Recurrence of Paroxysmal Cold Hemoglobinuria in a Boy After Physical Cooling for Fever Elpis Mantadakis, MD,* Zoe Bezirgiannidou, MD,w George Martinis, MD,w and Athanassios Chatzimichael, MD* Summary: Hemolysis and hemoglobinuria after direct exposure to cold has rarely been reported in paroxysmal cold hemoglobinuria (PCH). The authors describe a 2.5-year-old boy with PCH (Donath-Landsteiner autoimmune hemolytic anemia), in whom 16 days after presentation, the hemoglobinuria and hemolysis recurred, when he was subjected to physical cooling, as a means to control fever associated with hospital-acquired croup. The hemolysis resolved with warmth, and administration of dexa- methasone. PCH should be suspected in children with hemolytic anemia and positive direct antiglobulin test for complement. Avoidance of cold in the recovery period is imperative to prevent recurrences, whereas a short course of corticosteroids may be of benefit in suppressing the antibody production. Key Words: paroxysmal cold hemoglobinuria, autoimmune hemo- lysis, complement, Donath-Landsteiner antibody, recurrence, corticosteroids (J Pediatr Hematol Oncol 2011;33:40–42) P aroxysmal cold hemoglobinuria (PCH) is a clinical entity, characterized by autoimmune hemolysis of the sudden onset accompanied by hemoglobinuria, extreme pallor, mild jaundice, and malaise. 1 In the past, the most common association of this condition was with syphilis. Nowadays that syphilis is becoming less common, most cases of PCH follow viral infections, although the responsible pathogens are rarely identified. The laboratory hallmark of PCH is the demonstration of a biphasic hemolysin, that is, of an antibody, usually IgG that binds to the red cells at low temperatures and causes hemolysis at 371C. Despite the name of the condition owing to the binding properties of the responsible autoantibody, intra- vascular hemolysis, and hemoglobinuria after direct ex- posure to cold has rarely been reported. 2 Therefore, the disease is almost never clinically suspected based on cold- induced acute hemolysis. We report a 2.5-year-old boy who developed PCH owing to a hemolysin with anti-P specificity after an undefined viral infection. Despite initial recovery after a red cell transfusion, the child recurred 16 days later with severe hemolysis and accompanying hemoglobinuria, when he was subjected to physical cooling to control fever associated with hospital-acquired croup. CASE REPORT A ´ n appropriately immunized 2.5-year-old boy with spastic diplegia and periventricular leukomalacia because of prematurity presented to his pediatrician with a low-grade fever for 3 days. The morning of his visit, he also vomited twice, plus he had several episodes of watery diarrhea. On examination, the child was pale and tachycardic, for which he was promptly referred to us. On arrival to the hospital, he was afebrile, lethargic, with dry mucous membranes, a heart rate of 165 bpm, and blood pressure 80/50 mm Hg. Except for prominent pallor and a gallop rhythm, he had no hepatomegaly or splenomegaly, and no petechiae, bruises, or other bleeding signs. Complete blood count revealed leukocytes 31,420/mL, hemo- globin 3.1 g/dL, hematocrit 8.3%, platelets 270,000/mL, reticulo- cytes 2.76%, MCV 79fl, MCH 29.5pg, MCHC 37.3 g/dL, RDW 14.5%, BUN 78 mg/dL (normal 5 to 18), creatinine 1.3 mg/dL (normal for age <0.6), fibrinogen 420 mg/dL, haptoglobin 5.83 mg/dL (normal 36 to 195), total bilirubin 6.7 mg/dL (normal up to 1.2), direct bilirubin 0.7 mg/dL, SGOT 175 U/L (normal <35), SGPT 27 U/L, and LDH 3766 U/L (normal <248). The erythrocyte sedimentation rate was 130 mm/h. A semiquantitative test for G6PD deficiency was normal. Stool, urine, and blood cultures were obtained, and cefotaxime was prescribed pending culture results. The antibiotic was discontinued 3 days later when the cultures were negative for enteropathogens (including Escher- ichia coli O157:H7), uropathogens, or blood isolates. Examination of the peripheral blood smear confirmed the presence of leukocytosis with intense left shift, showing no circulating blasts, no nucleated or fragmented red cells, several spherocytes and red cell agglutinates. Moreover, it showed intense polymorphonuclear erythrophagocytosis, i.e., segmented neutrophils engulfing red cells (Fig. 1). The patient’s urine that was black colored was positive for hemoglobin (4+), whereas no hematuria was present. Immunohematological work-up was carried out using a gel technique (Diamed GmbH, Cressier, Switzerland). Direct anti- globulin test (DAT) was positive for anti-C3c (3+) and anti-C3d (4+) only, whereas no IgG, IgM, or IgA antibody was detected on the red cells with specific antiserums. Indirect antiglobulin test carried out at various temperatures and conditions did not reveal the presence of an antibody. Antibody acid elution (Diacidel, Diamed) was also carried out and was negative. Hence, the patient who was extremely symptomatic was transfused with 20 mL/kg of compatible packed red cells to hemoglobin 7.3 g/dL. As the DAT was only positive for anti-C3c and anti-C3d, testing to rule out the presence of cold agglutinins was also carried out, by obtaining blood with a warm syringe and transporting it to the lab at 371C. This testing was also negative. However, the indirect antiglobulin test (IAT) test at 41C was positive when incubating the patient’s serum with the donor group O, P1-positive red cells, even after the adsorption of possible anti-H, anti-I, anti-HI antibodies with rabbit erythrocyte stroma (RESt Immucor, Gamma Diagnostics, Houston, TX). The final diagnosis of PCH was confirmed with Donath-Landsteiner testing after incubation of patient’s serum Copyright r 2011 by Lippincott Williams & Wilkins Received for publication June 14, 2010; accepted July 23, 2010. From the *Department of Pediatrics, Democritus University of Thrace and University General District Hospital of Alexandroupolis; and wBlood Transfusion Center, University General District Hospital of Alexandroupolis, Thrace, Greece. Reprints: Elpis Mantadakis, MD, Democritus University of Thrace and University General District Hospital of Alexandroupolis, 6th Kilometre Alexandroupolis-Makris, 68 100 Alexandroupolis, Thrace, Greece (e-mail: emantada@med.duth.gr). CLINICAL AND LABORATORY OBSERVATIONS 40 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 33, Number 1, January 2011