Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort

Abstract The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56–25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43–4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.


Introduction
In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease , emerged in Wuhan, China [1,2]. SARS-CoV-2 has since gone on to cause a global pandemic, which has caused significant disruption to routine healthcare.
Individuals with cancer are more prone to respiratory viruses as a result of immunosuppression from either the underlying disease or therapy. For example, the mortality rate from influenza [3,4], and even rhinovirus, can be increased in certain populations [5]. The mortality rate in cancer patients with COVID-19 is higher than the background population and patients with no history of cancer, when adjusted for other potentially explanatory variables, such as age and comorbidities [6].
As a result, patients receiving chemotherapy for malignancy have been classified as high risk in the UK [7]. However, it is not clear whether the risk is the same across all cancer types. Patients with haematological malignancy, who are usually more immunosuppressed than those with solid organ tumors, may have a higher risk of death from COVID- 19. To examine the effect of COVID-19 on our patients, we conducted a multicentre retrospective audit. We examined the difference in outcomes between solid organ and haematological malignancy and the outcome effect of recent chemotherapy treatment, to inform management of cancer patients.

Study design and participants
This multicentre audit collected data from cancer patients who were hospitalized with COVID-19 between 1 March 2020 and 10 June 2020 across six NHS hospitals in England: The Clatterbridge Cancer Center, Liverpool University Hospitals, Arrowe Park Hospital, Royal Albert Edward Infirmary, The Christie and North Middlesex University Hospital. The mortality in patients with cancer in a large prospective cohort UK study (ISARIC WHO CCP-UK) was 44% [6,8], with which we compared our outcomes. To allow comparison with the CCP-UK patient cohort, we only recorded hospitalized patients with COVID-19. Each centre's governance team approved the audit. All patients included were SARS-CoV-2 positive as determined by each center's approved PCR testing protocolirrespective of signs or symptoms [9].

Data collection
Data were collected locally from patients' medical records using a standard proforma. We collected age, sex, ethnicity, postcode, cancer history, comorbidities (defined in Supplementary Methods), presenting symptoms, results of radiological examinations (Supplementary Methods), and laboratory results. Details of the COVID-19 episode, duration of hospital admission, and any related complications were also collected. Patients were monitored until discharge, death, or last available follow-up. The final date of data collection was 17 June 2020.

Cancer-specific information
Cancer-related data included date of diagnosis, type of primary cancer, treatment history including nature (surgery, radiotherapy, chemotherapy, endocrine therapy, or immunotherapy), and intent of treatment (induce remission, curative, adjuvant, neoadjuvant, radical, watch and wait, non-curative and palliative) as well as the date of last treatment. Where treatments were halted due to COVID-19 and the patient survived, information relating to whether treatment was restarted was sought. Definitions used have been summarized in Supplementary Methods.

Severity of illness and mortality rate
Definitions of severity of illness were adapted from other publications [9,[11][12][13][14]. Disease was 'mild' if patients did not require oxygen throughout admission; 'moderate,' if the oxygen saturations were recorded to be <93% or they required at least 0.35 FiO2 therapy; and 'severe,' if they required intensive care unit (ICU) admission or died. Mortality rate was the proportion of patients who died at any point before final data extraction.

Statistical analyses
Continuous data are presented as median (IQR) and categorical data are reported as frequencies of counts and associated percentages. Differences in the distribution of data between haematological and solid malignancy types were assessed using Wilcox test/t-test for continuous data and Fisher's/Chi-square test for categorical data. The main outcomes were the mortality rate, which was compared to ISARIC WHO CCP-UK and time-to-death from positive SARS-CoV-2 test. Additional methodology has been summarized in Supplementary Methods document.

Clinical characteristics
In total, 179 SARS-CoV-2 positive cancer patients were identified ( There were no significant differences in comorbidity between groups. HM patients came from more deprived areas, with an index of multiple deprivation decile score of 4 (IQR 1.75, 8), compared with a score in SM patients of 3 (IQR 1, 5), p ¼ 0.039.

Anticancer treatment
Systemic anticancer treatment was administered to 58% (30 of 52) of HM patients and 39% (49 of 127) of SM patients within 4 weeks preceding the COVID-19 episode. Within 4 weeks to 12 months preceding the COVID-19 episode, 14% (18 of 127) of HM patients and 4% (2 of 52) of SM patients received prior treatment, and 9% (12 of 127) vs 11% (6 of 52) received prior therapy more than 12 months of COVID-19 episode in the HM and SM groups, respectively. None of the HM patients underwent prior radiotherapy or surgery with 4 weeks of COVID-19 compared to 7% (9 of 127) of SM patients. All patients receiving anticancer therapy at the time of COVID-19 had their treatment stopped. Of these patients, 27% (8 of 30) and 30% (17 of 56) of HM and SM patients respectively had restarted treatment at the time of the last recorded follow-up. Cancer treatment and the treatment intent are summarized in Table 2 and Supplementary  Table 3.

Laboratory findings and viral load
More patients in the SM group had lymphopaenia with a count <1 Â 10 9 /L (78% versus 59% in the HM group, p ¼ 0.003), however median counts were actually lower in HM (Supplementary Table 1 Figure 2(A)].
Of interest was that ex-smokers appeared to have worse overall survival compared with patients who never smoked and active smokers (Supplementary Figure 2(A)). However, even though this effect was again seen in univariable Cox proportional model for ex-smokers compared with active smokers [HR 3.52 (95% CI, 1.09-11.36), p ¼ 0.035], it was not seen between ex-smokers and nonsmokers (p ¼ 0.386, Table 3).
Furthermore, in the multivariable model, every 1year increase in age [HR 1.04 (95% CI, 1.01-1.07), p ¼ 0.003] was also seen to be an independent factor associated with increased risk of death. There was a trend toward increasing CRP level being associated with increased risk of death which did not reach statistical significance [HR 1.34 (95% CI, 1.00-1.80), p ¼ 0.052, also see Supplementary Figure 2

Radiological imaging
Chest radiograph was performed in all but one asymptomatic patient, and 13% (23 of 179) underwent computerized tomography (CT) of the thorax. Bilateral airspace consolidation was the commonest finding with 51% (26 of 51) and 41% (52 of 127) reported in HM and SM groups, respectively (Figure 1(C)). Unilateral pleural effusion (11.5 vs 13.4% for HM and SM) was seen more frequently than bilateral pleural effusions (9.6 vs 7.1% for HM and SM). ARDS was seen in 9.6 and 7.1% of HM and SM cases, with pneumothorax being a rare finding.

Medical complications during COVID-19 admission
Medical complications during the COVID-19 admission occurred in 28% (51 of 179) of all cancer patients. Acute kidney injury was the commonest complication in cancer patients occurring in 21% (37 of 179). For patients who developed AKI compared with those who did not, the HR was 2.26 (95% CI, 1.34-3.82, p ¼ 0.002). Symptomatic CCF and VTE occurred in 4.5% (8 of 179) and 4% (7 of 179) of cancer patients respectively with breakdown shown between HM and SM in Figure 1(C).

Hospital stay and discharge
Fifty percent (26 of 52) of HM patients were discharged compared to 68% (86 of 127) SM patients at the time of last follow-up. The median hospital stay for patients who were discharged was 8 (IQR 3,14) days whereas the median hospital stay for patients who died was 9 (IQR 5.5, 16) days. When comparing HM and SM groups, the median follow-up time, estimated using the reverse Kaplan-Meier method was 42 (IQR 38, 46) and 45 (IQR 42, 46) days, respectively.

Discussion
Patients with cancer appear to have a higher infection rate with SARS-CoV-2 than the general population [12,[14][15][16][17][18], and also higher mortality [6]. In our multicentre audit, the mortality rate was 37% amongst all cancer patients. This compares with a 44% hospital mortality overall in the ISARIC WHO CCP-UK study [6,8] which is the key national characterization protocol for the SARS-CoV-2 pandemic within the UK. This supports the notion that cancer patients with COVID-19 have worse outcomes compared to those without cancer [11][12][13][14]17,[19][20][21][22][23][24][25], although this is not confirmed in all studies [26,27]. Here, we report a significantly higher mortality rate for patients with haematological malignancy (HM, 48%) than with solid malignancy (SM, 32%), also seen in other studies [11,23,28]. Other haematological case series report a high mortality in HM patients of 35.9% [25] and 33% Table 3. Univariable and multivariable analysis of covariates grouped into demographics, cancer type and nosocomial infection, anticancer treatment and investigations with death as an outcome. in a study focused on patients with chronic lymphocytic leukemia [24]. In our cohort, the overall nosocomial infection rate was 16%. The outcome from nosocomial infection was markedly worse than from community-acquired infection. Although this difference was not maintained in multivariable analysis, this does not detract from the importance of this result. The reason that nosocomial infection does not remain significant in multivariable analysis is simply that it is likely to be a marker for patients who have a high degree of healthcare interaction, and either have significant co-morbidities, advanced cancer, are immunocompromised from their treatment, or combination of these factors. It is therefore likely that the patient population accounts for this and not the location of SARS-CoV-2 acquisition. This result indicates that the in-patient cancer population is extremely vulnerable to the effects of COVID-19, and underlines the need to avoid nosocomial transmission to these patients at all costs.
Systemic treatments for cancer are heterogeneous, ranging from endocrine therapy right through to high dose chemotherapy. In our cohort, when HM and SM patients were compared, marked differences were seen. The administration of systemic therapy increased the risk of death from COVID-19, whereas in SM patients it appeared to be protective. Given the particular effects of chemotherapy a further comparison was performed where an even greater difference in mortality between HM and SM was seen (62 vs 17%, p < 0.001). The worse outcomes observed in HM patients are likely due to the fact they are severely immunocompromisedthe resultant effect of the underlying haematological malignancy and systemic chemotherapy. It is however unclear why outcome improves in the counterpart group of SM patients receiving chemotherapy. Possibilities include: i) greater marrow reserve, ii) differences in the use of granulocyte colony-stimulating factors and iii) chemotherapyinduced reduction in the neutrophil to lymphocyte ratio, leading to improved outcomes, as previously suggested [19].
While a number of studies have reported no impact of chemotherapy on outcome [21,22,28], there are others who have reported otherwise. For example, Zhang et al. [13] reported that anticancer treatment within 14 days of COVID-19 increased the risk of severe events. Similarly, Lee et al. showed that patients with HM receiving recent chemotherapy had worse outcomes, supporting the findings of our study [28,29]. Chemotherapy appeared to be protective in patients with solid organ malignancies, however, perhaps because this delineates a group of patients who are fitter than average, by virtue of being fit enough to receive chemotherapy. Finally, it must be acknowledged that the difference in the absolute number of deaths between these groups in this cohort is small, so these findings may be due to chance alone.
Interestingly, ex-smokers appeared to have an improved survival compared to nonsmokers as suggested in previous reports [21,30]. The reasons for this remain unclear and require further detailed exploration. One possibility is that COPD predominantly affects smokers so these patients receive steroids, which are now known to improve outcome in COVID-19 [31].
Various limitations exist in our study. Firstly, although this is one of the largest cancer cohorts reported with COVID-19, the numbers remain small to infer definite conclusions and therefore larger studies will be required to confirm our findings. Secondly, the retrospective design of the study limited the quality of data collected. Thirdly, an attempt was made to standardize definitions used, however, due to variation in practices across England, complications may have been coded differently in various hospitals. Fourthly, data were incomplete in some cases, further affecting the interpretability of results. Due to the small numbers, subgroup analysis was limited. Since there is no real-time capture of data, current studies are affected by issues of selection and recall bias. Furthermore, absence of non-cancer controls prevents stratification of patients which is important to adjust for unmeasured confounders.
We have observed that appreciable mortality exists in this cohort of UK cancer patients hospitalized with COVID-19. Patients with haematological malignancies are at the highest risk of death within this group, either because of the immunosuppressive effects of cytotoxic chemotherapy, their underlying disease or both. Nosocomial infection carries a high mortality, especially in those who have HM and have received chemotherapy recently (Figure 3) not because of where infection takes place, but most likely because the patients who acquire infection in hospital represent a particularly vulnerable group. Preventing in-hospital transmission to highly vulnerable patients should be a priority for care providers going forward into the first full winter season since the emergence of COVID-19 in the UK. Potential measures include 'clean' sites where cancer patients can be admitted away from patients being cared for with COVID-19, the use of dedicated teams for the most vulnerable patients, regular testing of staff, and strict adherence to hospital infection control measures. Further work is now underway to understand the impact of COVID-19 in cancer patients in the UK when controlled for key factors including age and ethnicity.