [PubMed]
45. Silverio A, Di Maio M, Citro R, et al. Cardiovascular risk factors and mortality in hospitalized patients with COVID-19: systematic review and meta-analysis of 45 studies and 18,300 patients. BMC Cardiovasc Disord 2021;21:23. [Crossref] [PubMed]
46. Palaiodimos L, Chamorro-Pareja N, Karamanis D, et al. Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis comprising 18,506 patients. Hormones (Athens) 2021;20:305-14. [Crossref] [PubMed]
47. Chen L, Lou J, Bai Y, et al. COVID-19 Disease With Positive Fecal and Negative Pharyngeal and Sputum Viral Tests. Am J Gastroenterol 2020;115:790. [Crossref] [PubMed]
48. Xiao F, Tang M, Zheng X, et al. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology 2020;158:1831-1833.e3. [Crossref] [PubMed]
49. Xu Y, Li X, Zhu B, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med 2020;26:502-5. [Crossref] [PubMed]