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.
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.
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:<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 (>200 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 mgkg−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.
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 NLE-associated 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.
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 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.
In mothers with autoimmune diseases, if the newborn presents multiple problems that are not fully explained by NLE, MAS should be considered promptly.
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The authors declare no conflict of interest.
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Park, J., Kim, S., Kim, H. et al. Macrophage activation syndrome in a newborn infant born to a mother with autoimmune disease. J Perinatol 35, 158–160 (2015). https://doi.org/10.1038/jp.2014.207
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