key: cord-0713381-iu49pfq7
authors: Tsai, Chin-Shiang; Huang, Tang-Hsiu; Su, Po-Lan; Chen, Chiung-Zuei; Chen, Chang-Wen; Ko, Wen-Chien; Lee, Nan-Yao
title: The occurrence of and risk factors for developing acute critical illness during quarantine as a response to the COVID-19 pandemic
date: 2021-01-22
journal: J Formos Med Assoc
DOI: 10.1016/j.jfma.2021.01.013
sha: 098efb3f2c8c1cf7f7a84e87373e1723f28d4ff9
doc_id: 713381
cord_uid: iu49pfq7

Objective Early detection and timely quarantine measures are necessary to control disease spread and prevent nosocomial outbreaks of Coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the impact of a quarantine strategy on patient safety and quality of care. Material and methods This retrospective cohort study enrolled patients admitted to the quarantine ward in a tertiary hospital in southern Taiwan. The incidence and causes of acute critical illness, including clinical deterioration and unexpected complications during the quarantine period, were reviewed. Further investigation was performed to identify risk factors for acute critical illness during quarantine. Results Of 320 patients admitted to the quarantine ward, more than two-thirds were elderly, and 37.8% were bedridden. During the quarantine period, 68 (21.2%) developed acute critical illness, which more commonly occurred among patients older than 80 years and with a bedridden status, nasogastric tube feeding, or dyspnea symptoms. Bedridden status was an independent predictor of acute critical illness. Through optimization of sampling for COVID-19 and laboratory schedules, both the duration of quarantine and the proportion of acute critical illness among bedridden patients during quarantine exhibited a decreasing trend. There was no COVID-19 nosocomial transmission during the study period. Conclusions The quarantine ward is a key measure to prevent nosocomial transmission of COVID-19 but may carry a potential negative impact on patient care and safety. For patients with multiple comorbidities and a bedridden status, healthcare workers should remain alert to rapid deterioration and unexpected adverse events during quarantine.

and safety. For patients with multiple comorbidities and a bedridden status, healthcare 1 workers should remain alert to rapid deterioration and unexpected adverse events 2 during quarantine. large-scale public gatherings 3 , clinical management 4 , and infection prevention. The 7 stringency of border quarantine measures was enhanced, including 14-day home 8 quarantine for any arrivals regardless of symptoms 5 . To minimize the risk of any 9 community or hospital outbreak, the CECC has enhanced the community 10 surveillance system since mid-February; patients with unresolved pneumonia or 11 without specific microbiological evidence were recommended to quarantine for 12 COVID-19 surveillance even without history of travel, occupation, cluster, or 13 contact (TOCC) 6 . Accordingly, these patients should be isolated in a single-patient 

Based on recommendations by the CECC 9 , the strategy of managing a quarantine 3 ward was implemented at National Cheng Kung University Hospital (NCKUH), a 4 tertiary medical center in southern Taiwan. Patients with radiographic evidence of 5 suspicious pulmonary infiltrates and symptoms of fever, dyspnea, or cough were 6 admitted to the quarantine ward. If presenting with critical illness when arriving at 7 the emergency room, patients would be transferred to the intensive care unit. The 8 quarantine process is illustrated in Figure 1 . The quarantine ward, which began to 9 operate on March 9, 2020, was composed of 10 single rooms with personal 10 bathrooms inside. The patients were managed by pulmonologists or infectious 11 disease specialists and were cared for with appropriate personal protective 12 equipment (PPE). If necessary, hemodialysis therapy was performed within the 13 quarantine ward. Respiratory specimens (namely, sputum samples or 14 nasopharyngeal swabs) were collected for SARS-CoV-2 RNA detection using 15 real-time reverse-transcription polymerase chain reaction (RT-PCR) for the 16 Patient isolation was discontinued if results for the detection of SARS-CoV-2 3 RNA from at least two consecutive respiratory specimens collected ≥12 hours apart 4 (total of two negative specimens) were negative or if there was one negative result 5 of SARS-CoV-2 RNA plus evidence of an alternative etiology (such as positive 6 blood culture results, Mycoplasma IgM positivity, or other pathogens detected by 7 multiplex PCR) at the same time that matched the patient's condition. Eventually, 8 these patients were discharged or transferred to other ordinary wards for further 9 inpatient care. 10

All patients who were admitted to the quarantine ward from March to May 2020 12 were eligible for inclusion. The study was approved by the NCKUH Institutional 13

Review Board (B-BR-109-032). 14

The electronic medical records and laboratory data for all the patients were 16 thoroughly reviewed. Their clinical information was recorded in a standardized data 17 collection form, including age, sex, site of care before admission, date of admission, 18 initial clinical manifestations (such as fever, cough, or dyspnea), underlying disease 19 (such as congestive heart failure, diabetes mellitus, structural lung disease, 20 end-stage renal disease, solid-organ or hematologic malignancies), records of 21 unstable conditions, and duration of quarantine (DOQ). Acute critical illness was 22 defined as a rapid change in a patient's condition or an adverse event that occurred 23 in the quarantine period and led to severe respiratory, cardiovascular or 24 J o u r n a l P r e -p r o o f neurological derangement, combined with abnormal laboratory or physiological 1 parameters. Examples of acute critical illness in our study included respiratory 2 failure (with a PaO 2 /FiO 2 ratio < 200), shock (systolic blood pressure <90 mmHg or 3 mean arterial pressure <65 mmHg), uncontrolled hepatic encephalopathy, untreated 4 acute myeloid leukemia, gastrointestinal bleeding, acute myocardial infarction, and 5 cardiac arrest. We also determined the "reporting time", which reflects how long it 6 takes to discontinue quarantine. The reporting time started upon the patient's arrival 7

at the emergency department and ended when there were two negative results for 8 SARS-CoV-2 RNA detection ≥12 hours apart or there was one negative 9 SARS-CoV-2 RNA result plus a positive result for other pathogens detected at the 10 same time. 11

Baseline demographic and clinical characteristics between patients with and 13 without acute critical illness were analyzed using the Mann-Whitney U test for 14 continuous nonparametric variables and the chi-square test for categorical variables. 15

The association between candidate predictors and the risk of developing acute 16 critical illness during quarantine was examined with the use of univariate and 17 multivariable logistic regression and Cox proportional hazard regression (after 18 ascertaining no violation of the assumption of proportional hazard by the Shoenfeld 19 test). The median and mean "reporting time" and DOQ of all quarantined patients 20 were also evaluated. A p value of less than 0.05 was considered to indicate 21 statistical significance. Moreover, to determine the potential influence of a 22 hypothetically unidentified confounder on the multivariable logistic regression 23 models, sensitivity analysis was carried out using the R packages "survival" and 24 J o u r n a l P r e -p r o o f "obsSens". Except for the sensitivity analysis, which was conducted using R 1 (Version 3.6.1), all statistical analyses were performed using the statistical software 2 IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., USA). Graphs were 3 plotted using MedCal (Version 16.8.4, MedCal Software, Belgium) and GraphPad 4 Prism (Version 8.0.0, GraphPad Software, Inc., USA). 5

During the study period, 320 patients were admitted to the quarantine ward for 7 surveillance of COVID-19. The clinical characteristics of these 320 quarantined 8 patients are shown in Table 1 Table 1 , including acute myeloid leukemia with altered mental 15 status, hepatic encephalopathy, massive gastrointestinal bleeding, acute heart failure, 16 pulmonary embolism, and ST-elevation myocardial infarction requiring emergent 17 coronary intervention. Of note, cardiac arrest occurred in two patients (0.6%). In 18 total, five patients (1.6%) needed to be transferred to the intensive care unit during 19 their quarantine period. Two hundred and twenty-one (69.1%) of the quarantine 20 patients were 65 years old or older. Notably, 117 (36.6%) patients were aged 80 21 years or above. One hundred and twenty-one patients (37.8%) were bedridden and 22 needed intensive nursing care. Compared with those without acute critical illness, 23 patients with acute critical illness had a higher neutrophil-lymphocyte ratio 24 J o u r n a l P r e -p r o o f (P=0.026) and higher serum levels of C-reactive protein (P=0.002) and 1 procalcitonin (P=0.064; Table 1 ). 2 Etiologies other than COVID-19 that could explain fever or respiratory 3 symptoms in the 320 patients in the quarantine ward are provided in Table 2 . Of 4 287 patients for whom multiplex PCR for respiratory pathogens was carried out, 5 rapid identification of alternative pathogens was reported for 19 (6.6%), which 6 helped shorten the quarantine period of these patients. Four patients were newly 7 diagnosed with acute myeloid leukemia (AML) based on peripheral blood smear 8 and were admitted to the quarantine ward because of persistent fever, respiratory 9 symptoms, and unspecified pulmonary infiltrates on their chest radiographs. One of 10 them died due to intracerebral hemorrhage, a complication of untreated AML, on 11 the fifth day of hospitalization. The rates of old age, bedridden status, presence of 12 pressure sores, and nasogastric tube feeding were significantly higher among cases 13 that progressed to acute critical illness than those without acute critical illness; 14 dyspnea as the initial presentation was also more common among patients with 15 acute critical illness (Table 1) . Although age, bedridden status, long-term 16 nasogastric feeding, and the presence of pressure sores were associated with a 17 significantly increased risk of acute critical illness in univariate logistic regression 18 analysis, only bedridden status remained a significant predictor in multivariable 19 analysis, with the odds ratio 2.29 (95% confidence interval, 1.14 to 4.60; P=0.02; 20 To the best of our knowledge, this is the first report to evaluate the quality of 19 patient care using a quarantine strategy among patients in isolation for COVID-19 20 during the global outbreak. Our study shows that patients who developed 21 COVID-19-unrelated acute critical illness during quarantine were more likely than 22 those without acute critical illness to have an older age, a bedridden status, and a 23 nasogastric tube feeding. Baseline bedridden status, in particular, stands out as a 24 J o u r n a l P r e -p r o o f predictor for the risk of in-quarantine acute critical illness. In general, clinical 1 assessment, interventions and escalation of care should be unanimous for all 2 patients irrespective of isolation status. Although there is no evidence to date 3 suggesting that patients in isolation are more likely to develop clinical deterioration 4 or unexpected adverse events 8 , it is still an essential responsibility of HCWs to 5 recognize early and respond promptly to the first sign of clinical deterioration, even 6 when confronted with all the precautions and inconveniences relating to 7 quarantine 12 , particularly for at-risk patients, as implicated by the findings of our 8 present study. 9

Recent studies have reported several COVID-19 outbreaks in hospitals or 10 long-term care facilities (LTCFs) associated with unfavorable outcomes [13] [14] [15] . To 11 prevent outbreaks in hospitals and in community settings, the quarantine policy was 12 advised to enhance community surveillance of COVID-19. Delgado et al found that 13 the presence of respiratory tract infections is a predictor of unplanned ICU 14 admission, and pre-existing comorbidities and age were also pertinent factors 16 . In 15 our cohort, most patients had airway symptoms associated with radiologic evidence 16 of pulmonary infiltrates and were elderly (the median age was 74.15 years), and the 17 existing comorbidities of these patients increased the challenge to avoid adverse 18 events in progression, such as in-hospital patient falls or sudden death. 19

It is also difficult to prevent the spread of a dangerous and highly contagious 20 infection while minimizing compromise of patient safety and the quality of general 21 care 17 . The PPE for suspected COVID-19 cases is more complicated than that for 22 simple contact isolation and is associated with higher monetary costs; moreover, 23 physicians and nurses must spend a considerable amount of time wearing and 24 removing PPE 18 . The literature has shown that isolated patients are less likely to be 1 examined by physicians 19,20 . Overall, access to quarantined patients is more 2 difficult and may result in delay of emergent interventions (e.g., cardiopulmonary 3 resuscitation or intubation) and discourage frequent care (e.g., changing position 4 and chest physiotherapies for bedridden patients). In our study, advanced age, 5 nasogastric tube feeding, pressure sores, and symptom of dyspnea were 6 well-established predictors of poor prognosis for patients with pneumonia. Because 7 bedridden patients are physically dependent and are unable to perform self-care, the 8 rate of bedridden status among critically ill patients will undoubtedly be higher than 9 among those not in a critical condition. Patients with these poor prognostic factors 10 are at an enhanced risk of rapid deterioration. In our cohort, more than one-third of 11 the patients were aged 80 years and older. Prior research has demonstrated that 12 excessive containment may result in adverse psychological stress, such as 13 depression, delirium, and anxiety, among isolated, elderly patients 19,21,22 . In 14 addition, patients and their family members may hesitate to seek medical aid 15 because of the threat of quarantine 23 . 16

The diagnosis of COVID-19 was based on PCR testing for SARS-CoV-2, 17 which may be dependent on the quality and type of respiratory tract sample. 18

Considering that quarantine may impair adequate monitoring and timely 19 management of these patients, it is therefore important and beneficial to shorten the 20 duration of quarantine whenever appropriate. The interval of two consecutive 21 SARS-CoV-2 RNA detections in our cohort was at least 12 hours apart. Thus, the 22 mean reporting time was 1.26 days, and the mean DOQ was 1.04 days, both of 23 which were much shorter than the times reported by the respiratory surveillance 24 J o u r n a l P r e -p r o o f ward in Singapore (1.89 days) 7 , without missing a diagnosis of COVID-19. 1

However, there is no strong evidence showing that shortening the period between 2 two respiratory specimens will decrease the sensitivity of COVID-19 testing. 3

There are some limitations of this study. This study was performed in a tertiary 4 medical center; therefore, selection bias was inevitable. Moreover, this was a 5 retrospective investigation, and it was not possible to include a parallel control 6 group (consisting of patients with similar presentation but without quarantine) for 7 comparison, as this would be a major violation of the policy of TCDC to contain 8 the pandemic. The ultimate goal of this study was not to find predictors of 9 unexpected adverse events but to disclose the potentially deleterious impact of 10 quarantine on elderly and bedridden patients as well as the importance of 11 maintaining a balance between patient safety and infection control in response to 12 the COVID-19 global pandemic. 13

In conclusion, with a relatively low prevalence of COVID-19 in the 14 community in Taiwan The results of the sensitivity analysis are presented graphically in the figure above. 6

Regardless of the various ratios of prevalence of potentially unidentified confounders, 7 bedridden status remained a significant risk factor for acute critical illness. The 8 sensitivity analysis was performed using the packages "survival" and "obsSens" of R 9 (version 3.6.1). The graph was plotted by GraphPad Prism (Version 8.0.0, GraphPad 10 Software, Inc., USA). 11 12 13 

Clinical Characteristics of 2 Coronavirus Disease 2019 in China

CECC issues Guidelines for Large-Scale Public Gatherings to prevent 7 widespread community transmissions

Interim Guidelines for Clinical 12 Management of SARS-CoV-2 Infection

CECC raises travel notice for all countries to Level 3: Warning; advises against 14 all nonessential travel

To strengthen community-based surveillance, groups with foreign travel or 18 contact history or other groups of potential risks included in COVID-19 testing 19 procedure