COVID-19 outcomes in patients with hematologic disease.

To the Editor:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus of zoonotic origin that emerged in China at the end of 2019. The infection, named Coronavirus Disease 2019 (COVID-19), is now spreading worldwide. As of April 16, 2020, the virus had affected more than 2,000,000 individuals and resulted in over 125,000 deaths worldwide. Mortality can be as high as 15% in elderly patients, and/or in patients with comorbidities [ 1 , 2 ]. Based on the current available data, the incubation period (time from exposure to symptom development) is estimated as between 2 and 14 days [ 3 ]. At present, there are no approved treatment options in Europe and no available vaccine. Avoiding exposure by adhering to recommended hygiene procedures, isolation of infected persons and social distancing are the only prevention strategies recommended by the WHO [ 4 ].

Risk factors for COVID-19 severity and death include older age, along with comorbidities such as diabetes, hypertension, or cardiac disease [ 1 , 2 ]. In addition, data from China suggest that patients with cancer have a significantly higher incidence of severe events (including intensive care unit admission, need of assisted ventilation, death) after contracting the virus (39% versus 8% in patients without cancer) [ 5 ]. Another study reported that cancer patients appear to be twice as likely to contract infection with SARS-CoV-2 [ 6 ]. Importantly, that study suggests that hospital admission and recurrent hospital visits, inherent to cancer patients’ management, are potential risk factors for SARS-CoV-2 infection [ 6 ]. To date, very few data are available on COVID-19 outcomes in patients with hematologic diseases. Only one 47-year-old patient with a lymphoma has been included in a previous report [ 5 ], and two articles have reported on the course of COVID-19 infection in a 39-year-old patient with chronic lymphocytic leukemia [ 7 ] and in a 60-year-old patient with multiple myeloma (MM) [ 8 ]. All three patients had a favorable outcome. Nevertheless, these were relatively young, unlike the overall patient population with hematologic neoplasms which is usually aged, comorbid and highly immunosuppressed. These patients are therefore expected to be a particularly vulnerable group for COVID-19. A better characterization of those infected with the virus is important. Here we describe the demographic characteristics, coexisting conditions, imaging findings, and outcomes among patients with hematologic disease and COVID-19 infection.

We included all consecutive adult patients with a hematologic disease admitted to the Hematology Department (inpatient and outpatient admissions) of the Saint-Antoine-Hospital, AP-HP, Paris, France, with laboratory-confirmed COVID-19 infection between March 9 and April 4, 2020 and with at least 10 days of follow-up. A confirmed case of COVID-19 was defined by a positive result on a real-time RT-PCR assay of a specimen collected on a nasopharyngeal swab. We reviewed medical records to collect demographic, clinical, and treatment data and outcomes of COVID-19. All laboratory tests and radiologic assessments, including plain chest radiography and computerized chest tomography, were performed at the discretion of the treating physician.

COVID-19 was suspected and screened by PCR in 48 patients with a hematologic disease and the infection was identified in 25. Clinical details on hematologic and treatment history and COVID-19 infection are listed in Table 1 . The median patient age was 72 (range, 40–96) years, 68% were male. The median duration of symptoms before the COVID-19 PCR assay was performed, was 4 (range, 0–22) days. None of the patients had recently traveled to a country with known transmission such as China, Iran, or Italy, but five had direct contact with a COVID-19 positive family member. Among the remaining patients, six were already hospitalized (none of them in the hematology department) at the time of viral infection symptoms’ onset due to a fall episode ( n = 2), MM diagnosis ( n = 3) or accidental cardiac drug overdose ( n = 1). Ten patients had one or more outpatient visits to the hematology department, suggesting a possible nosocomial origin of their infection. In the remaining four patients, the origin of COVID-19 infection was unknown. Table 1 Clinical characteristics, treatments and outcomes of patients with hematological malignancies and SARS-CoV-2 infection. Patient No Age Sex BMI Hemalogical disease Hematological status Hematological treatment Ongoing corticosteroids Number of treatment lines Previous transplant Comorbidities Time between onset of symptoms and diagnosis (days) Radiologic diagnosis ARDS Invasive mechanical ventilation COVID-19 management Follow-up since first symptoms (days) Survival status 1 65 M 28.7 Myeloma Complete remission Ongoing isatuximab + DXM maintenance Yes 2 Autologous HBP 3 Positive CT Yes Yes Best supportive care 17 Dead 2 73 F 30.2 Myeloma Diagnosis None No 0 No Diabetes, HBP, stroke, obesity 4 Positive X-ray Yes Yes Best supportive care 13 Dead 3 65 M 24.3 Myeloma Complete remission Ongoing lenalidomide maintenance No 1 Autologous HBP 4 ND No No HCQ/AZT + Tociluzumab 40 Alive 4 61 M 41.5 Lymphoma (DLBCL) Complete remission None, 3 months post CAR T-cell No 4 Autologous and allogeneic Diabetes, HBP, obesity 7 Positive CT Yes Yes Best supportive care 38 Alive 5 61 F 31.6 Myeloma Partial remission Ongoing carfilzomib + lenalidomide + DXM Yes 6 Autologous Diabetes, HBP, stroke, obesity 7 Positive CT No No Lopinavir-ritonavir 34 Alive 6 45 M 45.8 PNH Partial remission Ongoing eculizumab No 1 No Obesity 4 Positive CT Yes Yes Best supportive care 32 Alive 7 40 F 26.7 ALL Complete remission None, 9 months post allo-HSCT No 1 Allogeneic No 0 Positive CT Yes Yes Best supportive care 23 Alive 8 78 M 26.3 MDS Progressive disease Best supportive care Yes 0 No Glioma, stroke 1 Positive X-ray Yes No Tociluzumab + corticosteroids 10 Dead 9 79 M 37.8 Lymphoma (hairy cell) Complete remission None, 12 years post Cladribine No 2 No HBP, obesity, CKD, MDS, MGUS 2 Positive X-ray No No Lopinavir-ritonavir 26 Alive 10 62 F 24.2 LGL leukemia Complete remission None, 18 months post cyclophosphamide No 1 No No 1 Positive CT No No Best supportive care 32 Alive 11 75 M 28.7 MDS Progressive disease Best supportive care No 0 No Diabetes, HBP 7 Positive CT Yes No Best supportive care 27 Dead 12 81 M 21.3 Myeloma Partial remission Ongoing lenalidomide + DXM Yes 1 No HBP 3 Positive CT Yes No Best supportive care 10 Dead 13 81 M 30.1 Lymphoma (Marginal zone) Progressive disease None, 14 months post rituximab + bendamustine No 1 No Diabetes, HBP, stroke, obesity, COPD 0 ND No No Best supportive care 35 Alive 14 63 M 25.0 Lymphoma (hairy cell) Complete remission None, 5 years post rituximab No 2 No HBP 5 ND No No Best supportive care 32 Alive 15 92 M 20.0 Myeloma Progressive disease Ongoing cyclophosphamide + prednisone Yes 3 No HBP 14 Positive X-ray Yes No Best supportive care 14 Dead 16 89 M 23.6 Myeloma Stable disease Ongoing lenalidomide + DXM Yes 2 No CKD 6 Positive CT Yes No Best supportive care 21 Dead 17 61 M 23.9 Myeloma Complete remission Ongoing bortezomib maintenance No 2 Autologous Cardiomyopathy 12 Positive X-ray No No Best supportive care 29 Alive 18 86 M 22.3 CLL Stable disease Wait and watch No 0 No HBP, stroke, CKD 10 Positive X-ray Yes No Lopinavir-ritonavir + corticosteroids 17 Dead 19 68 F 24.4 Myeloma Partial remission Ongoing daratumumab + lenalidomide + DXM Yes 2 No Diabetes, HBP 1 Positive CT Yes Yes Lopinavir-ritonavir + corticosteroids + tociluzumab 17 Alive 20 72 F 31.5 Myeloma Partial remission Ongoing daratumumab + lenalidomide + DXM Yes 1 No HBP, obesity 0 Positive CT No No Best supportive care 20 Alive 21 76 M 19.3 MDS Progressive disease Best supportive care No 1 No CKD, COPD 3 Positive CT No No Best supportive care 20 Alive 22 97 F 17.2 MDS Progressive disease Best supportive care No 1 No Pancreatic adenocarcinoma, CKD 2 ND Yes No Best supportive care 4 Dead 23 71 M 24.1 Lymphoma (DLBCL) Complete remission Ongoing rituximab maintenance No 2 Autologous HBP, stroke 22 Positive CT No No Anakinra 29 Alive 24 63 M 22.8 Lymphoma (Poppema) Complete remission Ongoing rituximab-CHOP Yes 1 No HBP 10 Positive X-ray No No Best supportive care 19 Alive 25 75 F 41.4 Waldenström macroglobulinemia Partial remission Ongoing rituximab + cyclophosphamide + DXM Yes 3 No HBP, obesity, epidermoid carcinoma of the anal canal 1 Positive CT No No Best supportive care 14 Alive M male, F female, BMI body mass index (kg/m 2 ), DLBLC diffuse large B-cell lymphoma, PNH paroxysmal nocturnal hemoglobinuria, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndrome, LGL large granular lymphocyte, CLL chronic lymphoid leukemia, DXM dexamethasone, allo-HSCT allogeneic hematopoietic stem cell transplantation, HBP high blood pressure, CKD chronic kidney disease, MGUS monoclonal gammopathy of undertemined significance, COPD chronic obstructive pulmonary disease, CT computed tomography, HCQ hydroxychloroquine, AZT azithromycine.

The most common symptoms at diagnosis were fever ( n = 22, 89%), cough ( n = 19, 79%), and shortness of breath ( n = 19, 79%). The majority ( n = 20, 80%) of patients had a lymphoid malignancy, including 10 with MM (40%), and only 4 (16%) had a myeloid malignancy (myelodysplastic syndrome). One patient had paroxysmal nocturnal hemoglobinuria. Patients received a median of 1 (range, 0-6) line of treatment. Fourteen patients (56%) were being treated for their underlying disease at the time of COVID-19 diagnosis, with 10 (40%) receiving corticosteroids. Seven patients had a history of hematopoietic stem cell transplantation (autologous, n = 5, allogeneic, n = 1, and both, n = 1) and one had been treated with anti-CD19 CAR T cells 3 months before. Of note, the four patients with myelodysplastic syndrome received only supportive care, one patient with MM had just been diagnosed and had not initiated therapy, and one with stage A chronic lymphoid leukemia was on a ‘wait and watch’ strategy. In addition, all patients but two (92%) had additional chronic medical conditions. In particular, 17 (68%) patients had high blood pressure, 8 (32%) were obese, and 6 (25%) had diabetes mellitus. Fourteen (56%) patients had more than one coexisting condition besides the hematologic disease.

As reported elsewhere [ 1 ], lymphopenia was common at hospital admission ( n = 23, 92%), with a median lymphocyte count of 760/µL (range, 150–5910). Only one patient had severe neutropenia at the time of COVID-19 diagnosis (median, 2,350/µL; range, 70–11,400). A computerized tomographic scan of the chest was performed in 14 patients and bilateral ground glass opacities were evident in all of them. A chest radiography was performed in seven additional patients and all radiographs showed bilateral pulmonary opacities.

As of April 16, 2020, with a median follow-up since symptom onset of 29 days (range, 14–40), 13 of the 18 patients (52%) developed acute respiratory distress syndrome (ARDS) [ 9 ] and 6 received mechanical ventilation (Supplementary Fig. 1 ). It was decided not to transfer the remaining seven patients with ARDS to the intensive care unit because of their age and hematological disease history. All patients who did not develop ARDS were alive at last follow-up. Of patients with ARDS, nine died, including two who received mechanical ventilation. The Kaplan–Meier estimate of overall survival at 1 month was 60%.

It is hypothesized that similarly to patients with solid malignancies, those with hematologic neoplasms are more susceptible to COVID-19 and develop severe forms. This study highlighted the following observations: patients with a hematologic malignancy harbored a higher risk of developing a severe form of COVID-19 with ARDS, requiring mechanical ventilation, compared to those in the general French population without an underlying medical condition [ 1 ]. This translated into a very high mortality (estimated as 40% at 1 month) which we can expect to be even higher with a longer follow-up. Furthermore, fewer than half of the patients were receiving active anti-neoplastic treatment before COVID-19, highlighting that vigilance must remain high in every patient given the long-term immunosuppressive effect of prior therapies. Interestingly, for the majority of the patients, a nosocomial origin was suspected, owing to their hospitalized status or to outpatient visits within the 14 previous days.

We observed an overrepresentation of patients with MM in our cohort (although MM is not overrepresented in our department), suggesting that such patients are particularly vulnerable, owning to the immunosuppression associated with the disease and its treatment, in particular steroids. In fact, the detrimental effect of steroids on patient outcome has been established during previous coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) [ 10 , 11 ], and a similar impact is expected in patients infected with SARS-CoV-2 [ 12 ]. Finally, we must emphasize that more than half of the patients were over 65 years of age, and 92% had at least one additional comorbidity, factors which have been associated with COVID-19 severity [ 1 , 2 ], and which have possibly contributed to the seriousness of the infection and high mortality rate observed in our study.

Overall, patients with hematologic malignancies appear to be a population very vulnerable to COVID-19 infection. Therefore, hematology departments should remain COVID-19 free zones dedicated solely to hematologic treatment. Furthermore, patients should strictly comply with social distancing and hospital outpatient visits should be reduced to mitigate the risk of COVID-19.

Supplementary information

Supplementary Figure

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These authors contributed equally: Florent Malard, Alexis Genthon

These authors jointly supervised this work: Rémy Dulery, Mohamad Mohty

Supplementary information

The online version of this article (10.1038/s41409-020-0931-4) contains supplementary material, which is available to authorized users.

Acknowledgements

The authors acknowledge the Association for Training, Education, and Research in Hematology, Immunology, and Transplantation (ATERHIT) for the generous and continuous support of our research work. We thank Dr Tounes Ledraa, Anne Vekhoff, Paul Coppo, Marie-Paule Lemonnier, and our nursing staff for offering the best care to our patients. We thank Prof. Junia V. Melo for critical reading of the manuscript.

Author contributions

FM designed the study, recruited patients, collected, assembled, and analyzed the data, and wrote the manuscript. AG recruited patients, collected, assembled, and analyzed the data and helped writing the manuscript. EB, ZW, ZM, SI, AB, SL, SS, EC, AP, RA, FMB, and OL recruited patients, collected data, and approved the manuscript. ML performed statistical analysis and helped writing the manuscript. RD and MM designed the study, recruited patients, assembled, and analyzed the data, supervised research, and wrote the manuscript.

Compliance with ethical standards

Conflict of interest

MM reports grants and/or lecture honoraria from Janssen, Sanofi, Maat Pharma, JAZZ pharmaceutical, Celgene, Amgen, BMS, Takeda, Pfizer, and Roche, all outside the submitted work. FM reports lecture honoraria from Therakos/Mallinckrodt, Biocodex, Janssen, Keocyt, Sanofi, JAZZ pharmaceutical and Astellas, all outside the submitted work. RD reports lecture honoraria from Keocyt, Sanofi, and Novartis, all outside the submitted work. The other authors declare no competing financial interests.

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