Journal of Perinatology (2015) 35, 158–160 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Macrophage activation syndrome in a newborn infant born to a mother with autoimmune disease JH Park, SH Kim, HJ Kim, SJ Lee, DC Jeong and SY Kim Macrophage activation syndrome (MAS) is a complication of rheumatic disorders characterized by cytopenia, multiple organ dysfunction and coagulopathy associated with an inappropriate activation of macrophage. In neonatal lupus erythematosus, MAS is rare but fatal, requiring early diagnosis and treatment for optimal outcome. We report a case of MAS in a neonate born to a mother with autoimmune disease, improved by treatment with steroid, intravenous immunoglobulin and cyclosporine. Journal of Perinatology (2015) 35, 158–160; doi:10.1038/jp.2014.207
INTRODUCTION Macrophage activation syndrome (MAS) is recognized as a form of secondary hemophagocytic lymphohistiocytosis (HLH) syndrome related to autoimmune pathology.1 MAS is rare, but presents in a fulminant, fatal course, requiring a high index of suspicion for diagnosis.2 We report a case of a neonate diagnosed with MAS that may be caused by the transplacental transfer of autoantibodies. CASE A 2550 g female infant was born at 37+6 weeks of gestation by normal vaginal delivery. The mother was diagnosed with adult-onset Still’s disease 10 years previously. During pregnancy, the mother did not take any medication and was asymptomatic. Antibody screening was done 2 years ago and was negative. Despite normal electrocardiogram results, the baby was admitted to the neonatal intensive care unit owing to tachypnea and fever 12 h after delivery. Empirical antibiotics were started under the impression of sepsis. Her initial hemoglobin (12.8 g dl − 1) and platelet count (71.0 × 103 μl − 1) was low and C-reactive protein (CRP) was negative (2.18 mg dl − 1, normal range:o 5 mg dl − 1). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 93 and 33 IU l − 1, and lactate dehydrogenase was 1845 IU l − 1. Tests for disseminated intravascular coagulation (DIC) were nonspecific, and studies for bacterial and viral infection were negative. Autoantibody screening showed positive anti-nuclear antibody (ANA; speckled, 1:160) and anti-SSA/Ro antibody (4200 U ml − 1). On the basis of her test results the mother’s autoantibody screening was repeated, and the anti-SSA/Ro antibody was positive, identical to her baby’s. Gene study for Munc gene, K-ras and N-ras was negative, and evaluation of serum cytokine levels, bone marrow and cerebrospinal fluid was not done. On the 10th hospital day (HD), abdominal distension, hepatosplenomegaly and hematemesis were observed. Laboratory results demonstrated elevated triglyceride (280 mg dl − 1), ferritin (2891 ng ml − 1), AST (459 IU l − 1), ALT (463 IU l − 1) and CRP (112 mg dl − 1). Repeated tests for DIC showed normal fibrinogen (287.6 mg dl − 1), elevated D-dimer (2.54 mg ml − 1 FEU) and fibrin
degradation products (FDP; 7.6 μg ml − 1) levels. On the 18th HD, deterioration of overall condition with high ferritin (2891.8 ng ml − 1), ALT (362 IU l − 1) and thrombocytopenia (12.0 × 103 μl − 1) was observed. On the basis of the guidelines (Table 1), MAS was diagnosed3. After treatment with intravenous immunoglobulin (IVIG, 1 g kg − 1 per day, for 2 days) and steroid (pulse, methylprednisolone, 30 mgkg − 1 per day), the dose was tapered according to the 2004 HLH treatment protocol4. On the 26th HD, laboratory findings demonstrated reactivation of MAS. Hyperferritinemia (2770 ng ml − 1) and thrombocytopenia (7.1 × 103 μl − 1) persisted. Cyclosporine (6 mg kg − 1 per day, divided in 2 doses, oral) was added to therapy. She had received packed red blood cell transfusions (75 ml kg − 1), possibly contributing to the re-elevated ferritin level. After 54 days of treatment with steroid, 2 courses of IVIG and 34 days of cyclosporine, she was symptom free with normal laboratory results. We discharged the patient after 2 months, stopping medication at 12 weeks of age. Figure 1 shows the clinical course and treatment. DISCUSSION MAS may occur spontaneously, or may be triggered by infection or a change in therapy which leads to excessive activation and proliferation of T lymphocytes and macrophages with massive activation of proinflammatory cytokines. Clinically, patients present with nonremitting fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver failure, encephalopathy, coagulopathy and elevated ferritin.2,5 It is estimated that 1 to 2% of mothers with autoimmune disease associated with SSA/Ro and/or SSB/La antibodies give birth to neonates diagnosed NLE.6 Even in NLE, MAS is an extremely rare complication. There was no case report on MAS complicating NLE, and the case Suzuki et al.7 reported on NLEassociated HLH in a neonate born to a mother with Sjogren syndrome was the only case associated with the transplacental transmission of autoantibodies. In neonates, features can mimic sepsis and the incidence of symptoms in the criteria may be diverse.
Department of Pediatrics, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, Seoul, Republic of Korea. Correspondence: Dr SY Kim, Department of Pediatrics, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, 10, 63-ro, Yeongdeungpo-gu, Seoul 137-701, Republic of Korea. E-mail: [email protected] Received 21 July 2014; revised 5 October 2014; accepted 14 October 2014
Macrophage activation syndrome in neonatal lupus erythematosus JH Park et al
159 Table 1.
3
Preliminary guidelines for macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus
Clinical criteria 1. Fever (438 °C) 2. Hepatomegaly (⩾3 cm below the costal arch) 3. Splenomegaly (⩾3 cm below the costal arch) 4. Hemorrhagic manifestations (purpura, easy bruising or mucosal bleeding) 5. CNS dysfunction (irritability, disorientation, lethargy, headache, seizures or coma) Laboratory criteria 1. Cytopenia affecting two or more cell lineages (WBC count ⩽ 4000 mm − 3, Hb ⩽ 9 g dl − 1 or PLT count ⩽ 150 000 mm − 3) 2. Increased AST (440 U l − 1) 3. Increased LDH (4567 U l − 1) 4. Hypofibrinogenemia (fibrinogen ⩽ 150 mg dl − 1) 5. Hypertriglyceridemia (triglycerides 4178 mg dl − 1) 6. Hyperferritinemia (ferritin 4500 μg l − 1) Histopathologic criterion Evidence of macrophage hemophagocytosis in the bone marrow aspirate Abbreviations: AST, aspartate aminotransferase; CNS, central nervous system; Hb, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; WBC, white blood cell. The diagnosis of macrophage activation syndrome: at least one clinical criterion and at least two laboratory criteria. Bone marrow aspiration for evidence of macrophage hemophagocytosis may be required only in doubtful cases.
MPD Pulse
Oral PD (2mg kg–1 day–1) Cyclosporine
IVIG
IVIG
3,500
600 Ferritin
TG
500
2,500
400
2,000 300 1,500 200
1,000
TG (mg dL–1)
Ferrintin (ng mL–1)
3,000
100
500
0
0 18HD
24HD
26HD
31HD
48HD
52HD
55HD
59HD
ALT (U L–1)
362
40
31
38
126
149
82
50
LDH (U L–1)
818
760
449
460
404
642
411
417
ANC (µL–1)
770
270
500
40
740
930
820
630
Platelet (x 1000 µL–1) 12
78
71
44
95
182
224
241
Fibrinogen (mg dL–1) 291.4
126
Figure 1. Clinical course of a neonate diagnosed with macrophage activation syndrome. ALT, alanine aminotransferase; HD, hospital day; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MPD, Methylprednisolone; PD, Prednisolone.
possible that the persistent hyperferritinemia might be a consequence of transfusion, leading to reactivation. There is no agreed treatment protocol for MAS, especially in neonates. Glucocorticoid, IVIG and various immunosuppressive agents have been used.2,14 In our case, clinical and laboratory findings improved rapidly after initiation of corticosteroid, immunoglobulin and cyclosporine. This report is the first case of neonatal MAS induced by the transplacental passage of autoimmune antibodies, and the outlines of diagnosis and treatment are not established. In mothers with autoimmune diseases, if the newborn presents multiple problems that are not fully explained by NLE, MAS should be considered. More information on neonatal MAS should be accumulated to propose specific guidelines. CONCLUSION In mothers with autoimmune diseases, if the newborn presents multiple problems that are not fully explained by NLE, MAS should be considered promptly. CONFLICT OF INTEREST The authors declare no conflict of interest.
In this case, several factors complicated early diagnosis. NLE usually presents with cardiac or cutaneous symptoms, which can be detected early by electrocardiogram and physical examination,8,9 but our patient showed normal electrocardiogram and no rash. Thrombocytopenia, which is seen in 1 to 5% of normal neonates10 was the only symptom until other symptoms emerged. Compared with other age groups, the incidence of hypertriglyceridemia is low owing to differences in lipid metabolism.11 During therapy the platelet, ferritin and CRP level moved in a similar pattern associated with the disease, but we were not able to correlate triglyceride level to the clinical course. During treatment, we experienced reactivation of MAS. The baby had received multiple transfusions prior to diagnosis. The lifespan of transfused RBC is shorter than normal RBC, and repeated transfusions may lead to iron overload, causing multiple organ injury including alteration of innate immunity.12,13 It may be © 2015 Nature America, Inc.
REFERENCES 1 Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage activation syndrome in autoimmune disease. Int Arch Allergy Immunol 2010; 153: 109–120. 2 Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol 2012; 31: 1223–1230. 3 Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum 2009; 60: 3388–3399. 4 Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124–131. 5 Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage activation syndrome in autoimmune disease.Int Arch Allergy Immunol 2010, 153(2): 109–120. 6 Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol 2011; 40(1): 27–41.
Journal of Perinatology (2015), 158 – 160
Macrophage activation syndrome in neonatal lupus erythematosus JH Park et al
160 7 Suzuki Y, Takahashi N, Yada Y, Koike Y, Matano M, Nishimura H et al. Hemophagocytic lymphohistiocytosis in a newborn infant born to a mother with Sjogren syndrome antibodies. J Perinatol 2013; 33: 569–571. 8 Buyon JP, Clancy RM. Neonatal lupus syndromes. Curr Opin Rheumatol 2003; 15: 535–541. 9 Liu J, Yang YH, Lin YT, Chiang BL. Clinical characteristics of neonatal lupus erythematosus. J Microbiol Immunol Infect 2001; 34: 265–268. 10 Roberts I, Murray NA. Neonatal thrombocytopenia: causes and management. Arch Dis Child Fetal Neonatal Ed 2003; 88: F359–F364.
Journal of Perinatology (2015), 158 – 160
11 Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96: 688–693. 12 Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang 2009; 97: 185–197. 13 Shander A, Sazama K. Clinical consequences of iron overload from chronic red blood cell transfusions, its diagnosis, and its management by chelation therapy. Transfusion 2010; 50: 1144–1155. 14 Kumakura S, Ishikura H, Kondo M, Murakawa Y, Masuda J, Kobayashi S. Autoimmuneassociated hemophagocytic syndrome. Mod Rheumatol 2004; 14: 205–215.
© 2015 Nature America, Inc.
PERINATAL/NEONATAL CASE PRESENTATION
Macrophage activation syndrome in a newborn infant born to a mother with autoimmune disease JH Park, SH Kim, HJ Kim, SJ Lee, DC Jeong and SY Kim Macrophage activation syndrome (MAS) is a complication of rheumatic disorders characterized by cytopenia, multiple organ dysfunction and coagulopathy associated with an inappropriate activation of macrophage. In neonatal lupus erythematosus, MAS is rare but fatal, requiring early diagnosis and treatment for optimal outcome. We report a case of MAS in a neonate born to a mother with autoimmune disease, improved by treatment with steroid, intravenous immunoglobulin and cyclosporine. Journal of Perinatology (2015) 35, 158–160; doi:10.1038/jp.2014.207
INTRODUCTION Macrophage activation syndrome (MAS) is recognized as a form of secondary hemophagocytic lymphohistiocytosis (HLH) syndrome related to autoimmune pathology.1 MAS is rare, but presents in a fulminant, fatal course, requiring a high index of suspicion for diagnosis.2 We report a case of a neonate diagnosed with MAS that may be caused by the transplacental transfer of autoantibodies. CASE A 2550 g female infant was born at 37+6 weeks of gestation by normal vaginal delivery. The mother was diagnosed with adult-onset Still’s disease 10 years previously. During pregnancy, the mother did not take any medication and was asymptomatic. Antibody screening was done 2 years ago and was negative. Despite normal electrocardiogram results, the baby was admitted to the neonatal intensive care unit owing to tachypnea and fever 12 h after delivery. Empirical antibiotics were started under the impression of sepsis. Her initial hemoglobin (12.8 g dl − 1) and platelet count (71.0 × 103 μl − 1) was low and C-reactive protein (CRP) was negative (2.18 mg dl − 1, normal range:o 5 mg dl − 1). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 93 and 33 IU l − 1, and lactate dehydrogenase was 1845 IU l − 1. Tests for disseminated intravascular coagulation (DIC) were nonspecific, and studies for bacterial and viral infection were negative. Autoantibody screening showed positive anti-nuclear antibody (ANA; speckled, 1:160) and anti-SSA/Ro antibody (4200 U ml − 1). On the basis of her test results the mother’s autoantibody screening was repeated, and the anti-SSA/Ro antibody was positive, identical to her baby’s. Gene study for Munc gene, K-ras and N-ras was negative, and evaluation of serum cytokine levels, bone marrow and cerebrospinal fluid was not done. On the 10th hospital day (HD), abdominal distension, hepatosplenomegaly and hematemesis were observed. Laboratory results demonstrated elevated triglyceride (280 mg dl − 1), ferritin (2891 ng ml − 1), AST (459 IU l − 1), ALT (463 IU l − 1) and CRP (112 mg dl − 1). Repeated tests for DIC showed normal fibrinogen (287.6 mg dl − 1), elevated D-dimer (2.54 mg ml − 1 FEU) and fibrin
degradation products (FDP; 7.6 μg ml − 1) levels. On the 18th HD, deterioration of overall condition with high ferritin (2891.8 ng ml − 1), ALT (362 IU l − 1) and thrombocytopenia (12.0 × 103 μl − 1) was observed. On the basis of the guidelines (Table 1), MAS was diagnosed3. After treatment with intravenous immunoglobulin (IVIG, 1 g kg − 1 per day, for 2 days) and steroid (pulse, methylprednisolone, 30 mgkg − 1 per day), the dose was tapered according to the 2004 HLH treatment protocol4. On the 26th HD, laboratory findings demonstrated reactivation of MAS. Hyperferritinemia (2770 ng ml − 1) and thrombocytopenia (7.1 × 103 μl − 1) persisted. Cyclosporine (6 mg kg − 1 per day, divided in 2 doses, oral) was added to therapy. She had received packed red blood cell transfusions (75 ml kg − 1), possibly contributing to the re-elevated ferritin level. After 54 days of treatment with steroid, 2 courses of IVIG and 34 days of cyclosporine, she was symptom free with normal laboratory results. We discharged the patient after 2 months, stopping medication at 12 weeks of age. Figure 1 shows the clinical course and treatment. DISCUSSION MAS may occur spontaneously, or may be triggered by infection or a change in therapy which leads to excessive activation and proliferation of T lymphocytes and macrophages with massive activation of proinflammatory cytokines. Clinically, patients present with nonremitting fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver failure, encephalopathy, coagulopathy and elevated ferritin.2,5 It is estimated that 1 to 2% of mothers with autoimmune disease associated with SSA/Ro and/or SSB/La antibodies give birth to neonates diagnosed NLE.6 Even in NLE, MAS is an extremely rare complication. There was no case report on MAS complicating NLE, and the case Suzuki et al.7 reported on NLEassociated HLH in a neonate born to a mother with Sjogren syndrome was the only case associated with the transplacental transmission of autoantibodies. In neonates, features can mimic sepsis and the incidence of symptoms in the criteria may be diverse.
Department of Pediatrics, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, Seoul, Republic of Korea. Correspondence: Dr SY Kim, Department of Pediatrics, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, 10, 63-ro, Yeongdeungpo-gu, Seoul 137-701, Republic of Korea. E-mail: [email protected] Received 21 July 2014; revised 5 October 2014; accepted 14 October 2014
Macrophage activation syndrome in neonatal lupus erythematosus JH Park et al
159 Table 1.
3
Preliminary guidelines for macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus
Clinical criteria 1. Fever (438 °C) 2. Hepatomegaly (⩾3 cm below the costal arch) 3. Splenomegaly (⩾3 cm below the costal arch) 4. Hemorrhagic manifestations (purpura, easy bruising or mucosal bleeding) 5. CNS dysfunction (irritability, disorientation, lethargy, headache, seizures or coma) Laboratory criteria 1. Cytopenia affecting two or more cell lineages (WBC count ⩽ 4000 mm − 3, Hb ⩽ 9 g dl − 1 or PLT count ⩽ 150 000 mm − 3) 2. Increased AST (440 U l − 1) 3. Increased LDH (4567 U l − 1) 4. Hypofibrinogenemia (fibrinogen ⩽ 150 mg dl − 1) 5. Hypertriglyceridemia (triglycerides 4178 mg dl − 1) 6. Hyperferritinemia (ferritin 4500 μg l − 1) Histopathologic criterion Evidence of macrophage hemophagocytosis in the bone marrow aspirate Abbreviations: AST, aspartate aminotransferase; CNS, central nervous system; Hb, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; WBC, white blood cell. The diagnosis of macrophage activation syndrome: at least one clinical criterion and at least two laboratory criteria. Bone marrow aspiration for evidence of macrophage hemophagocytosis may be required only in doubtful cases.
MPD Pulse
Oral PD (2mg kg–1 day–1) Cyclosporine
IVIG
IVIG
3,500
600 Ferritin
TG
500
2,500
400
2,000 300 1,500 200
1,000
TG (mg dL–1)
Ferrintin (ng mL–1)
3,000
100
500
0
0 18HD
24HD
26HD
31HD
48HD
52HD
55HD
59HD
ALT (U L–1)
362
40
31
38
126
149
82
50
LDH (U L–1)
818
760
449
460
404
642
411
417
ANC (µL–1)
770
270
500
40
740
930
820
630
Platelet (x 1000 µL–1) 12
78
71
44
95
182
224
241
Fibrinogen (mg dL–1) 291.4
126
Figure 1. Clinical course of a neonate diagnosed with macrophage activation syndrome. ALT, alanine aminotransferase; HD, hospital day; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MPD, Methylprednisolone; PD, Prednisolone.
possible that the persistent hyperferritinemia might be a consequence of transfusion, leading to reactivation. There is no agreed treatment protocol for MAS, especially in neonates. Glucocorticoid, IVIG and various immunosuppressive agents have been used.2,14 In our case, clinical and laboratory findings improved rapidly after initiation of corticosteroid, immunoglobulin and cyclosporine. This report is the first case of neonatal MAS induced by the transplacental passage of autoimmune antibodies, and the outlines of diagnosis and treatment are not established. In mothers with autoimmune diseases, if the newborn presents multiple problems that are not fully explained by NLE, MAS should be considered. More information on neonatal MAS should be accumulated to propose specific guidelines. CONCLUSION In mothers with autoimmune diseases, if the newborn presents multiple problems that are not fully explained by NLE, MAS should be considered promptly. CONFLICT OF INTEREST The authors declare no conflict of interest.
In this case, several factors complicated early diagnosis. NLE usually presents with cardiac or cutaneous symptoms, which can be detected early by electrocardiogram and physical examination,8,9 but our patient showed normal electrocardiogram and no rash. Thrombocytopenia, which is seen in 1 to 5% of normal neonates10 was the only symptom until other symptoms emerged. Compared with other age groups, the incidence of hypertriglyceridemia is low owing to differences in lipid metabolism.11 During therapy the platelet, ferritin and CRP level moved in a similar pattern associated with the disease, but we were not able to correlate triglyceride level to the clinical course. During treatment, we experienced reactivation of MAS. The baby had received multiple transfusions prior to diagnosis. The lifespan of transfused RBC is shorter than normal RBC, and repeated transfusions may lead to iron overload, causing multiple organ injury including alteration of innate immunity.12,13 It may be © 2015 Nature America, Inc.
REFERENCES 1 Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage activation syndrome in autoimmune disease. Int Arch Allergy Immunol 2010; 153: 109–120. 2 Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol 2012; 31: 1223–1230. 3 Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum 2009; 60: 3388–3399. 4 Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124–131. 5 Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage activation syndrome in autoimmune disease.Int Arch Allergy Immunol 2010, 153(2): 109–120. 6 Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol 2011; 40(1): 27–41.
Journal of Perinatology (2015), 158 – 160
Macrophage activation syndrome in neonatal lupus erythematosus JH Park et al
160 7 Suzuki Y, Takahashi N, Yada Y, Koike Y, Matano M, Nishimura H et al. Hemophagocytic lymphohistiocytosis in a newborn infant born to a mother with Sjogren syndrome antibodies. J Perinatol 2013; 33: 569–571. 8 Buyon JP, Clancy RM. Neonatal lupus syndromes. Curr Opin Rheumatol 2003; 15: 535–541. 9 Liu J, Yang YH, Lin YT, Chiang BL. Clinical characteristics of neonatal lupus erythematosus. J Microbiol Immunol Infect 2001; 34: 265–268. 10 Roberts I, Murray NA. Neonatal thrombocytopenia: causes and management. Arch Dis Child Fetal Neonatal Ed 2003; 88: F359–F364.
Journal of Perinatology (2015), 158 – 160
11 Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96: 688–693. 12 Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang 2009; 97: 185–197. 13 Shander A, Sazama K. Clinical consequences of iron overload from chronic red blood cell transfusions, its diagnosis, and its management by chelation therapy. Transfusion 2010; 50: 1144–1155. 14 Kumakura S, Ishikura H, Kondo M, Murakawa Y, Masuda J, Kobayashi S. Autoimmuneassociated hemophagocytic syndrome. Mod Rheumatol 2004; 14: 205–215.
© 2015 Nature America, Inc.
![[Autoimmune hemolytic anemia transmitted to the newborn infant from the mother affected with an ovarian cyst].](/assets/img/hold.png)
