Among patients with SARS‐CoV‐2 infection (also known as COVID‐19), pneumonia, respiratory
failure and acute respiratory distress syndrome are frequently encountered complications.
1
Although the pathophysiology underlying severe COVID‐19 remains poorly understood,
accumulating evidence argues for hyperinflammatory syndrome causing fulminant and
fatal cytokines release associated with disease severity and poor outcome.
2
However, the spectrum of complications is broader and includes among others various
auto‐immune disorders such as autoimmune thrombocytopenia, Guillain–Barré and antiphospholipid
syndrome.
3
,
4
,
5
In this report we describe seven patients from six French and Belgian Hospitals who
developed a first episode of autoimmune haemolytic anaemia (AIHA) during a COVID‐19
infection.
Patient characteristics are detailed in Table I. Briefly, median age was 62 years
(range, 61–89 years), and all patients presented with risk factors for developing
a severe form of COVID‐19 such as hypertension, diabetes and chronic renal failure.
All patients had both a positive oropharyngeal swab for SARS‐CoV‐2 and typical images
of COVID‐19 infection on chest computed tomography scans (25–75% extension). Three
patients were admitted in an intensive care unit but only one required invasive ventilation.
Treatment for COVID‐19 infection differed according to the standards of each centre.
Thus, three patients received hydroxychloroquine, in association with azithromycin
for two of them, and one patient received lopinavir and ritonavir.
Table I
Characteristics of seven patients with autoimmune haemolytic anaemia after the onset
of COVID‐19.
Patient
Age
Gender
Comorbidity
CT‐scan*
Oropharyngeal swab (tested by PCR)
Haemoglobin (g/l)
Reticulocyte count (109/l)
Lymphocyte count (109/l)
Lactate dehydrogenase (U/l)
Haptoglobin (g/l)
DAT specificity
Optimum temperature
Day between COVID‐19 symptoms and AIHA
Related pathology
AIHA treatment
Response
#1
61
M
Hypertension, chronic renal failure
Moderate
Positive
60
477
250
1000
<0·1
IgG + C3d
warm
13
CLL
Steroids
Ongoing
#2
89
F
Hypertension, chronic renal failure, atrial fibrillation
Mild
Positive
84
103
1·7
598
<0·1
IgG + C3d
warm
7
MGUS
Steroids
Ongoing
#3
62
F
Hypertension, cirrhosis
Severe
Positive
108
101
1·3
357
<0·1
C3d
cold
4
MZL†
1. Steroids
2. Rituximab
PR
Planed
#4
69
F
Obesity
Moderate
Positive
38
215
5·9
2610
<0·1
IgG + C3d
cold
10
MZL
Steroids
PR
#5
61
M
Hypertension, chronic renal failure, diabetes, hypercholesterolaemia
Mild
Positive
72
145
3
807
0·8
C3d
cold
11
Prostate cancer
RBC infusion
Ongoing
#6
61
M
Diabetes
Severe
Positive
70
155
1·2
1800
<0·1
IgG
warm
9
None
1. Steroids
2. Rituximab‡
Failure
Ongoing
#7
75
M
Diabetes, hypercholesterolaemia, cardiopathy, obesity, chronic obstructive bronchopneumopathy
Moderate
Positive
71
98
108
2000
<0·1
IgG
warm
6
CLL
RBC infusion
Ongoing
CT, computed tomography; PCR, polymerase chain reaction; DAT, direct antiglobulin
test; AIHA, autoimmune haemolytic anaemia; CLL, chronic lymphocytic leukaemia; MGUS,
monoclonal gammopathy of undetermined significance; MZL, marginal zone lymphoma; RBC,
red blood cells; PR, partial response.
*
Degree of involvement of the lung was classified as none (0%), minimal (1–25%), mild
(26–50%), moderate (51–75%), or severe (76–100%).
†
MZL B cell clone was detected in the bone marrow.
‡
Patient 6 received rituximab injection because of corticosteroid failure.
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
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source, for the duration of the public health emergency.
The median time between the first COVID‐19 symptoms and AIHA onset was nine days (range
4–13 days), and haemoglobin level decreased by more than 30 g/l in all cases. Median
haemoglobin level at the time of AIHA diagnosis was 70 g/l (range 3·8–10·8), and all
patients presented with marked haemolysis signs. Direct antiglobulin test (DAT) was
positive in all cases either for IgG (n = 2), for C3d (n = 2), or for both IgG and
C3d (n = 3). Anti‐erythrocyte antibodies were warm antibodies in four cases (two of
IgG specificity and two IgG + C3d) and cold agglutinins in three cases (two of C3d
specificity and one IgG + C3d). At the time of AIHA onset, all patients had elevated
markers of inflammation (i.e. fibrinogen, D‐dimers and C‐reactive protein).
Interestingly, among the patients with warm antibodies, two patients were known for
stable untreated Binet stage A chronic lymphocytic leukaemia (CLL); an IgG kappa monoclonal
gammopathy of undetermined significance was demonstrated in a third one. In 2/3 patients
with cold agglutinin, systematic lymphocyte immunophenotyping demonstrated the presence
of a monotypic B lymphoid population with a phenotype compatible with marginal zone
lymphoma (MZL). The third one was diagnosed with prostate cancer.
AIHA management included corticosteroids for five patients, and red blood cells infusions
for two. Even if the follow‐up is still short, three patients receiving corticosteroids
were evaluable for response of AIHA. Two patients reached partial response defined
by haemoglobin level >100 g/l along with an increase of 20 g/l at least seven days
after an infusion with red blood cells.
Corticosteroid failure lead to rituximab injection in the third case (patient #6),
and one responding patient is scheduled to receive rituximab because of a MZL clone
(patient #3).
At the time of last follow‐up, all patients were alive and had at least partly recovered
from COVID‐19.
To conclude, we report seven cases of warm and cold AIHA associated with COVID‐19
disease, all of them occurring after the beginning of the symptoms of the infection
and within a timeframe compatible with that of the cytokine storm. Four out of the
seven patients had indolent B lymphoid malignancy either already known or discovered
because of the haemolytic episode. AIHA is a classical complication of both CLL and
MZL,
6
,
7
and viral infections are known to trigger autoimmune cytopenias.
8
Whether the presence of an underlying malignant B lymphoid clone facilitated the onset
of AIHA is unknown. Nonetheless, these observations argue for systematically investigating
for the presence of a lymphoid clone in patients presenting with COVID‐19 infections
and autoimmune cytopenias.
Author contributions
GL, AQ and FC designed the research study, analyzed the data and wrote the paper.
MB, JS, CJ, DR, FM, AM, TB, GD and AD contributed to conception, patient enrollment
and data collection.