key: cord-1048060-0hig671f authors: Shah, Vallari; Ko Ko, Thinzar; Zuckerman, Mark; Vidler, Jennifer; Sharif, Sobia; Mehra, Varun; Gandhi, Shreyans; Kuhnl, Andrea; Yallop, Deborah; Avenoso, Daniele; Rice, Carmel; Sanderson, Robin; Sarma, Anita; Marsh, Judith; de Lavallade, Hugues; Krishnamurthy, Pramila; Patten, Piers; Benjamin, Reuben; Potter, Victoria; Ceesay, M. Mansour; Mufti, Ghulam J; Norton, Sam; Pagliuca, Antonio; Galloway, James; Kulasekararaj, Austin G title: Poor outcome and prolonged persistence of SARS‐CoV‐2 RNA in COVID‐19 patients with haematological malignancies; King's College Hospital experience date: 2020-06-11 journal: Br J Haematol DOI: 10.1111/bjh.16935 sha: 128d19c4f5b5e36c624e200b79f70838dcdfe49e doc_id: 1048060 cord_uid: 0hig671f Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), emerged at the end of 2019 and caused an infection named COVID‐19 (Guan, Ni et al. 2020). Patients with compromised immune systems are at increased risk of complications but this risk is not precisely defined (Liang, Guan et al. 2020). Although age, gender, comorbidities and ethnicity are risk factors for adverse outcomes (Huang, Wang et al. 2020), various pre‐existing conditions, including haematological cancers, have also been reported to correlate with poor outcomes (Aries, Davies et al. 2020, He, Chen et al. 2020, Malard, Genthon et al. 2020, Martin‐Moro, Marquet et al. 2020, medRxiv 2020) Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged at the end of 2019 and caused an infection named COVID-19 (Guan, Ni et al. 2020) . Patients with compromised immune systems are at increased risk of complications but this risk is not precisely defined (Liang, Guan et al. 2020) . Although age, gender, comorbidities and ethnicity are risk factors for adverse outcomes (Huang, Wang et al. 2020) , various pre-existing conditions, including haematological cancers, have also been reported to correlate with poor outcomes (Aries, Davies et al. 2020 , He, Chen et al. 2020 , Malard, Genthon et al. 2020 , Martin-Moro, Marquet et al. 2020 , medRxiv 2020 Our aim was to compare the first 80 patients with haematological malignancy with all other patients admitted to our hospital with COVID-19 in the same time frame to precisely define their relative risk and identify factors that increase mortality within this subgroup. The mean age of our cohort was 69.4 years (range 30-95), with 65% males (n=52) and 76% had at least 1 co-morbidity. Overall, 62 (77%) patients had lymphoid malignancies/plasma cell dyscrasias and 18 (23%) had myeloid neoplasms. Nine patients had previously undergone an allogeneic (n=6) and autologous (n=3) HSCT. One patient had received CAR-T therapy. Treatment type included intensive therapy (20%, n=16), non-intensive therapy (44%, n=35) and 'watch and wait' (36%, n=29), with 40% (n=31) on active treatment (supplementary table 1 and supplementary table 2 ). This article is protected by copyright. All rights reserved The most common symptoms on admission were fever (60%), cough (58%), dyspnoea (54%) and gastrointestinal (13%) (Supplementary table 1) . Both the baseline pre-COVID-19 (median 1.25 x 10 9 /l) and the nadir (median 0.6 x 10 9 /l) lymphocyte count were lower than normal range (1.3-4). Overall, 23 (29%) patients had mild disease, 22 (27%) had moderate disease requiring ward-based care and oxygen requirement, and 35 (44%) had severe disease. On the date of censoring, 28 patients had died due to COVID-19, with a crude case fatality rate of 39%. Haemato-oncology patients who died or were transferred to ITU were older (73 years vs 66; P=0.065), but male gender (61% vs 67%, P=0.76) was not associated with poorer outcome. Differences in ethnicity were noted with a higher black population among those who died (45% vs 17%, P=0.02). Higher total white cell count (15.8 vs 4.9 x10 9 /L, P=0.015), neutrophil count (5.7 vs 3.8x10 9 /L, P=0.04) and CRP (200 vs 82, P<0.001) were associated with poorer outcome (Supplementary Table 1 ). Lower baseline pre-COVID-19 lymphocyte count (1.1 vs 1.5 x10 9 /L, P=0.02) was associated with better outcome, even when CLL cases were removed from the analysis. Supplementary Figure 1 demonstrates the fall in lymphocyte count from prior to COVID-19 infection to its nadir during COVID-19 infection. We compared baseline characteristics and outcome of COVID-19 in hospitalised patients with no underlying haematological malignancy (n=1115) with our haemato-oncology cohort (n=68) ( Table 1 ) admitted within the same timeframe where identical follow up was available. No difference was observed in age, gender or co-morbidities between the two groups. There were higher proportion (60.3% vs 45%, p=0.011) of white British and lower incidence of social deprivation (22% vs 40.3%, p=0.018) in the haematology cohort. The median lymphocyte and neutrophil count were lower (0.6 vs 1.0 x10 9 /l, p<0.001 and 3.8 vs 5.7 x 10 9 /l, P<0.001, respectively) in the haemato-oncology group. The crude mortality rate at day 28 from admission was significantly worse for the haematology cohort 39% (95% CI 27-52) versus 20% (95% CI 18-23) in the medical cohort (HR 2.06; 95% CI, 1.36-3.14; P = 0.001) and was retained on adjusting for age and gender (HR 1.74; 95% CI, 1.12-2.71; P = 0.014) (Supplementary Table 3 and Figure 1A&B ). Although the type of underlying malignancy (lymphoid vs myeloid), did not influence the outcome (Supplementary Table 3 and Figure 1C ), the intensity of treatment had a strongly negative impact on the mortality. Patients on both intensive (HR 4.66; 95% CI, 2.29-9.47; P = 0.001) and non-intensive (HR 1.90; 95% CI, This article is protected by copyright. All rights reserved 1.05-3.48; P = 0.035) treatments, did worse compared to age/gender matched general cohort (Table 3 and Figure 2D ). SARS-CoV-2 ribonucleic acid was detected in nasopharyngeal swabs/ bronchoalveolar lavage in all 80 patients. We evaluated the persistence of viral RNA in 22 patients who had a repeat positive test beyond 7 days. The median duration of virus detection in the respiratory samples was 29 days (Supplementary Figure 2A) . Of the 22 patients, 9 patients became negative at a median of 13 days (range 7-60) and 13 patients had ongoing RNA persistence (Supplementary Figure 2&3) . We noted several cases of clinical deterioration beyond the 10-14 day window. In conclusion, we report on outcomes and predictive factors for the largest series to date of patients with COVID-19 and underlying haematological malignancies (n=80) and compare outcomes to general medical patients admitted with COVID-19 during the same time. We found no correlation between age or male gender between survivors and non-survivors with COVID-19 and haematological cancer, compared to a general non-haematology cohort, and contrary to previous publications (Guan, Ni et al. 2020 ). However, haemato-oncology patients with COVID-19 had a 2-fold increased risk of death, with a 28-day mortality rate of 39%, which was 4-fold higher in those undergoing intensive treatment. Our data suggests that the current caution around delivery of intensive treatments during the COVID-19 outbreak is justified and that continuation of shielding in this subgroup should be considered. Lymphopenia during COVID-19 is present in high proportion (40-83%) of cases and is also associated with worse prognosis in the general population (Guan, Ni et al. 2020 , Huang, Wang et al. 2020 , Terpos, Ntanasis-Stathopoulos et al. 2020 , Wang, Hu et al. 2020 . Our data show a lower lymphocyte and neutrophil count in haematology cohort. Furthermore, both worsening of lymphopenia during, the depth of lymphopenia prior to, infection had a beneficial impact on survival. This is in line with several recent studies suggesting that overactivation of the adaptive immune system can be responsible for the high mortality associated with COVID-19. This is however speculative, and further study of both the innate and adaptive immunity within the haematology cohort may be useful. Prolonged detection of viral RNA, for up to 2 months in a subset of patients, has not been reported in the immunocompromised setting (Zheng, Fan et al. 2020) . Prolonged persistence in haematooncology patients has significant implications for scheduling subsequent chemotherapies, shielding and self-isolation. This article is protected by copyright. All rights reserved Despite limitations and caveats, our data with the added benefit of a large non-haematology COVID-19 patients, show a doubling of mortality in haemato-oncology patients with COVID-19 and a prolonged persistence of viral RNA. The authors wish to thank the patients and all the staff who were involved in managing COVID-19 at our institution. This article is protected by copyright. All rights reserved Tables and Figures: Table 1 : Comparison of baseline characteristics of patients with COVID-19 without underlying haematological malignancies (general cohort, group 2, n=1115) and haemato-oncology patients with COVID-19 (haematology cohort, group 1, n=68). Note: All haemato-oncology patients admitted until 15 th April (n=68) were compared to group 2 patients during the same period to calculate time-to-event (death), so all patients had at least a follow-up period of 30 days. This article is protected by copyright. All rights reserved * was calculated using index of multiple deprivation (IMD), with lowest three deciles of deprivation according to IMD @ Radiological score-Chest radiographs were assessed using an adapted radiographic assessment of lung oedema (RALE) score for COVID-19. (Wong, Lam et al. 2019) The severity score attributes a number between 0-4 to each lung depending on extent of consolidation or ground glass opacities (0 = no involvement, 1 = <25%, 2 = 25-49%, 3 = 50-75%, 4 = >75% involvement) CRP-C reactive protein, DM-Diabetes mellitus, HTN-hypertension, IHD-ischaemic heart disease, COPD-chronic obstructive pulmonary disease, other lung disease-includes asthma, interstitial lung disease. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Clinical Outcome of Coronavirus Disease 2019 in Haemato-oncology Patients Clinical Characteristics of Coronavirus Disease 2019 in China COVID-19 in persons with haematological cancers Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China COVID-19 outcomes in patients with hematologic disease Survival study of hospitalized patients with concurrent Covid-19 and haematological malignancies OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients Hematological findings and complications of COVID-19 Novel Coronavirus-Infected Pneumonia in Wuhan, China Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province Accepted Article This article is protected by copyright. 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