Neutrophil-Erythrocyte Rosettes in COVID-19
Bingwen Eugene Fan1,2,3,4 | Jia Qi Wendy Leong5 | Bernard Pui Lam Leung4,6,7 |Weng Yik Ng8 | Wendy Siew Lian Lim5 | Wei Yong Kevin Wong5 | Wei Yin Lim5 |Siew Ping Connie Chen5 | Sheem Ying Rachel Yap5 | Guat Bee Tan5 |Minyang Chow3,4,9 | Sharavan Sadasiv Mucheli3,4,10,11 | Ponnudurai Kuperan1,2,3,4 |Christian Aledia Gallardo1
1Department of Haematology, Tan Tock Seng Hospital, Singapore
2Department of Laboratory Medicine, Khoo Teck Puat Hospital, Singapore
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
4Yong Loo Lin School of Medicine, National University of Singapore, Singapore
5Department of Laboratory Medicine, Tan Tock Seng Hospital, Singapore
6Health and Social Sciences, Singapore Institute of Technology, Singapore
7Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore
8Health Sciences Authority, Blood Support Group, Red Cell Reference Laboratory, Singapore
9Department of General Medicine, Tan Tock Seng Hospital, Singapore
10Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore
11National Centre for Infectious Diseases, Singapore
Correspondence
Bingwen Eugene Fan, Department of Haematology, Tan Tock Seng Hospital, Singapore.
Email: bingwen_eugene_fan@ttsh.com.sg
FIGURE 1 Neutrophil-erythrocyte rosettes in acute SARS-CoV-2 infection.
An 85-year-old Chinese female, known to have hypertension, hyperlipidemia,
diabetes mellitus, atrial fibrillation, osteoporosis, and Alzheimer's
dementia was admitted to the National Centre for Infectious Diseases,
Singapore for clinical monitoring due to a mild COVID-19 infection. She
had completed a primary series of COVID-19 vaccination with two doses
of Pfizer BNT162b2 mRNA SARS-CoV-2 and received a booster dose of
vaccination (BNT162b2 mRNA SARS-CoV-2), 1 month prior to her admission.
Nasopharyngeal swab taken for COVID-19 real-time polymerase
chain reaction was positive, with a cycle threshold value of 24.6, and she
did not require supplemental oxygen throughout admission. The peripheral
blood film (PBF) done on Day 2 of her symptoms showed numerous
neutrophil-erythrocyte rosettes (FIGURE 1, Wright stain, 80 objective,
Motic EasyScan One), but no spherocytes, red cell agglutination, or reactive
lymphocytes were observed. Monocyte-Erythroid rosetting was also
not seen. Repeat PBF performed on a blood specimen taken with a lithium
heparin tube (non-EDTA) as well as from finger prick showed persistence
of neutrophil-erythrocyte rosettes, excluding pre-analytical causes. A previous
PBF performed 3 years prior to her admission did not show any
neutrophil-erythrocyte rosettes. Full blood count revealed a hemoglobin
of 11.4 g/dl, white blood cell count of 5.8 109/L, and platelet count of
161 109/L. Hemolytic screen did not reveal any evidence of hemolysis,
with normal lactate dehydrogenase levels of 461 U/L (reference range
(RR): 270–550 U/L), total bilirubin of 18 μmol/L (RR: 5–30 μmol/L), and a
haptoglobin of 46 mg/dl (RR: 36–200 mg/dl). However, her absolute reticulocyte
count was slightly elevated at 95.6 109/L (RR: 25–85 109/L).
Autoimmune screen with anti-nuclear antibodies was negative and a pan
computer-tomography scan of her neck, thorax, abdomen, and pelvis did
not show any lung infiltrates or features of malignancy.
Further testing was performed to evaluate the cause of the
neutrophil-erythrocyte rosettes. Specimens were sent to the Health
Sciences Authority Blood Services Group (HSA BSG), Red Cell Reference
Laboratory, where the direct Coombs test was weakly positive (1+)
for anti-C3b and anti C3d. Testing of serum for red cell antibody identification
showed an Anti-Mia, with the red cell eluate negative for common
red cell antibodies. Serology testing (Elecsys Anti-SARS-CoV-2 S and
Elecsys Anti SARS-CoV-2) on Day 3 of illness showed an elevated antibody
titer against the SARS-CoV-2 spike (S) protein receptor binding
domain of 250 U/ml and was negative for nucleocapsid-antigen (N-antigen).
The red cell eluate was further tested with the Euroimmune anti-
SARS-CoV-2 Spike S1 ELISA and was negative, suggesting that the
neutrophil-erythrocyte rosettes seen were unlikely due to anti S1 IgG
immunoglobulins. 2 months after recovery from COVID-19, the repeat
PBF showed resolution of neutrophil-erythrocyte rosettes with a negative
direct Coombs test and no biochemical features of hemolysis.
Neutrophil-erythrocyte rosettes are rare. They are associated with
autoimmune hemolytic anemia (AIHA)1–4 and paroxysmal cold hemoglobinuria. 5 The mechanism of neutrophil-erythrocyte rosettes in AIHA is
still poorly defined. It is postulated to be due to a factor in the IgG fraction
of immunoglobulin, primarily directed at some red blood cell surface
antigen(s).6 Shulman et al2 recently proposed the mechanism of the interaction
of neutrophil surface Fc receptors with IgG1- or IgG3-coated
erythrocytes. This usually requires a high titer of antibody-coated target
cells to mediate neutrophil adhesion. In our patient, further testing with a red cell flow cytometry for Immunoglobulin G, A, or complement could
have identified the antibody; however, these studies are unavailable at
our center and at the HSA BSG, and thus we have not been able to pursue
confirmatory testing.
To our knowledge, this is the first reported case of COVID-19 associated
neutrophil-erythrocyte rosettes, given the temporal association of
neutrophil-erythrocyte rosettes with acute SARS-CoV-2 infection and subsequent
resolution on convalescence, which is most likely secondary to an
unidentified IgG antibody or complement. Clinicians should be aware of
the rare possibility of neutrophil-erythrocyte rosettes in COVID-19 and
exclude AIHA which is commonly associated with such cases.
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ACKNOWLEDGMENTS
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To our knowledge, this is the first reported case of COVID-19 associated
neutrophil-erythrocyte rosettes, given the temporal association of
neutrophil-erythrocyte rosettes with acute SARS-CoV-2 infection and subsequent
resolution on convalescence, which is most likely secondary to an
unidentified IgG antibody or complement. Clinicians should be aware of
the rare possibility of neutrophil-erythrocyte rosettes in COVID-19 and
exclude AIHA which is commonly associated with such cases.
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CONFLICT OF INTEREST
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The authors declare that they have no conflict of interest.
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DATA AVAILABILITY STATEMENT
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The data that support the findings of this study are available from the
corresponding author upon reasonable request.
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ORCID
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Bingwen Eugene Fan https://orcid.org/0000-0003-4367-5182
Christian Aledia Gallardo https://orcid.org/0000-0001-5048-4259
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REFERENCES
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2. 2022;9(4):e312. doi:10.1016/S2352-3026(21)00373-2Schulman S, Awad MM, Kuter DJ. Neutrophil-erythrocyte rosettes in autoimmune hemolytic anemia. Am J Hematol. 2013;88:333-334. doi:10.1002/ajh.23277
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3. Park HS, Shin KS, Son BR. Neutrophil-erythrocyte rosettes in directantiglobulin test-negative autoimmune hemolytic anemia. Blood Res.2019;54(3):164. doi:10.5045/br.2019.54.3.164
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4. Yadav G, Rahman K, Gupta R. Neutrophil erythrocyte rosettes: an unusualmanifestation of autoimmune hemolytic anemia. Indian J Hematol Blood Transfus. 2016;32(1):309-310. doi:10.1007/s12288-015-0546-x
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5. Peña VN, Naik RP. Paroxysmal cold hemoglobinuria: a unique constellation of peripheral smear findings. Blood. 2020;135(5):393. doi:10. 1182/blood.2019003989
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6. Mirchandani I, Palutke M, Kithier K, Tabaczka P, Suffian J. In vitro neutrophil-erythrocyte rosette formation mediated by a serum factor (IgG). Am J Hematol. 1984;17(1):79-83. doi:10.1002/ajh.2830170110
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