Comprehensive infection control measures prevent hospital-acquired severe acute respiratory syndrome coronavirus 2 infection: A single-center prospective cohort study and seroprevalence survey

Background Coronavirus disease (COVID-19) is associated with a high mortality rate in older adults; therefore, it is important for medical institutions to take measures to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. This study aimed to assess the risk of SARS-CoV-2 infection among healthcare workers (HCWs) and the effectiveness of infection control measures. Methods This study had a cross-sectional component and a prospective cohort component. The cross-sectional component comprised an anti-SARS-CoV-2 antibody survey among HCWs at a medical center in Saitama City, Japan. In the prospective cohort component, HCWs at the same medical center were tested for anti-SARS-CoV-2 antibodies monthly over a 3-month period (May to July 2020) to assess the effectiveness of infection prevention measures, including personal protective equipment use. All participants in the cohort study also participated in the antibody survey. The primary outcome was anti-SARS-CoV-2 antibody (measured using Elecsys® Anti-SARS-CoV-2) positivity based on whether participants were engaged in COVID-19-related medical care. Other risk factors considered included occupational category, age, and sex. Results In total, 607 HCWs participated in the antibody survey and 116 doctors and nurses participated in the cohort study. Only one of the 607 participants in the survey tested positive for anti-SARS-CoV-2 antibodies. All participants in the cohort study were anti-SARS-CoV-2 antibody negative at baseline and remained antibody negative. Engaging in the care of COVID-19 patients did not increase the risk of antibody positivity. During the study period, a total of 30 COVID-19 in-patients were treated in the hospital. Conclusions The infection control measures in the hospital protected HCWs from nosocomially acquired SARS-CoV-2 infection; thus, HCWs should engage in COVID-19-related medical care with confidence provided that they adhere to infectious disease precautions.

To clarify the prevalence of SARS-COV-2 antibodies among healthcare workers at our center.  To clarify the characteristics of SARS-COV-2 antibody-positive patients.
(2) Significance  IgG antibody-positive patients are predicted to have a low risk of reinfection, at least in the short term. This information is particularly useful for health care workers during the COVID-19 pandemic in terms of nosocomial infection prevention.

Research Methods and Duration Research Methods Research Design ■Clinical Research ■Observational research
Specific Outline  The subject shall be from volunteers recruited by posting posters in the Research Implementation Section and Research Cooperation Section. An email shall be sent to staff members who have expressed interest in volunteering, and if they respond to the email, they shall be considered to be willing to participate.  The researcher shall explain the research directly to the volunteers who responded to the email and give them the explanation and consent forms.  At a later date, the volunteer who signed the consent form shall be the research subject (doctor or nurse).  Blood samples shall be collected from all the subjects at the start of the research, one month after the start of the research, and two months after the start of the research, and the serum shall be frozen and stored. Two to four weeks after the start of the research, each of the stored specimens at the start of the research shall be subjected to a qualitative test for SARS-CoV-2 IgG/IgM antibodies by immunochromatography. Three months after the start of the research, the same qualitative test shall be performed on each of the remaining specimens. This test kit is a research reagent only and it is clearly labeled as "may not be used for therapeutic or diagnostic purposes".  The percentage of antibody-positive subjects among all the subjects shall be measured.  Following items as at the time of the research shall be recorded: The subject's age, gender, history of living abroad, city or town of residence, underlying medical conditions, medication history, whether or not they have received medical checkups, smoking history, alcohol consumption history, place of residence within the past year, department of work, BCG intake history, the presence and timing of COVID19 (novel coronavirus infection) in patients under their care (location, date and time), symptoms of the common cold (cough, nasal discharge, sore throat, malaise, taste disorder, respiratory distress) within the last 3 months and the date (how many days before the examination), and the presence of fever.  Analyze whether there are statistically significant differences in the proportions of these factors among the subjects who test positive for antibodies compared to the subjects who test negative.  All the subjects shall be asked every month about the presence or absence of airway symptoms, fever, taste disturbance, and COVID-19 diagnosis at a medical institution in the last month. This shall be continued for the duration of the research.  As of April 6, 2020, there is no antibody test that can guarantee high accuracy. Research on antibody accuracy verification is ongoing worldwide, and it is possible that antibody test kits with verified/guaranteed accuracy will be identified in the future. If antibody tests with proven accuracy are available during the research period, the research reagents may be changed.

Expected Number of Research Subjects and Rationale for Setting
Planned number of research subjects: 60 Rationale: Looking at the increasing tendency of infection, it is predicted that the IgG antibody positive rate as of April 2020 is quite low, but in Japan, there are no statistics so far and it is difficult to make an accurate assumption. The sample size would be 35 or less with a margin of error of 10% and a confidence level of 95%, and 49 or less with 15% or less under the same conditions. The total number of participants is set at 60, including 10 who withdrew during the course of the research. If the number of positive subjects is less than 5% at the beginning of the research, additional recruitment may be conducted.

Method of Statistical Analysis, Evaluation Items and Methods a. Method of Statistical Analysis 
The actual number of subjects who tested positive for antibodies at the beginning of the research, after 1 month, and after 2 months, and the percentage of all subjects is measured, and 95% confidence intervals is obtained.  Obtain the aforementioned predetermined factors: The subject's age, gender, history of living abroad, city of residence, underlying illness, medication history, whether or not he or she has received medical checkups, smoking history, drinking history, place of residence within the past year, department of work, BCG intake history, the presence or absence of COVID-19 (novel coronavirus infection) in the patient in charge, history of travel in the last year, the presence or absence of access to cluster infection sites, the presence or absence of the common cold symptoms (cough, nasal discharge, sore throat, malaise, dysgeusia, respiratory distress) within 3 months, and the presence or absence of fever.
The differences in these factors between IgG antibody-positive and antibody-negative subjects are tested by chi-square test, Fisher's exact test, and logistic analysis, and for continuous variables by Mann-Whitney U test and logistic analysis. In addition, the characteristics of the above factors in the research subjects who test positive for antibodies will be described.  Measure the percentage of antibody-positive individuals who develop COVID-19 after a positive test. b. Evaluation Items  The primary outcome is the rate of antibody positivity in the entire research population, and the change in the rate of positivity  The secondary outcome is the detection of significant differences in each factor among antibodypositive and antibody-negative subjects (age, sex, place of residence, department, the presence of COVID19 in the patient in charge if not an early resident, travel history in the past year, access to cluster-infected areas, the presence of cold symptoms and fever within 3 months), and subsequent incidence of COVID-19 in antibody-positive individuals.
Research Period  The research shall start within one month after the approval.  The research period shall be 4 months. It may be postponed for up to one year.  To be published in a conference or paper within one year after completion of the analysis. (2) Selection Policy Selection criteria: Healthy medical personnel who are engaged in this hospital including junior resident, physicians in general medicine Division, physicians in emergency department, physicians ICU, EICU nurses, emergency and ward 2A nurses who have given consent for this research, who have been or will be engaged in the treatment of SARS-COV-2 infected patients Exclusion criteria: Those with fever, cough, or respiratory distress at the time of the initial examination, and those who do not consent to the research.

Selection of Research
6. Scientific Rationality  Currently, PCR tests for SARS-CoV-2 infection are less common in Japan than in other countries, and the actual spread of the infection is not known. By detecting antibody positivity, the percentage of previously infected individuals in the control group can be measured.

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Since it is currently difficult to assume the SARS-CoV-2 infection rate, the followings are the subject of the research: Physicians in general medicine and emergency departments who have frequent contact with patients diagnosed with COVID-19 or with patients who complain of respiratory tract symptoms such as the common cold, physicians in ICU, ward and emergency nurses who have actually been involved in the treatment of COVID-19, and junior resident as healthy adults who rotate through multiple departments.  For statistical analysis, all antibody-positive subjects are assumed to have a history of infection, and the percentage of subjects tested is determined.
7. Procedures for Obtaining Informed Consent, etc.
(1) Collection of Samples and Information, etc. ■Use of new samples and information The content: The COVID-19 IgG/IgM immunochromatography kit (sold by TK Research Co., Ltd.) is used, and the stored serum of the research subjects is used. Have them fill out a research statement, consent form, and a separate questionnaire for each research subject. ■Obtain consent in writing (2) Selection of a Substitute ■No Substitute ■This is not research using a substitute (including cases where opt-out by the substitute is allowed) (3) Procedures for Obtaining Informed Assent (oral assent is generally for minors of elementary school age and older but less than 16 years of age; written assent is generally for minors of junior high school age and older but less than 16 years of age) ■Do not obtain informed assent ■There is no need to obtain informed assent.

) Cost burden
There is no cost burden on research subjects when they participate in the research.

2) Other burdens
There is no other burden on research subjects when they participate in the research.
(2) Anticipated Risks to Research Subjects 1) Disadvantage ■ None 2) Risks ■None 3) Discomfort ■Yes Description: Pain associated with blood collection (3) Benefits Accruing to the Research Subjects 1) Gratuities to subjects ■None 2) Other benefits ■No (4) A comprehensive Assessment of the Burdens and Anticipated Risks and Benefits to Research Subjects, and Measures to Minimize Such Burdens and Risks 1) Overall evaluation  The possibility of direct disadvantage or benefit to the research subjects is low. 2) Measures to minimize burden and risk Minimize pain during blood collection.  The pain during the blood collection process should be minimized  The test should be performed during or after work breaks to minimize the possibility that work may be interfered  There is a possibility of interference with work due to infectivity evaluation (PCR test, etc.) in the case of antibody positivity. Therefore, by allowing a period of one month from the time of blood collection to the time of antibody measurement, the infectivity evaluation shall be unnecessary and the burden shall be eliminated.  In order to minimize the psychological burden of knowing the results, the results shall be disclosed only to those who wish to receive them.

3) Compensation for loss
There shall be no compensation for losses incurred through the implementation of this research.