key: cord-0840540-jwn2lk8v
authors: Harada, Sei; Uno, Shunsuke; Ando, Takayuki; Iida, Miho; Takano, Yaoko; Ishibashi, Yoshiki; Uwamino, Yoshifumi; Nishimura, Tomoyasu; Takeda, Ayano; Uchida, Sho; Hirata, , Aya; Sata, Mizuki; Matsumoto, Minako; Takeuchi, Ayano; Obara, , Hideaki; Yokoyama, Hirokazu; Fukunaga, Koichi; Amagai, , Masayuki; Kitagawa, Yuko; Takebayashi, Toru; Hasegawa, Naoki
title: Control of a Nosocomial Outbreak of COVID-19 in a University Hospital
date: 2020-10-22
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofaa512
sha: e82cf914f39d4d90fa0ce8cfb347e940d925fdc0
doc_id: 840540
cord_uid: jwn2lk8v

BACKGROUND: Nosocomial spread of COVID-19 causes clusters of infection among high-risk individuals. Controlling this spread is critical to reducing COVID-19 morbidity and mortality. We describe an outbreak of COVID-19 in Keio University Hospital, Japan, and its control, and propose effective control measures. METHODS: When an outbreak was suspected, immediate isolation and thorough polymerase chain reaction (PCR) testing of patients and healthcare workers (HCWs) using an in-house system, together with extensive contact tracing and social distancing measures, were conducted. Nosocomial infections (NIs) were defined as having an onset or positive test after the fifth day of admission for patients, and having high-risk contacts in our hospital for HCWs. We performed descriptive analyses for this outbreak. RESULTS: Between March 24 and April 24, 2020, 27 of 562 tested patients were confirmed positive, of whom 5 (18.5%) were suspected as NIs. For HCWs, 52 of 697 tested positive, and 40 (76.9%) were considered NIs. Among transmissions, 95.5% were suspected of having occurred during the asymptomatic period. Large-scale isolation and testing at the first sign of outbreak terminated NIs. The number of secondary cases directly generated by a single primary case found before March 31 was 1.74, compared to 0 after April 1. Only 4 of 28 primary cases generated definite secondary infection, which were all asymptomatic. CONCLUSIONS: Viral shedding from asymptomatic cases played a major role in NIs. PCR screening of asymptomatic individuals helped clarify the pattern of spread. Immediate large-scale isolation, contact tracing, and social distancing measures were essential to containing outbreaks.

The COVID-19 pandemic has put hospitals at risk of nosocomial infection (NI) worldwide.

Health care workers (HCWs) account for 4%-6% of cases in several countries [1] [2] [3] . In Japan, more than 9.4% of all COVID-19 cases were reported as NIs [4] . With its markedly higher rate of morbidity and mortality in people with underlying diseases [5] , the first nosocomial outbreak in a hospital in Tokyo was in 109 patients with 38 deaths resulting within 43 days [6] . This underscores the urgent need for preventive measures, not only to reduce severe complications and deaths, but also to preserve hospital function to provide adequate care to all patients.

Located in Tokyo, Japan, Keio University Hospital confirmed its first NI case on March 24 , when an outbreak occurred in the hospital. The cumulative numbers of confirmed cases and deaths from COVID-19 in the Tokyo metropolitan area on that day were reported to be 172 and 5, respectively [7] . Within the next month, those increased to 3,742 (0.27 per 1000 of the population in Tokyo) and 93 (0.007 per 1000), respectively (as of April 24) .

Given that governmentally sanctioned testing was limited to patients with severe symptoms or who were symptomatic for > 4 d [8] , and that most infected individuals remain mildly symptomatic or asymptomatic [9] [10] [11] , the number of confirmed cases was in danger of being underestimated. Approximately 40% of transmissions might occur from presymptomatic cases [12, 13] ; thus, growing community-wide infections could increase presymptomatic infections among HCWs and pre-admission patients and lead to outbreaks of NIs.

Identification of NI is particularly challenging for COVID-19. Since SARS-CoV-2 can be transmitted during the incubation period [14] , it is possible to come into contact with an infected person without being aware of it. A literature review and a case-series from China reported that nosocomial transmission occurred in over 40% of diagnosed cases [15, 16] , A c c e p t e d M a n u s c r i p t 7 whereas a multi-center international cohort study in the United Kingdom and Italy estimated the proportion of NI cases as 12.5% [17] . The numbers could vary depending on the definition of NI or the number of hospitalizations for community-acquired infection (CAI), which makes it difficult to argue whether a facility has more or fewer NIs per patient population. Although there is no dispute that NIs need to be reduced, discussing actions to reduce them requires careful visualization of patient numbers, infection dynamics and preventive measures.

Controlling nosocomial and institutional infections of COVID-19 presents a marked challenge [11, 18] ; however, measures to mitigate outbreaks in large acute-care hospitals have been scarcely reported. Thus, we describe our strict and immediate isolation measures, with the establishment of an in-house PCR testing system with contact tracing, to control the outbreak. 

Persons under investigation (PUI) were defined as patients hospitalized between March 1 and April 24, 2020, or HCWs who worked at Keio University Hospital during the same period. We defined a confirmed case as a PUI with a positive PCR test for SARS-CoV-2 regardless of symptomatic status. In-house PCR testing was performed on all patients and HCWs clinically suspected of infection based on fever or respiratory symptoms. PCR testing was also performed on all high-risk contacts based on thorough contact tracing regardless of symptomatic status. Patients were defined as high-risk contacts if they had been examined or nursed by an infected HCW, or had been admitted in the same room as an infected patient or to a ward where a nosocomial outbreak occurred. HCWs were defined as high-risk contacts if they had had exposure to an infected patient (exposure grading A-C, supplementary Table 1) , had been at a conversational distance from an infected person without either person wearing a mask for more than a few minutes, such as during breaks and meals, or belonged to a division or ward where multiple confirmed cases among HCWs were noted. From April 6, universal PCR testing on patients before hospital admission was implemented. Each case was monitored for a minimum of two weeks after the test was found positive until May 8, 2020.

Cases were classified according to the maximum observed severity: asymptomatic, mild, severe, and critical [19] . Mild cases presented with fever and respiratory symptoms (cough, sputum, or sore throat). Severe cases were those with oxygen saturation of ≤ 93% in ambient air, and requiring oxygen administration. Critical cases were defined as having respiratory failure requiring mechanical ventilation.

A c c e p t e d M a n u s c r i p t 9 Confirmed cases were assigned to one of four groups according to their status (patients/HCWs) and place of virus transmission (community-acquired/nosocomial). Patients were defined as having NI if they developed symptoms and their specimens were collected after the fifth day of admission, which is the median incubation period of COVID-19 [20, 21] . All remaining patient cases were defined as having community-acquired infections (CAIs), except those with a history of hospitalization within two weeks (unclassifiable cases).

HCWs were defined as having NI if they were high-risk contacts, as defined above, and CAI if they had close contacts with positive cases outside of our hospital. If the links were unknown, or both NI and CAI were probable for HCWs, we defined them as unclassifiable.

Identification of infection sources was based on the information gathered from thorough contact tracing using structured questionnaires (Supplementary Table 2 ) or telephone interviews, if needed, dating back to one month before the positive date. When we suspected that a case had initiated a chain of nosocomial transmission, we considered the case to be the primary case and the accumulation of those NI cases was determined as a cluster.

Presumptive sources of infection were classified as symptomatic, presymptomatic, or never-symptomatic based on the symptoms at the time of transmission. Asymptomatic sources were classified as presymptomatic if they developed symptoms within two weeks of contact. If they did not develop symptoms within two weeks of contact, they were classified as never-symptomatic. If multiple sources are assumed possible in NIs, including sources of symptomatic transmission, we defined it as a symptomatic transmission. Information on symptoms in positive patients was collected from medical records and telephone interviews with their physicians, and that of positive HCWs was based on daily health monitoring and contact tracing. After February 17, all the HCWs were required to report fever (≥37.5°C) or respiratory symptoms to their department head as well as to Keio University Health Center, after which they were asked to self-isolate at home. Permission from the Health Center was required to return to work. From April 8, negative PCR tests were also required. From April 6, universal PCR testing on patients before hospital admission was implemented. In addition, all emergently admitted patients were routinely isolated for two to seven days and relaxed according to their clinical course or condition.

After March 24, when clusters of COVID-19 had been identified, immediate isolation of the index case and thorough contact tracing was performed. Specifically, all HCWs who had had contact with a confirmed patient were assessed on their exposure level according to our exposure grading (Supplementary Table 1 ). A 14-day work restriction was instituted regardless of PCR test results for those without a face shield during aerosol-generating procedures. When transmission of infection was suspected within a ward, the ward was immediately closed, disinfected, and comprehensive PCR testing of all patients and HCWs assigned to the ward was conducted, followed by 14-day quarantine for HCWs irrespective of the result of PCR testing. From March 30, stringent social distancing measures were implemented (e.g., HCWs were to have meals alone).

A c c e p t e d M a n u s c r i p t

The real-time one-step RT-PCR assays were performed using a BD MAX system with BD MAX TNA MMK SPC and BD MAX ExK TNA reagents (Becton Dickinson, Franklin Lakes NJ, USA). We used two primer and probe sets to detect two regions in the SARS-CoV-2 nucleocapsid (N) gene (N1 and N2) [22] . Assays in which either N1 or N2 or both were positive before 45 cycles were judged as positive. In cases of single N1 gene positivity or unclear amplification curves, testing was repeated to avoid false-positive results [23] .

Data were collected ambidirectionally from March 24 as part of the nosocomial infection control program, including contact tracing. Demographic and clinical information was collected from medical records. We performed descriptive analyses for this outbreak. The number of secondary cases directly generated by a single primary case was calculated both before and after March 31, when the more rigid safety measures had been put in place.

Resident physicians were assumed to represent an independent population, and the basic reproduction number (R0) as the expected number of cases directly generated by one case in this population was estimated using the susceptible-exposed-infectious-recovered (SEIR) model [24] . Details are shown in the Appendix. Statistical analyses were performed using R.3.6.2 (R Core Team 2019, R Foundation for Statistical Computing, Vienna, Austria.), except for SEIR modeling, which was performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). 

We found four major clusters, A to D (Figure 3 ). The first cluster visualized (cluster A) had originated from the index case, the patient transferred to our hospital for the treatment of lower limb ischemia from Hospital A. PCR testing of the three patients in the same room confirmed transmission of COVID-19. Then, PCR testing was conducted on all 44 inpatients and 100 HCWs assigned to the ward, and one patient and 3 HCWs were additionally identified. Although the incubation period was longer in the primary case and shorter in the secondary infected patients, the secondary infected patients in the same room were admitted to our hospital more than 44 days before onset; and considering the spread of infection, the patient from Hospital A, where the outbreak of COVID-19 occurred, was most likely to be the primary case. Suspecting that NIs were spreading within the ward, we decided to close it. A c c e p t e d M a n u s c r i p t 14 Next, a cluster arising among physicians working at both Keio University Hospital and Hospital A was identified (cluster B). Quarantine of all 99 physicians was imposed from March 27. Infection was confirmed in five, and one never-symptomatic source had generated two secondary cases.

Another cluster appeared from a presymptomatic pediatric outpatient (cluster C). Four HCWs were infected from the primary case; however, no further spread of infection was detected. At the same time, a cluster of resident physicians were discovered to be febrile (cluster D). Quarantine of all 99 resident physicians was imposed; in addition, those whose initial PCR test was negative were retested a week later and 20 were confirmed to be positive.

Detailed contact tracing revealed that none of the resident physicians had contacts with confirmed or suspected COVID-19 patients in our hospital for the past month. Transmission was considered due to exposure in the resident lounge. Also, 15, excluding the potential primary case, had gathered for meals on March 26. The number of secondary cases directly generated by the primary case was considered to be 4.4, as R0 in cluster D was estimated as 4.4 by the SEIR model.

The mean number of secondary cases directly generated by a single primary case in the hospital was 17.4/28 = 0.62, as summarized in proportion of NI was much higher than in previous reports [15] [16] [17] . This high proportion could be due to two reasons: one was the limited acceptance of new COVID-19 patients due to the temporary decline in hospital functions, and the other was that the rate of communityacquired infection in Japan was considerably lower than that in other reports. In addition, although the HCWs adhered to universal masks, hand hygiene and standard precautions during medical practice, there may have been many transmissions outside of practice, such as during use of the staff lounge and eating with other staff members. The implementation of self-quarantine of the hospital staff with close contact for 14 days, universal masking, visitor restriction, and social distancing have been previously reported [25, 26] ; however, in the event of a larger scale nosocomial infection, as presented here, a more consequential decision, such as ward closure, may be necessary. Prompt and rigorous implementation of containment measures led to successful control of the viral transmission.

One common feature of our primary cases producing widespread transmission was that they were presymptomatic or never-symptomatic, and all transmissions had occurred before their diagnoses. In the hospital, symptomatic individuals were immediately isolated and carefully controlled, and as a result, infection from symptomatic individuals was unlikely to occur, with the majority of infections coming from asymptomatic individuals. In addition, 19 of 42 asymptomatic transmissions were observed from a single cluster, which also contributed to the rise in numbers for asymptomatic transmission. Reports on COVID-19 A c c e p t e d M a n u s c r i p t 16 have demonstrated a large percentage of presymptomatic cases [9] [10] [11] and the finding of presymptomatic carriers infecting others [11, 12, 27] . When clusters were discovered, aggressive contact tracing, thorough isolation regardless of PCR results or the presence of symptoms, and testing of highly-exposed persons was conducted, which allowed us to suppress further infection. In particular, for cluster A, all employees in the ward were NIs of COVID-19 in our hospital did not occur from every case in the same manner: most cases did not infect anyone, and only 4 of 28 primary cases resulted in clusters. This suggests that even if the reproductive number is large, the spread of infection may be impeded by isolating the most contagious individuals or circumstances that give rise to many infections. The large variance of the number of secondary cases generated by a single primary within the hospital, which is a confined space, is consistent with the findings observed in CAIs in Japan [28] .

Our findings suggest that screening of symptomatic individuals is not sufficient to prevent nosocomial outbreaks of COVID-19. Detecting and isolating asymptomatic individuals, paying attention to asymptomatic shedding of the virus from patients, and avoiding contact between healthcare personnel are key to preventing the virus from spreading in a hospital or similar facility.

On April 6, our hospital implemented in-house PCR screening for every patient prior to admission. This led to a rise in the number of confirmed COVID-19-positive inpatients, who were mostly asymptomatic. No NIs occurred from these confirmed patients who were diagnosed before admission. This suggests that if healthcare providers are aware of asymptomatic COVID-19 patients and take adequate care to protect against them, the probability of cluster outbreaks from any patient can be reduced. However, PCR testing can have insufficient sensitivity to rule out COVID-19 [29] [30] [31] , indicating an urgent need to increase the testing capacity and establish sufficiently sensitive systems to rule out COVID-19 within healthcare facilities in asymptomatic individuals. Age, y mean ± SD 56.9 ± 21.0 74.0 ± 9. A c c e p t e d M a n u s c r i p t 

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