Severe Neutropenia After Leukocytosis During an Acute Attack of Mycoplasma Infection-associated Paroxysmal Cold Hemoglobinuria

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To the Editor:
Paroxysmal cold hemoglobinuria (PCH) is characterized by Donath-Landsteiner antibody (D-L antibody), and comprises 1% of autoimmune hemolytic anemias.1 D-L antibody (primarily IgG) binds to P or I antigen on red blood cells (RBCs) along with complement after cold exposure, and only the complement remains bound to the RBCs when the body temperature returns to the baseline. The classic complement pathway is then activated to induce intravascular hemolysis.
In the past, PCH was common after syphilis infection, but this is now rare. PCH cases after acute viral and Mycoplasma infections have been reported seasonally in children, especially in boys ≤5 years of age. The onset is sudden and progressive and may lead to acute renal failure.2
A 3-year-old boy with cough for 1 week was referred to our hospital and admitted because of pallor and brown-colored urine. The chest radiograph revealed no infiltrates. He received no medications before admission. Blood tests revealed a white blood cell (WBC) count of 34,200/μL (myelo 1%, meta 2%, band 1%, seg 53%, eos 3%, lym 38%, and mon 2%), hemoglobin (Hb) 3.2 g/dL, platelets 31.8×104/μL, and reticulocytes 3.8%. The peripheral blood smear showed no fragmentation of RBCs or blast cells. Lactate dehydrogenase was increased to 1398 IU/L, with direct bilirubin of 3.2 mg/dL and indirect bilirubin of 0.8 mg/dL. Serum creatinine was 0.21 mg/dL and renal function was fine. Haptoglobin was undetectable and CH50 was decreased to 16.4 U/mL. The direct Coombs test was positive for C3d and negative for IgG; antinuclear antibody was negative. C-reactive protein was 1.19 mg/dL and the cold agglutinin titer was increased at 1:64. Three days later, D-L antibody was found to be positive, with P antigen reactivity. He received a unit of packed RBCs on the first and second days, and 2 mg/kg/d prednisolone, which was promptly tapered and discontinued after PCH diagnosis. Reticulocytes increased to 22.2% on day 6. An infection survey revealed only increased passive agglutinin antibody for Mycoplasma pneumoniae at 1:320, and he was diagnosed with Mycoplasma infection-associated PCH. Serum ferritin was 10,350 ng/mL at admission, but it decreased to 175 ng/mL on day 7. Hb increased to 7.6 g/dL, and neutrophils eventually decreased to 936/μL on day 9 and 150/μL on day 14. On day 38, the neutrophil count recovered to 1890/μL. D-L antibody became undetectable on day 38. Three months later, his Hb was 12.8 g/dL and the WBC count was 6000/μL, with 40% neutrophils (Fig. 1).
In PCH, WBC counts are usually normal, but marked leukocytosis during acute attacks has been reported.3 A 63-year-old woman with a novel hemotropic Mycoplasma infection had pyrexia, hemolytic anemia, and chronic moderate neutropenia, which was resolved with doxycycline.4 Hemotropic microorganisms were probably not involved in this case, because hemolytic anemia and neutropenia spontaneously resolved without antimycoplasma antibiotics. Hemophagocytic syndrome was also unlikely based on the criteria,5 because platelets were not decreased and fever and hepatosplenomegaly were absent. A rare case of cold agglutinin-related hemolytic anemia, with thrombocytopenia and leukopenia secondary to M. pneumoniae, has been reported.6 Although we did not investigate in this case, transient antineutrophil antibody might have caused neutropenia, because this has been reported during Mycoplasma infection7 but not in PCH. This case was notable for initially marked leukocytosis with PCH, followed by severe neutropenia during hemolysis resolution. In PCH, cells other than RBCs should be carefully monitored.
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