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/m2), 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