key: cord-0775471-vkmm15nc
authors: Biernat, Monika M; Zińczuk, Aleksander; Biernat, Paweł; Bogucka-Fedorczuk, Aleksandra; Kwiatkowski, Jacek; Kalicińska, Elżbieta; Marciniak, Dominik; Simon, Krzysztof; Wróbel, Tomasz
title: Nosocomial outbreak of SARS-CoV-2 infection in a haematological unit – high mortality rate in infected patients with haematologic malignancies
date: 2020-08-01
journal: J Clin Virol
DOI: 10.1016/j.jcv.2020.104574
sha: 1bf5566d6a4871dd644cbb1fa42fedf23751201c
doc_id: 775471
cord_uid: vkmm15nc

BACKGROUND: Here we report nosocomial outbreak of COVID-19 among patients in a haematological unit. To our knowledge this is the first report from Central Europe comparing morbidity and mortality in infected and non-infected patients after exposure to SARS-CoV-2. METHODS: The outbreak involved 39 individuals: 19 patients and 20 health care workers. The SARS-CoV-2 test by nasopharyngeal swabs was performed by real-time RT-PCR. Exposed patients were divided into two groups: quarantine patients with and without COVID-19. All patients were prospectively examined at the following time points: 0, 7 days, 14 days, 21 days and 28 days after confirmation or exclusion of SARS-CoV-2. RESULTS: Infection was confirmed in a total of 5/20 health care workers and 10/19 patients. Among the patients positive for SARS-CoV-2 infection, the mortality rate was 36.8%. The probability of death in patients infected with SARS-CoV-2 increased 8-fold (p = 0.03). Bacterial, fungal, and viral co-infection significantly decreased survival in these patients (p < 0.05). Additionally, the probability of death was much higher in patients older than 40 years of age (p = 0.032). CONCLUSION: This study showed significantly higher mortality rate in COVID-19 patients with haematologic diseases compared to the non-infected patient group. Haematologic patients with COVID-19 have 50% less chance of survival.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic was announced relatively low compared to other European countries with about 14,000. By June 25 th , the number of infected people was 30,000+, over 1,396 people have died, and the mortality rate was 2.6. Furthermore, the number of infected people in Lower Silesia has increased to 2,851 and 150 people have died [3] .

SARS-CoV-2 is a new coronavirus similar to SARS-CoV-1 and MERS-CoVprobably originating from bats and has the ability to activate the immune system uncontrollably, causing massive inflammation [4] . SARS-CoV-2 multiplies rapidly in the upper respiratory tract epithelium, and can infiltrate further into the lungs leading to inflammation, oxidative stress, thrombosis, and death [5, 6] .

The infection spreads rapidly from person to person through virus-laden droplets that are aerosolised during speech or by coughing [7] . The main symptoms of infection are fever, shortness of breath cough, sore throat, and loss of taste or smell. However, in many cases the infection is asymptomatic. Severe infections are also possible, especially in older people with comorbidities such as: cancer, hypertension, diabetes, obesity, cardiopathies, or chronic respiratory diseases [8, 9] .

In haematologic patients, the disease status with chemotherapy can lead to severe immunosuppression. This critical state may lead to the increase risk of serious SARS-CoV-2-related complications. However, clinical observations show conflicting results [10, 11] . Additionally, data on the spread of the virus in the hospital environment, the course of the infection, and the outcome in this group of patients are non-existent. Due to the fact that Poland's number of cases is consistently high, it is important to implement effective infection control strategies to protect haematologic patients. Here we report a nosocomial COVID-19 outbreak among patients and medical staff in our haematological unit. We report the details for demographics, laboratory tests, clinical course, and outcome of infection in patients with haematologic malignancies, positive and negative for SARS-CoV-2. To our knowledge this is the first report on COVID-19 infections in haematologic patients from Central Europe, and the first report comparing morbidity and mortality in infected and non-infected patients after exposure to SARS-CoV-2.

Since the first COVID-19 case in Poland, visitors have been limited in both the hospital and clinic. The first ward infection was confirmed in a medical staff member on April 7 th , and was considered J o u r n a l P r e -p r o o f the index case. COVID-19 diagnosis was determined by the WHO's interim guidance, where a patient must test positive for SARS-CoV-2 by two independent laboratory tests [12] . Positive cases were classified as hospital acquired if the infection was confirmed by RT-PCR and appeared 48 hours after hospital admission and were in contact with the index case. Screening tests were performed on the all patients and medical staff in the ward after the infection in the index case was confirmed. SARS-CoV-2 testing was carried out by swabbing the nasopharynx region and immediately processing the sample in house at our hospital laboratory. The test was carried out twice with the Vitassay dual-generation realtime RT-PCR test using the Quant Studio 6 Flex from Applied Biosystems. The test detects the ORF1ab and N gene. Results were obtained within 8 hours. SARS-CoV-2 tests were performed every seven days until a negative result was obtained. Patients were divided into two groups: patients with and without COVID-19. These patients were prospectively examined at the following time points: day of infection confirmation as 0, 7 days, 14 days, 21 days and 28 days after confirmation or exclusion of SARS-CoV-2. Demographics, laboratory data, clinical characteristics and outcome in both groups were then analysed. All patients had given their written consent to participate in and to publish the study. The study was approved by the local Bioethics Committee No 315/2020.

The analysed variables were nominal, including dichotomous. The statistical analysis was based on the assigned multi-divisional quantity tables. First, general correlations between the analysed variables were assessed using correspondence analysis and generalised analysis of main PCA components. Built PCA model was estimated using NIPALS iterative algorithm. The Convergence

Criterion was set at 0.00001-setting the maximum number of iterations equal to 50. The number of components was found by determining the maximum predictive capacity Q^2 using the V-fold crosscheck method, and setting the maximum number of them at Vmax=7. The obtained optimal PCA model was reduced to 2 components. The PCA analysis, the results of which are presented in the pca1 vs. pca2 load diagram, allowed to preselect the variables with the most significant impact on the built model and to select the most significant correlations between them. The variables selected were then subjected to further statistical evaluation. The statistical significance between nominal variables was evaluated by J o u r n a l P r e -p r o o f the chi-quadrant test with a Yates correction, and the accurate Fisher test. A non-parametric analysis of survival was performed based on a non-parametric model of proportional Cox gambling. In all tests a significance level of p=0.05 was assumed, the assumption of proportionality of the Cox model was evaluated graphically.

COVID-19 was confirmed in a total of 5/20 health care workers and 10/19 patients. A positive result was obtained initially in one medical staff member, a nurse who was considered as the index case and in six patients within seven days after exposure, followed by four more patients and four medical staff members after 14 days of exposure. The nurse who was the index case and one doctor with confirmed COVID-19 had symptoms of upper respiratory tract infection, two another nurses were asymptomatic. The clinical characteristics of patients involved in the COVID-19 outbreak presents Table 1 . All patients exposed to SARS-CoV-2 had recently received chemotherapy or immunosuppressive treatment. COVID-19 positive patients were transferred immediately to the Infectious Diseases Unit for further treatment. A strict sanitary regime was introduced in the ward, the remaining patients were isolated and staff who had contact with the patients were quarantined for two weeks. The outbreak was reported to the local public health department. The staff who took care of the exposed and infected patients followed strict personal protective equipment guidelines, using filtering face peace (FFP)-3 masks, gowns, aprons, and gloves. After 14 days from the first contact with the index case, another 4 quarantined patients were confirmed as SARS-CoV-2 positive. These patients were immediately transferred to the infectious disease ward. The local infection control team performed contact tracing and testing until no further cases among health care workers or patients in quarantine were identified. The results among the staff after 7 days and 14 days were negative. The unit was disinfected.

Positive SARS-CoV-2 patients presented a variety of symptoms and the course of infection was different (Supplementary materials). Out of the ten COVID-19-positive patients, three displayed a fever, one had dyspnoea, and one patient had a sore throat. None of the patients complained about loss of taste or smell, so these symptoms were excluded from the analysis. Tracking the symptoms that COVID-19 J o u r n a l P r e -p r o o f positive patients on day 0, 7, 14 21, 28 showed a present fever at the beginning of the infection (p=0.04), dyspnoea on day 7 from infection (p=0.007), and a cough on day 14 from infection (p=0.007). These factors significantly increased the probability of death in haematologic patients (Table 2) .

About three days before the infection was confirmed, 7/10 patients with leukopenia with lymphopenia had increased levels in C-reactive protein (CRP) and D-dimers. One another patient who recovered is still receiving chemotherapy for multiple myeloma, while the other two patients have not yet started their cytostatic treatment due to persistent pancytopenia and poor clinical condition. Among the patients exposed to SARS-CoV-2 infection, the mortality rate was 7/19 (36.8%); of the infected patients, 7/10 (70%) died. These data suggest that after contact with a person infected with SARS-CoV-2, the probability of death increased 8 times (p=0.03, OR=8.166). Taking into account the age of the examined patients, the probability of death was much higher in patients older than 40 years of age (p=0.032). The difference for patients over 65 and older was not statistically significant.

We examined the overall survival and showed that COVID-19 patients with acute leukaemia and MDS and compared to COVID-19 patients with lymphoid malignancies is decreased by half (figure1 and figure 2). This data suggests patients with COVID-19 are 50% less likely to survive by day 30 vs. 

After an early epidemic introduction in Poland, the freezing of the economy, closing of schools, locking down people temporarily in their homes, and restrictions to maintain social distance and cover mouths and noses in public has resulted in a dampened spread of COVID-19. The current rate of R virus reproduction for Poland in June is 1.11, at the beginning of the epidemic it was 3.4 [3] . Authors from Wuhan, China-the initial centre of the epidemic-and from other countries show that the frequency of infection in patients with cancer is higher than in COViD-19 patients without comorbidities [13, 14] .

The study presents a ward outbreak of SARS-CoV-2 infection in the haematology department. To our knowledge it is the first report concerning COVID-19 positive in patients with haematologic malignancies from Poland and the first report analysing the survival of infected and not infected after exposure to SARS-CoV-2. Our observations show that COVID-19-positive patients with haematologic malignancies have 8-times higher mortality rates than non-infected patients. Moreover, the overall survival in COVID-19-positive haematologic patients was about 40%, which is much lower than in the non-infected patients. Our study has shown that the symptoms of SARS-CoV-2 infection may be indistinguishable from other bacterial or viral infections. These observations are consistent with the clinical data from other studies [15] [16] [17] . Interestingly, the shedding of the virus may be prolonged, similarly to the influenza virus. We still detected SARS-CoV-2 after 14-21 days in the majority of the COVID-19-positive patients, which is consistent with other viral infections in patients with haematologic malignancies [16] . It is unclear whether the prolonged incubation period is related to the immunosuppression status or rather to the fact that the source virus inoculum was small that the infection was largely asymptomatic. Moreover, 4 patients were positive 14 days after contact with the index case.

Others, like Wu Y et al., reported on delayed COVID-19 cases after exposure [15] . In our experience, the infectivity potential of the virus is high and it is very easy to spread in the hospital environment. The patients with haematologic malignancies have poorer prognoses than patients with solid tumours [13] .

The authors showed that 41% of patients died, while mortality among our patients was slightly lower (36%). The high mortality of patients is significantly higher due to symptoms such as ECOG>2, dyspnoea and fever, or with elevated CRP and D-dimer at the beginning of infection. Immediately after the epidemic was introduced preventive measures were installed at the hospital including mandatory screening tests were performed on patients before admission to the haematology department, screening tests among medical staff were performed every 7 days, and we are insistent on wearing barrier clothes, masks and visors. Because the medical staff can be asymptomatic, it is necessary to implement these procedures to protect immunosuppressed patients against infection. Recent studies confirm the transmission of infection by asymptomatic individuals, including health care workers [19, 20] . The use of personal protective equipment and reduction of social interaction as well as isolation of patients is an effective way to reduce infection in the hospital environment [21] . Our actions were consistent with the global recommendations by our panel of experts that manage patients with acute leukaemia and myeloid neoplasms [22] .

In summary, the study showed significantly higher mortality rate in haematologic patients with and without COVID-19. Patients with COVID-19 had a 50% less chance of survival. Additionally, the J o u r n a l P r e -p r o o f risk of death in haematologic patients with COVID-19 in his population increases significantly already after 40 years of age. The use of personal protective equipment and screening tests among patients and medical staff, as well as isolating the infected was an effective way to reduce the spread of infection in the hospital environment. The main limitations of the study are the small cohort size and heterogeneous group of patients. We believe that multi-centre observational studies on a larger group of patients will better stratify of risk groups improved patient care, and improve our understanding of an effective treatment.

MMB and PB designed the study, was responsible for data analysis and interpretation, writing, 

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We thank Mark Jeremy Hunt and native speakers of English from Ecorrector for the correction of the manuscript.

There are no conflicts of interest by all authors.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.J o u r n a l P r e -p r o o f