Pediatr Blood Cancer 2015;62:2044–2046
BRIEF REPORT Paroxysmal Cold Hemoglobinuria due to an IgA Donath–Landsteiner Antibody Nicholas S. Whipple,
1 MD, *
Dawn AB. Moreau, BA, MT,2 JoAnn M. Moulds, PhD,3 Jane S. Hankins, Winfred C. Wang, MD,1 and Kerri A. Nottage, MD, MPH1
Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath–Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports
MD, MS,
1
confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described. Pediatr Blood Cancer 2015;62:2044–2046. © 2015 Wiley Periodicals, Inc.
Key words: autoimmune hemolytic anemia; Donath–Landsteiner antibody; IgA; paroxysmal cold hemoglobinuria
INTRODUCTION Paroxysmal cold hemoglobinuria (PCH) is a rare form of primary autoimmune hemolytic anemia (AIHA) occurring most often in young children following a viral infection. It was first described by Donath and Landsteiner in 1904 associated with congenital or acquired syphilis.[1] The associated antibody, the Donath–Landsteiner (D-L) antibody, is classically defined by the presence of a biphasic IgG hemolysin. It preferentially binds at 4˚C and fixes complement efficiently. Hemolysis occurs as a result of the complete activation of the complement cascade after rewarming to 37˚C. The initial process can occur when blood circulates in the periphery such as the superficial vessels of the hands and face, in which temperatures may easily fall below 30˚C. In cold ambient temperatures, this process is amplified. Upon rewarming via central circulation and exposure to core body temperature, hemolysis ensues. This process contrasts with cold agglutinin disease, which is caused by IgM autoantibody that readily fixes complement, causing immediate hemolysis regardless of subsequent temperature change. Although PCH is classically associated with D-L autoantibodies of the IgG isotype, there have been rare case reports of IgM D-L autoantibodies but none involving IgA.[2–5]
Case Report A 2-year-old Caucasian male presented with jaundice, scleral icterus, pallor, and fatigue. Two weeks earlier, he had exhibited signs of an upper respiratory infection including cough, conjunctivitis, and fever. On laboratory examination, he was found to have hemoglobin (Hb) of 6.5 g/dl, absolute reticulocyte count (ARC) 55.1 103/ml, total bilirubin 2.8 mg/dl, direct bilirubin 0.2 mg/dl, aspartate aminotransferase (AST) 64 U/l, and a positive direct antiglobulin test (DAT) for anti-C3b/d with 1þ agglutination and negative anti-IgG. Peripheral blood smear showed polychromasia, spherocytes, teardrop cells, schistocytes, and rouleaux formation, consistent with AIHA. Physical exam revealed tachycardia, scleral icterus, generalized pallor, and no organomegaly. Further investigation conducted at a reference lab concluded that the erythrocytes were negative with anti-IgG, anti-IgM, and anti-C3b but were 3þ positive with anti-IgA and anti-C4b as well as 4þ positive with anti-C3b/d. A D-L antibody test was positive, showing P-specificity. These initial results suggested that the D-L antibody may be IgA. To confirm this, the D-L test was repeated C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25591 Published online 5 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
after chloroquine treating the patient’s red blood cells (RBC); however, rather than rewarming the sample to 37˚C, a cold DAT was performed using both anti-IgA and anti-IgG. The test was 1þ positive for IgA and negative for IgG, confirming the presence of an IgA D-L antibody (Table I). Intravenous methylprednisolone was begun on the day of admission, 7 hr from presentation, at 2 mg/kg/day in two divided doses daily. At 47 hr from presentation, Hb was 5.2 g/dl and falling, concurrent ARC was 67.5 103/ml, and the patient was transfused with 10 cc/kg ABO/Rh compatible packed RBCs. At 64 hr from presentation, Hb level had stabilized at 7.8 g/dl, and he was discharged home on oral prednisolone 2 mg/kg/day which was gradually tapered and discontinued over a period of 10 weeks. At 10 months of follow up, the patient continued to do well with Hb 13.6 g/dl, ARC 37.4 103/ml, and no subsequent episodes of hemolysis or need for additional steroids.
DISCUSSION Without documentation of this entity occurring previously, the expectant course and management of this patient was largely unknown. This case demonstrates that IgA D-L antibodies may cause steroid responsive PCH with a good prognosis. Thermal amplitude of the D-L antibody may differ among patients, leading to varying clinical presentations. Other RBC antigen specificities have been described for both IgG and IgM D-L autoantibodies, including i, I, p, Pr, ITP, and HI, although mostly in atypical cases of PCH in adults.[5,6] In rare cases, the D-L antibody has been reported to be an IgM antibody (Table II). Importantly, there is heterogeneity of disease course and severity among these 1
Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee; 2Le Bonheur Children’s Hospital, Memphis, Tennessee; 3John J. Moulds Scientific Support Services, LifeShare Blood Centers, Shreveport, Louisiana Conflict of interest: JM now works for a commercial company, Grifols Shared Services. The remaining authors declare no conflicts of interest.
Correspondence to: Nicholas Whipple, Department of Hematology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 260, Memphis, TN 38105-3678. E-mail: [email protected] Received 2 February 2015; Accepted 10 April 2015
Pediatr Blood Cancer DOI 10.1002/pbc
4 yo male, acute, developed symptoms 10 days post pneumococcal vaccine (PCV7) 5 yo female, chronic, numerous episodes lasting in total greater than 5 years 54 yo male, chronic, anemia lasting 9 months
3 yo male, recurrent PCH (2 episodes, 7 months apart), viral induced.
Clinical presentation
Patient result
Fully resolved, negative D-L test
Avoidance of cold exposure
Steroids, rituximab, IVIG, RBC transfusions Prednisone, IVIG, splenectomy, cyclophosphamide, chlorambucil, plasmapheresis, RBC transfusions
anti-I anti ITP
Receiving monthly IVIG and steroid taper (poor tolerance), additional strategies being considered Death. Autopsy revealed metastatic non-Hodgkin’s lymphoma and disseminated fungal disease (pulmonary, bone marrow)
Fully resolved after second episode, now with negative DAT and D-L test
RBC transfusions, avoidance of cold exposure
Therapy
neither anti-P nor anti-I anti-P
IgM specificity
Outcome
Karafin et al.[3] Ramos et al.[5]
Hayashi et al.[2]
Ogose et al.[4]
Reference
Known antisera (Coombs reagents) are mixed with patient’s washed RBCs to detect anti-IgG (), anti-IgM (), anti-IgA (3þ), presence of antibody or complement on the RBC surface. anti-C3b/d (4þ), anti-C3b (), anti-C4b (3þ) Patient serum is mixed with P-antigen positive RBCs. The mixture is divided into 37˚C: negative for hemolysis 4˚C: negative for three aliquots and incubated at 1) 4˚C, 2) 37˚C, and 3) 4˚C then rewarmed to 37˚C. Hemolysis that hemolysis 4˚C ! 37˚C: positive for hemolysis occurs upon rewarming to 37˚C is indicative of a positive D-L test. anti-IgA: positive for agglutination (1þ) anti-IgG: Patient RBCs are treated with chloroquine which displaces antibodies from sensitized RBCs. The serum is then mixed with treated patient RBCs, and after incubation at 4˚C, a DAT is performed negative for agglutination using antisera.
Test methodology
TABLE II. Reported Cases of PCH Due to IgM Donath–Landsteiner Antibodies
Antibody testing with chloroquine treated RBCs
DAT anti-IgG, anti-IgM, anti-IgA, anti-C3b/d, anti-C3b, anti-C4b D-L antibody test
Test
TABLE I. Tests Performed to Identify RBC Antibodies
Paroxysmal Cold Hemoglobinuria Due to an IgA 2045
2046
Whipple et al.
patients, and it appears that young children are primarily affected. It was, thus, challenging to extrapolate from these cases for therapeutic decisions and prognostication. PCH in children is generally characterized by severe intravascular hemolytic anemia that is acute, transient, self-limited, and carries an overall good prognosis—though fatal cases in childhood have been reported. The median age at presentation is 5 years with a male-to-female ratio of 2.1:1.[7,8] PCH occurs most commonly following a viral infection but also may occur after bacterial and atypical bacterial infections such as mycoplasma pneumonia. In rare cases, it has been reported following measles and pneumococcal vaccination.[2,9] PCH has also been associated with autoimmune disorders and malignancies, including leukemia and lymphoma.[5,10–12] Patients often require transfusion support for symptomatic anemia as well as corticosteroid treatment which may lessen disease severity. Cyclophosphamide, azathioprine, rituximab, and intravenous immunoglobulin (IVIG) have all been used successfully to treat PCH, including some cases of refractory disease.[3,13] Splenectomy is not indicated in PCH as the spleen plays no role in the associated intravascular hemolysis. Warm AIHA accounts for roughly 95% of known cases of AIHA and has been reported to be associated with IgG, IgM, and IgA autoantibodies. The remaining 5% of AIHA comprise cold agglutinin disease (associated with IgM autoantibody) and PCH. PCH has, until now, solely been reported to be associated with the presence of IgG or more rarely IgM autoantibodies. In PCH, initial DAT is generally positive for anti-C3b/d but negative for IgG autoantibodies. The D-L antibody binds complement in a narrow thermal range, but the complement remains on the RBC surface, allowing its detection through the DAT. At room temperature, the temperature at which the DAT is performed, the D-L antibody dissociates causing a negative reaction for the IgG component of the DAT. Detection of the D-L antibody requires an additional step compared to standard testing, as the patient blood sample must be cooled to promote antibody binding and then rewarmed to activate hemolysis and confirm the biphasic nature of the antibody. Neither IgM nor IgA antibodies are reactive with the standard antiglobulin
Pediatr Blood Cancer DOI 10.1002/pbc
(Coombs) reagents. In order to detect the presence of cold agglutinin disease and its associated IgM antibody, additional testing must be performed which can promote antibody binding at lower temperatures (0–4˚C). To detect IgA autoantibodies, clinical suspicion must prompt testing with anti-IgA antisera. A few cases of PCH have been reported in which an antibody isotype was not determined following a positive D-L antibody test.[14] In conclusion, this case suggests that PCH can be associated with an IgA D-L autoantibody. In our patient, IgA-induced PCH followed a relatively benign course, responded well to steroids, did not appear chronic in nature, and was associated with a good prognosis. Providers must consider performing additional cold incubation tests with both IgM and IgA antisera when the classic IgG antibody is not identified in cases of suspected PCH.
REFERENCES 1. Donath J, Landsteiner K. Uber Paroxysmale Hamoglobinurie. M€unch Med Wochenschr 1904;51: 1590–1593. 2. Hayashi H, Yasutomi M, Hayashi T, Yuasa M, Kawakita A, Hata I, Tanizawa A, Muramatsu H, Kojima S, Ohshima Y. Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody. Pediatr Int 2013;55:664–666. 3. Karafin MS, Shirey RS, Ness PM, King KE, Keefer J. A case study of a child with chronic hemolytic anemia due to a Donath-Landsteiner positive, IgM anti-I autoantibody. Pediatr Blood Cancer 2012;59:953–955. 4. Ogose T, Wakata Y, Kaneko M, Shinahara K, Takechi T, Kotani H. A case of recurrent paroxysmal cold hemoglobinura with the different temperature thresholds of Donath-Landsteiner antibodies. J Pediatr Hematol Oncol 2007;29:716–719. 5. Ramos RR, Curtis BR, Eby CS, Ratkin GA, Chaplin H. Fatal outcome in a patient with autoimmune hemolytic anemia associated with an IgM bithermic anti-ITP. Transfusion 1994;34:427–431. 6. Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: A case report. Transfus Med 2003;13:319–321. 7. Sokol RJ, Booker DJ, Stamps R. Erythropoiesis: Paroxysmal cold haemoglobinuria: A clinicopathological study of patients with a positive Donath-Landsteiner test. Hematology 1999;4:137–164. 8. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev 2008;22:1–15. 9. Bunch C, Schwartz FC, Bird GW. Paroxysmal cold haemoglobinuria following measles immunization. Arch Dis Child 1972;47:299–300. 10. Shirey RS, Park K, Ness PM, Kickler TS, Rones J, Dawson RB, Jiji R. An anti-i biphasic hemolysin in chronic paroxysmal cold hemoglobinuria. Transfusion 1986;26:62–64. 11. Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with nonHodgkin’s lymphoma. South Med J 1994;87:397–399. 12. Sivakumaran M, Murphy PT, Booker DJ, Wood JK, Stamps R, Sokol RJ. Paroxysmal cold haemoglobinuria caused by non-Hodgkin’s lymphoma. Br J Haematol 1999;105:278–279. 13. Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion 2007;47:1902–1904. 14. Boccardi V, D’Annibali S, Di Natale G, Girelli G, Summonti D. Mycoplasma pneumoniae infection complicated by paroxysmal cold hemoglobinuria with anti-P specificity of biphasic hemolysin. Blut 1977;34:211–214.
BRIEF REPORT Paroxysmal Cold Hemoglobinuria due to an IgA Donath–Landsteiner Antibody Nicholas S. Whipple,
1 MD, *
Dawn AB. Moreau, BA, MT,2 JoAnn M. Moulds, PhD,3 Jane S. Hankins, Winfred C. Wang, MD,1 and Kerri A. Nottage, MD, MPH1
Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath–Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports
MD, MS,
1
confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described. Pediatr Blood Cancer 2015;62:2044–2046. © 2015 Wiley Periodicals, Inc.
Key words: autoimmune hemolytic anemia; Donath–Landsteiner antibody; IgA; paroxysmal cold hemoglobinuria
INTRODUCTION Paroxysmal cold hemoglobinuria (PCH) is a rare form of primary autoimmune hemolytic anemia (AIHA) occurring most often in young children following a viral infection. It was first described by Donath and Landsteiner in 1904 associated with congenital or acquired syphilis.[1] The associated antibody, the Donath–Landsteiner (D-L) antibody, is classically defined by the presence of a biphasic IgG hemolysin. It preferentially binds at 4˚C and fixes complement efficiently. Hemolysis occurs as a result of the complete activation of the complement cascade after rewarming to 37˚C. The initial process can occur when blood circulates in the periphery such as the superficial vessels of the hands and face, in which temperatures may easily fall below 30˚C. In cold ambient temperatures, this process is amplified. Upon rewarming via central circulation and exposure to core body temperature, hemolysis ensues. This process contrasts with cold agglutinin disease, which is caused by IgM autoantibody that readily fixes complement, causing immediate hemolysis regardless of subsequent temperature change. Although PCH is classically associated with D-L autoantibodies of the IgG isotype, there have been rare case reports of IgM D-L autoantibodies but none involving IgA.[2–5]
Case Report A 2-year-old Caucasian male presented with jaundice, scleral icterus, pallor, and fatigue. Two weeks earlier, he had exhibited signs of an upper respiratory infection including cough, conjunctivitis, and fever. On laboratory examination, he was found to have hemoglobin (Hb) of 6.5 g/dl, absolute reticulocyte count (ARC) 55.1 103/ml, total bilirubin 2.8 mg/dl, direct bilirubin 0.2 mg/dl, aspartate aminotransferase (AST) 64 U/l, and a positive direct antiglobulin test (DAT) for anti-C3b/d with 1þ agglutination and negative anti-IgG. Peripheral blood smear showed polychromasia, spherocytes, teardrop cells, schistocytes, and rouleaux formation, consistent with AIHA. Physical exam revealed tachycardia, scleral icterus, generalized pallor, and no organomegaly. Further investigation conducted at a reference lab concluded that the erythrocytes were negative with anti-IgG, anti-IgM, and anti-C3b but were 3þ positive with anti-IgA and anti-C4b as well as 4þ positive with anti-C3b/d. A D-L antibody test was positive, showing P-specificity. These initial results suggested that the D-L antibody may be IgA. To confirm this, the D-L test was repeated C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25591 Published online 5 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
after chloroquine treating the patient’s red blood cells (RBC); however, rather than rewarming the sample to 37˚C, a cold DAT was performed using both anti-IgA and anti-IgG. The test was 1þ positive for IgA and negative for IgG, confirming the presence of an IgA D-L antibody (Table I). Intravenous methylprednisolone was begun on the day of admission, 7 hr from presentation, at 2 mg/kg/day in two divided doses daily. At 47 hr from presentation, Hb was 5.2 g/dl and falling, concurrent ARC was 67.5 103/ml, and the patient was transfused with 10 cc/kg ABO/Rh compatible packed RBCs. At 64 hr from presentation, Hb level had stabilized at 7.8 g/dl, and he was discharged home on oral prednisolone 2 mg/kg/day which was gradually tapered and discontinued over a period of 10 weeks. At 10 months of follow up, the patient continued to do well with Hb 13.6 g/dl, ARC 37.4 103/ml, and no subsequent episodes of hemolysis or need for additional steroids.
DISCUSSION Without documentation of this entity occurring previously, the expectant course and management of this patient was largely unknown. This case demonstrates that IgA D-L antibodies may cause steroid responsive PCH with a good prognosis. Thermal amplitude of the D-L antibody may differ among patients, leading to varying clinical presentations. Other RBC antigen specificities have been described for both IgG and IgM D-L autoantibodies, including i, I, p, Pr, ITP, and HI, although mostly in atypical cases of PCH in adults.[5,6] In rare cases, the D-L antibody has been reported to be an IgM antibody (Table II). Importantly, there is heterogeneity of disease course and severity among these 1
Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee; 2Le Bonheur Children’s Hospital, Memphis, Tennessee; 3John J. Moulds Scientific Support Services, LifeShare Blood Centers, Shreveport, Louisiana Conflict of interest: JM now works for a commercial company, Grifols Shared Services. The remaining authors declare no conflicts of interest.
Correspondence to: Nicholas Whipple, Department of Hematology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 260, Memphis, TN 38105-3678. E-mail: [email protected] Received 2 February 2015; Accepted 10 April 2015
Pediatr Blood Cancer DOI 10.1002/pbc
4 yo male, acute, developed symptoms 10 days post pneumococcal vaccine (PCV7) 5 yo female, chronic, numerous episodes lasting in total greater than 5 years 54 yo male, chronic, anemia lasting 9 months
3 yo male, recurrent PCH (2 episodes, 7 months apart), viral induced.
Clinical presentation
Patient result
Fully resolved, negative D-L test
Avoidance of cold exposure
Steroids, rituximab, IVIG, RBC transfusions Prednisone, IVIG, splenectomy, cyclophosphamide, chlorambucil, plasmapheresis, RBC transfusions
anti-I anti ITP
Receiving monthly IVIG and steroid taper (poor tolerance), additional strategies being considered Death. Autopsy revealed metastatic non-Hodgkin’s lymphoma and disseminated fungal disease (pulmonary, bone marrow)
Fully resolved after second episode, now with negative DAT and D-L test
RBC transfusions, avoidance of cold exposure
Therapy
neither anti-P nor anti-I anti-P
IgM specificity
Outcome
Karafin et al.[3] Ramos et al.[5]
Hayashi et al.[2]
Ogose et al.[4]
Reference
Known antisera (Coombs reagents) are mixed with patient’s washed RBCs to detect anti-IgG (), anti-IgM (), anti-IgA (3þ), presence of antibody or complement on the RBC surface. anti-C3b/d (4þ), anti-C3b (), anti-C4b (3þ) Patient serum is mixed with P-antigen positive RBCs. The mixture is divided into 37˚C: negative for hemolysis 4˚C: negative for three aliquots and incubated at 1) 4˚C, 2) 37˚C, and 3) 4˚C then rewarmed to 37˚C. Hemolysis that hemolysis 4˚C ! 37˚C: positive for hemolysis occurs upon rewarming to 37˚C is indicative of a positive D-L test. anti-IgA: positive for agglutination (1þ) anti-IgG: Patient RBCs are treated with chloroquine which displaces antibodies from sensitized RBCs. The serum is then mixed with treated patient RBCs, and after incubation at 4˚C, a DAT is performed negative for agglutination using antisera.
Test methodology
TABLE II. Reported Cases of PCH Due to IgM Donath–Landsteiner Antibodies
Antibody testing with chloroquine treated RBCs
DAT anti-IgG, anti-IgM, anti-IgA, anti-C3b/d, anti-C3b, anti-C4b D-L antibody test
Test
TABLE I. Tests Performed to Identify RBC Antibodies
Paroxysmal Cold Hemoglobinuria Due to an IgA 2045
2046
Whipple et al.
patients, and it appears that young children are primarily affected. It was, thus, challenging to extrapolate from these cases for therapeutic decisions and prognostication. PCH in children is generally characterized by severe intravascular hemolytic anemia that is acute, transient, self-limited, and carries an overall good prognosis—though fatal cases in childhood have been reported. The median age at presentation is 5 years with a male-to-female ratio of 2.1:1.[7,8] PCH occurs most commonly following a viral infection but also may occur after bacterial and atypical bacterial infections such as mycoplasma pneumonia. In rare cases, it has been reported following measles and pneumococcal vaccination.[2,9] PCH has also been associated with autoimmune disorders and malignancies, including leukemia and lymphoma.[5,10–12] Patients often require transfusion support for symptomatic anemia as well as corticosteroid treatment which may lessen disease severity. Cyclophosphamide, azathioprine, rituximab, and intravenous immunoglobulin (IVIG) have all been used successfully to treat PCH, including some cases of refractory disease.[3,13] Splenectomy is not indicated in PCH as the spleen plays no role in the associated intravascular hemolysis. Warm AIHA accounts for roughly 95% of known cases of AIHA and has been reported to be associated with IgG, IgM, and IgA autoantibodies. The remaining 5% of AIHA comprise cold agglutinin disease (associated with IgM autoantibody) and PCH. PCH has, until now, solely been reported to be associated with the presence of IgG or more rarely IgM autoantibodies. In PCH, initial DAT is generally positive for anti-C3b/d but negative for IgG autoantibodies. The D-L antibody binds complement in a narrow thermal range, but the complement remains on the RBC surface, allowing its detection through the DAT. At room temperature, the temperature at which the DAT is performed, the D-L antibody dissociates causing a negative reaction for the IgG component of the DAT. Detection of the D-L antibody requires an additional step compared to standard testing, as the patient blood sample must be cooled to promote antibody binding and then rewarmed to activate hemolysis and confirm the biphasic nature of the antibody. Neither IgM nor IgA antibodies are reactive with the standard antiglobulin
Pediatr Blood Cancer DOI 10.1002/pbc
(Coombs) reagents. In order to detect the presence of cold agglutinin disease and its associated IgM antibody, additional testing must be performed which can promote antibody binding at lower temperatures (0–4˚C). To detect IgA autoantibodies, clinical suspicion must prompt testing with anti-IgA antisera. A few cases of PCH have been reported in which an antibody isotype was not determined following a positive D-L antibody test.[14] In conclusion, this case suggests that PCH can be associated with an IgA D-L autoantibody. In our patient, IgA-induced PCH followed a relatively benign course, responded well to steroids, did not appear chronic in nature, and was associated with a good prognosis. Providers must consider performing additional cold incubation tests with both IgM and IgA antisera when the classic IgG antibody is not identified in cases of suspected PCH.
REFERENCES 1. Donath J, Landsteiner K. Uber Paroxysmale Hamoglobinurie. M€unch Med Wochenschr 1904;51: 1590–1593. 2. Hayashi H, Yasutomi M, Hayashi T, Yuasa M, Kawakita A, Hata I, Tanizawa A, Muramatsu H, Kojima S, Ohshima Y. Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody. Pediatr Int 2013;55:664–666. 3. Karafin MS, Shirey RS, Ness PM, King KE, Keefer J. A case study of a child with chronic hemolytic anemia due to a Donath-Landsteiner positive, IgM anti-I autoantibody. Pediatr Blood Cancer 2012;59:953–955. 4. Ogose T, Wakata Y, Kaneko M, Shinahara K, Takechi T, Kotani H. A case of recurrent paroxysmal cold hemoglobinura with the different temperature thresholds of Donath-Landsteiner antibodies. J Pediatr Hematol Oncol 2007;29:716–719. 5. Ramos RR, Curtis BR, Eby CS, Ratkin GA, Chaplin H. Fatal outcome in a patient with autoimmune hemolytic anemia associated with an IgM bithermic anti-ITP. Transfusion 1994;34:427–431. 6. Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: A case report. Transfus Med 2003;13:319–321. 7. Sokol RJ, Booker DJ, Stamps R. Erythropoiesis: Paroxysmal cold haemoglobinuria: A clinicopathological study of patients with a positive Donath-Landsteiner test. Hematology 1999;4:137–164. 8. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev 2008;22:1–15. 9. Bunch C, Schwartz FC, Bird GW. Paroxysmal cold haemoglobinuria following measles immunization. Arch Dis Child 1972;47:299–300. 10. Shirey RS, Park K, Ness PM, Kickler TS, Rones J, Dawson RB, Jiji R. An anti-i biphasic hemolysin in chronic paroxysmal cold hemoglobinuria. Transfusion 1986;26:62–64. 11. Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with nonHodgkin’s lymphoma. South Med J 1994;87:397–399. 12. Sivakumaran M, Murphy PT, Booker DJ, Wood JK, Stamps R, Sokol RJ. Paroxysmal cold haemoglobinuria caused by non-Hodgkin’s lymphoma. Br J Haematol 1999;105:278–279. 13. Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion 2007;47:1902–1904. 14. Boccardi V, D’Annibali S, Di Natale G, Girelli G, Summonti D. Mycoplasma pneumoniae infection complicated by paroxysmal cold hemoglobinuria with anti-P specificity of biphasic hemolysin. Blut 1977;34:211–214.
