Which adsorption technique removes cold (igm) antibodies, particularly anti-i specificities?

1. Case 1

An 83-year-old male was admitted to the emergency department after several days of cough, sputum, and poor oral intake on March 22, 2022. The patient was quarantined under the suspicion of COVID-19, and the initial computed tomography (CT) scan of his chest revealed atypical pneumonia. The PCR test was positive, and the patient was admitted to quarantine ICU with respiratory support. His pre-admission laboratory tests first appeared to indicate a possibility of hemolysis as the total bilirubin was 3.22 mg/dL (reference range [RR] 0.20∼1.20 mg/dL) and hemoglobin (Hb) was 11.6 g/dL (RR 13∼17 g/dL), but the possibility was largely dismissed because additional tests that measured lactate dehydrogenase (LDH 321 IU/L, RR 100∼225 IU/L) and haptoglobin (315.5 mg/dL, RR 30∼180 mg/dL) revealed it to be unlikely (Table 1), although, other types of cell lysis still could have occurred. Hepatitis viral panels, rapid plasma reagin (RPR), anti-HIV, and urine pneumococcal antigen test were all negative; blood cultures conducted at the time of admission showed no growth after three days. Pre-transfusion testing revealed the presence of unexpected antibodies and, most importantly, an initial ABO discrepancy, which brought the patient to our attention. The ABO discrepancy, which showed weak aberrant reactivity with the anti-A antibody in the forward typing (the patient was ultimately determined to have blood type B＋), was resolved after a re-test with a warm saline bath at 37℃. The antibody identification test was performed using various commercial reagent cells: BioRad ID-DiaCell I-II, ID-DiaCell Dia＋, ID-DiaPanel (DiaMed GmbH, Pra Rond 23, 1785 Cressier FR, Switzerland); Grifols Serascan Diana 2, Serascan Diana Dia, Identisera Diana (Diagnostic Grifols, S.A., Passeig Fluvial, 24–08150 Parets del Vallès, Spain); Ortho Reagent Red Blood Cells Selectogen, Resolve Panel A (Ortho-Clinical Diagnostics, Inc., 1001 US Highway 202, Raritan, NJ 08869, USA). The unexpected antibody was a pan-reactive cold antibody of undetermined specificity, reactive optimally at 4℃ and reactive with both the patient’s and every antibody screening and identification RBCs. On the other hand, it showed no agglutination in the anti-human globulin (AHG) phase using the column agglutination method (BioRad DiaMed ID-Card LISS/Coombs, Grifols DG Gel Coombs). The anti-I test using the cord blood of a blood type O baby was performed at 4℃ using the tube method, which showed that it did not have anti-I specificity. A direct antiglobulin test (DAT) via BioRad DC-Screening I card was done, and strong agglutination against C3d was observed (Table 2). The patient received supportive care for approximately one week and was discharged without overt complications, even though the serial chest X-ray results did not improve despite clinical improvements in the general condition and symptoms.

Table 1

Patient demographics

*Laboratory tests were performed outside of our hospital.

Abbreviations: Dx, diagnosis; POI, poor oral intake; CTx, chemotherapy; CRP, C-reactive protein; NT, not tested; N/A, not available.

Table 2

Direct antiglobulin test, indirect antiglobulin test (tube method unless specified), and type O cord blood reactivity results

Abbreviations: DAT, direct antiglobulin test; IAT, indirect antiglobulin test; RT, room temperature; AHG, anti-human globulin. The test results are on the scale of 0 to 4＋, where 0 shows no agglutination, and 4＋ shows the strongest agglutination. The indirect antiglobulin column agglutination tests were performed using AHG columns (BioRad).

Cord blood reactivity at 4℃ refers to the test that measures the reactivity towards type O newborn’s umbilical cord blood at 4℃ to determine the presence of the anti-I antibody in the serum.

2. Case 2

A 62-year-old male, who was on a regular follow-up schedule because of chemotherapy for the treatment of undifferentiated pleomorphic sarcoma in his right thigh region, underwent a pre-transfusion test due to low Hb on the follow-up complete blood count (CBC) test (Table 1). He had to postpone his outpatient reservation as he and his family were quarantined due to COVID-19 (diagnosed on March 14, 2022). The patient later complained that COVID-19 was a worse experience than receiving chemotherapies. The pre-transfusion test showed ABO discrepancy again and a positive antibody screening test, suggesting that the SARS-CoV-2 infection and cold agglutinin syndrome may be related. Additional tests, including the newborn cord-blood reactivity test (anti-I test) and antibody identification test, showed that the antibody was not the anti-I type but still a pan-reactive cold antibody of undetermined specificity; DAT further indicated the presence of C3d, and interestingly, C3c as well. This time, the antibody was also weakly pan-reactive at 37℃, showing a wider thermal range than in the previous case, but it did not display any agglutination in the AHG phase using the column agglutination method (Table 2). The patient received one unit of packed RBC, which was warmed to body temperature to avoid possible hemolytic reaction. The general chemistry laboratory test showed a slightly increased total bilirubin level against the patient’s baseline value. Other than that, the results were mostly innocuous, and additional LDH and haptoglobin testing did not indicate overt hemolysis (see Table 1 for more information).

3. Case 3

A 69-year-old female was referred from another university hospital due to severe anemia. The patient had a long history of autoimmune disease, namely, Sjögren’s syndrome, diagnosed in 2004, and was taking synthyroid, a synthetic thyroid hormone, due to longstanding hypothyroidism. The chart indicated she had stable disease until October 2021, when chronic diarrhea started. Two to three months before her referral to the author’s hospital, her fingers started to show ischemic symptoms, including ulceration on the right middle finger. One month before referral, her hemoglobin dropped to 5.5 g/dL, but due to unexpected antibodies, the patient did not receive any transfusion and was instead placed on observation, where her hemoglobin improved to 7.2 g/dL after two weeks. She was finally referred to the author’s hospital after being diagnosed with COVID-19 by outside PCR testing on March 12, 2022, which prevented her from entering the original hospital she was being followed up. Upon arrival in the outpatient department, the CBC, general chemistry (Table 1), and additional tests were done, which showed anemia (Hb 8.0 g/dL) and signs of hemolysis (plasma LDH 342 IU/L; plasma haptoglobin below the detection limit (<5.0 mg/dL); plasma free hemoglobin 8.0mg/dL, RR 0∼5). Interestingly, her total and direct bilirubin were not elevated –0.6 mg/dL and 0.1 mg/dL, respectively. She had high autoantibody titers against anti-Sm, anti-Ro, anti-La, anti-dsDNA, and anti-RNP, but tested negative for anti-cardiolipin antibody. Her serum and urine protein electrophoresis results, hepatitis viral panels, and other infection screening results were unremarkable. During the pre-transfusion tests a positive antibody screening result was noted, and further identification attempts, as described above, yielded her unexpected antibody as, again, pan-reactive cold antibody of undetermined specificity. In the present case, the identified antibody was also reactive in the AHG phase of the column agglutination method, suggesting that she may have mixed cold and warm agglutinins – likely due to her autoantibodies (Table 2). This time, ABO discrepancy was absent. The patient was later admitted to the internal medicine ward for further workup and management of her autoimmune symptoms, and the investigation is currently ongoing. Although a cold-agglutinin test on April 7 yielded a positive result with a titer of 64 (RR≤titer of 16), no additional unexpected antibody screening was performed.

Which adsorption technique removes cold IgM antibodies?

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At what temperature do IgM antibodies react optimally?