The impact of cold agglutinin syndrome on clinical presentations in COVID-19

In a recent case report published in the Journal of Clinical Laboratory Analysis, researchers presented two cases to highlight the impact of cold agglutinin syndrome (CAS) on clinical presentations in coronavirus disease 2019 (COVID-19).

Study: Cold agglutinin anti-I antibodies in two patients with COVID-19. Image Credit: Kira_Yan/Shutterstock


CAS have been detected previously among individuals infected with Mycoplasma pneumoniae, Rubella virus, and Epstein Barr virus (EBV), with an elevated risk of thrombosis among individuals with lymphoproliferative disorders. Abnormalities in coagulation have been reported in severe cases of COVID-19. Studies have documented thrombosis and hemolytic anemia in COVID-19-associated CAS cases; however, the clinical relevance of CA in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is not clear.

About the case report

In the present case report, researchers described two patients with SARS-CoV-2 infections who developed high CA titers without thrombosis or hemolytic anemia.

The two patients had no known risk factors for CA and were diagnosed as SARS-CoV-2-positive. Sera were obtained from the first patient and second patient on day 11 and day 32 post-hospitalization, respectively. To determine CA presence, sera were applied to rabbit erythrocyte stroma, an absorber of anti-I immunoglobulin M (IgM) antibodies. Adult O-type red blood cells (RBCs) were used, and newborn (baby) O-type RBCs were obtained from residual peripheral blood specimens.

Autologous RBC could be obtained only from the second patient. Subsequently, RBCs agglutination assays were performed. Both patients showed RBC agglutination with elevated CA titers. The team retrospectively confirmed that the CAs were anti-I antibodies. Both the SARS-CoV-2-positive cases did not show hemolysis or thrombosis, although CA titers were elevated.

Case 1

The first case was of a male patient aged 64 years presenting with elevated body temperature (fever) for five days. He had suffered from myocardial infarction seven years ago. Nasopharyngeal swabs collected from the patient were subjected to rRT-PCR (real-time reverse transcription polymerase chain reaction) analysis, and he was diagnosed as SARS-CoV-2-positive. Chest imaging revealed infiltration bilaterally, and he presented clinically with hypoxia, for which he was hospitalized in January.

His peripheral blood smear (PBS) examination showed elevated MCHC (mean corpuscular hemoglobin concentration), and strong adult RBC agglutination at 4°C, which was impaired on the absorption of anti-I IgM antibodies by rabbit erythrocyte stroma (RES) at 25°C.No agglutination of newborn RBCs was observed. Further, laboratory tests showed low zinc levels and macrocytic anemia without hemolytic anemia.

DAT (direct antiglobulin test) showed a C3b/C3d-positive and immunoglobulin G (IgG)-negative result. Elevated CA titers were observed (1:512), much above the normal range (0 to 1:63 titers), and he was Donath–Landsteiner antibody-negative. Furthermore, bone marrow biopsy results did not show any malignant cells of lymphoma.

On day 6 post-hospitalization, he was mechanically ventilated due to worsening hypoxia. Subsequently, treatment with tocilizumab, piperacillin-tazobactam, and dexamethasone was initiated, and the mechanical ventilation was gradually stopped post-therapy. Supplementation of zinc and clinical treatment increased hemoglobin (Hb) levels and decreased CA titers to 10.6 mg/dl and 1:64, respectively, and he received hospital discharge on day 38-post hospitalization-P.

Case 2

The second case was of a female patient aged 76 years with rRT-PCR-diagnosed SARS-CoV-2 infection six days prior to hospitalization in May due to pneumonia and hypoxia. Following remdesivir and dexamethasone treatment, an improvement in pneumonia was observed, but she developed a urinary tract infection (UTI).

Her PBS was collected on day 25 post-hospitalization and showed strong adult RBC agglutination at 4°C. However, the decreased effect of RBC agglutination on adsorption of anti-I antibodies by RES was found to be weaker compared to that observed for the first patient. On further evaluation using RBC treated with ficin, the presence of anti-I antibodies was confirmed.

Her MCHC levels were high, Hb levels were 15 g/dl, and DAT showed C3b/C3d-positive and IgG-negative results. Elevated CA titers of 1:2048 were observed, which dropped to 1:512 on her initial outpatient visit post-hospital discharge.


The case report findings demonstrated that not all cases of COVID-19 with CAS (COVID-19/CAS) with anti-I antibodies may show clinical manifestations such as thrombosis and hemolysis due to elevated MCHC values. Therefore, subclinical cases of COVID-19/CAS could be overlooked. Clinical manifestations may not have been present since the two patients lacked cold stimulation exposure; however, further research is needed to clarify the pathophysiology of CA in SARS-CoV-2 infections.

SARS-CoV-2-positive patients may present with a hypercoagulable state due to the presence of underlying abnormalities in coagulation such as endothelial damage, hypercoagulation, and stasis (Virchow's triad). CAS may enhance the hypercoagulation state in SARS-CoV-2-positive patients; therefore, identifying COVID-19/ CAS complications could be clinically relevant.

Journal reference:
  • Imoto H, Yoshioka S, Nakagawa D, et al. Cold agglutinin anti-I antibodies in two patients with COVID-19. J Clin Lab Analdoi: 10.1002/jcla.24629

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Anemia, Antibodies, Antibody, Baby, Biopsy, Blood, Blood Smear, Bone, Bone Marrow, Cold, Coronavirus, Coronavirus Disease COVID-19, covid-19, Dexamethasone, Fever, Hemoglobin, Hospital, Hypoxia, Imaging, Immunoglobulin, Laboratory, Lymphoma, Malignant, Mycoplasma, Myocardial Infarction, Nasopharyngeal, Newborn, Pathophysiology, Pneumonia, Polymerase, Polymerase Chain Reaction, Red Blood Cells, Remdesivir, Research, Respiratory, Rubella, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Thrombosis, Transcription, Urinary Tract Infection, Virus, Zinc

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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