literature fails to reveal a clear association between hydrops fetalis ... infant's white blood cell count was 1800 per μl with 0% neutrophils, 89% lymphocytes, and ...
Perinatal/Neonatal Case Presentation Hemophagocytic Lymphohistiocytosis Presenting with Nonimmune Hydrops Fetalis Colleen Ann Malloy, MD Carol Polinski, NNP Serhan Alkan, MD Ricarchito Manera, MD Malliswari Challapalli, MD
Hydrops fetalis is a condition of diverse etiologies. An association between hemophagocytic lymphohistiocytosis (HLH) and hydrops fetalis has not been reported in the English literature. We describe an intrauterine case of HLH in an infant who presented with hydrops fetalis at 32 weeks gestation. We suggest that HLH should be considered in the differential diagnosis of nonimmune hydrops fetalis, especially in the presence of cytopenias. Journal of Perinatology (2004) 24, 458–460. doi:10.1038/sj.jp.7211121
INTRODUCTION Non-immune hydrops fetalis is a heterogenous condition for which more than 70 causes have been described.1 Despite advances in prenatal and post-mortem diagnostic techniques, the etiology remains enigmatic in 15% of cases.2 Review of the English literature fails to reveal a clear association between hydrops fetalis and hemophagocytic lymphohistiocytosis (HLH). HLH is caused by a benign, abnormal proliferation of histiocytes that invade tissues and organs causing multiorgan failure. This disease presents with systemic symptoms such as pancytopenia, splenomegaly, and coagulopathy, and is fatal without treatment. To our knowledge, we are first to describe in the English literature the association between HLH and nonimmune hydrops fetalis.
Ronald McDonald Children’s Hospital at Loyola University Medical Center (C.A.M., C.P., R.M., M.C.), Department of Pediatrics, Division of Neonatology, Division of Hematology and Oncology, Division of Infectious Disease, Maywood, IL, USA; and Department of Pathology (S.A.), Loyola University Medical Center, Maywood, IL, USA. Dr. Malloy is currently affiliated with Children’s Memorial Hospital, Chicago, IL. Address correspondence and reprint requests to Malliswari Challapalli, MD, Ronald McDonald Children’s Hospital at Loyola University Medical Center, Department of Pediatrics, Division of Pediatric Infectious Diseases, 2160 South First Avenue, Bldg. 105, Room 3313, Maywood, IL 60153, USA.
CASE REPORT A 29-year-old healthy woman conceived a twin pregnancy after in vitro fertilization. This G1P0 mother’s prenatal care began in the first trimester. There was no consanguinity, and the pregnancy was uneventful. An ultrasound performed at 32 weeks revealed polyhydramnios with an 18% discordancy. The larger twin had ascites, pleural effusions, and pericardial effusions. The infants were delivered via Cesarean section at 3227 weeks for worsening hydrops fetalis secondary to presumed twin–twin transfusion syndrome. The hydropic twin had Apgar scores of 5 and 9 at 1 and 5 minutes, respectively. Birth weight was 2190 g, and the head circumference and length were age appropriate. His temperature was 35.51C, heart rate was 156, respiratory rate was 70, and blood pressure was 45/29 mmHg. He required intubation and mechanical ventilation for respiratory distress. Physical examination was remarkable for a palpable liver edge and spleen tip. The infant had mild generalized edema. Shortly after birth, the infant became hypotensive and had worsening of his respiratory status. The initial chest radiograph showed diffuse granular pulmonary opacities with bilateral pleural effusions. Diagnostic evaluation included a complete blood count, reticulocyte count, blood culture, and an echocardiogram. The infant’s white blood cell count was 1800 per ml with 0% neutrophils, 89% lymphocytes, and 11% reactive lymphocytes. The platelet count was 43,000 per ml, and hemoglobin was 12.9 g/dl. The peripheral smear showed few ovalocytes, tear drop cells, target cells, and acanthocytes. The reticulocyte count was 0.4%. The echocardiogram showed a small pericardial effusion. Maternal and infant blood types were B þ , with a negative antibody screen. Fibrinogen was 63 mg%, activated partial thromboplastin time was Z200 seconds, and prothrombin time was 20.3 seconds. Albumin level was 2.6 g/dl, alkaline phosphatase was 58 iu/l, aminoaspartate was 94 iu/l, and alanine aminotransferase was 38 iu/l. Triglyceride level was 78 mg/dl. Pleurocentesis was performed; the pleural fluid had 1910 white blood cells per ml with 97% lymphocytes and 2800 mg/dl of protein. Blood cultures as well as urine, rectal, and tracheal viral cultures were negative. Cerebral spinal fluid was clear with 46 mg/ dl of glucose and 303 mg/dl of protein. The spinal fluid had 1 red cell per ml and 25 white cells per ml of which 81% were lymphocytes with many reactive monocytes. Spinal fluid culture was negative. Maternal HbsAg and RPR were nonreactive. Cord blood parvovirus IgM and maternal toxoplasmosis IgG antibody Journal of Perinatology 2004; 24:458–460 r 2004 Nature Publishing Group All rights reserved. 0743-8346/04 $30
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Association between Hemophagocytic Lymphohistiocytosis and Hydrops Fetalis
Figure 1. The bone marrow aspirate smear showing two macrophages with phagocytosis of red blood cells, a nucleated red blood cell precursor, and white blood cell (oil immersion 1000 power).
titers were negative. Ophthalmologic evaluation was unremarkable, and chromosomal karyotyping was 46, XY. The infant required multiple transfusions of platelets, red cells, fresh frozen plasma, and cryoprecipitate. On the fifth day, granulocyte colony stimulating factor (filgrastim) was started for persistent neutropenia. Bone marrow aspiration to evaluate the pancytopenia showed (Figure 1) hemophagocytosis with increased macrophages and histiocytes, consistent with HLH. On the eighth day, the infant developed multiorgan failure and worsening edema. He had a pulmonary hemorrhage and underwent high-frequency oscillatory ventilation. The parents decided against chemotherapy, and the infant died on day 11. Pathologic evaluation at autopsy revealed prominent lymphoid depletion of the thymus, consistent with HLH. Placental evaluation showed a dichorionic – diamniotic placenta, inconsistent with twin–twin transfusion. The twin brother had a normal complete blood count and an uneventful hospital course. He continues to be healthy at 1 year of age.
DISCUSSION The lymphoproliferative disorder of HLH can be divided into two categories: primary (familial) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH. The incidence of FHL is 1:50,000 births, with an equal gender distribution.3 In contrast to secondary HLH, which may affect any age and may resolve spontaneously, FHL is seen primarily in children and is fatal if untreated.3 Most cases of FHL are diagnosed before 2 years of age, and the disease may present in the newborn period.4–6 The diagnostic criteria for HLH include fever for 7 or more days, splenomegaly, cytopenia of two or three lineages (unassociated with a hypocellular or dysplastic marrow), hypertriglyceridemia Journal of Perinatology 2004; 24:458–460
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and/or hypofibrinogenemia, and histopathological evidence of hemophagocytosis in the bone marrow, spleen, liver, or lymph nodes.7 Hepatomegaly, jaundice, lymphadenopathy, edema, and rash are also seen. There can be central nervous system involvement, with meningsmus, seizures, encephalopathy, and/or spinal fluid pleocytosis. Our patient’s clinical picture, laboratory evaluation, and pathologic examination are consistent with HLH. Our case satisfied all diagnostic criteria with the exception of fever, which is rarely seen in neonatal HLH. The early manifestation of illness and fatal outcome in our patient are suggestive of FHL, although the distinction between primary and secondary HLH may not be obvious.8 Presence of infection at the onset of HLH does not help with disease classification, as both FHL and secondary HLH can involve infectious agents as triggers.9 Multiple immune defects are associated with HLH. Natural killer cell activity, T-lymphocyte mitogen response, antibody-dependent cellular cytotoxicity, and interleukin-1 and interferon production are all diminished.10,11 Mutations of the gene that encodes for perforin, an important mediator of lymphocyte cytotoxicity, are seen in 20 to 30% of FLH patients.12 HLH may be due to a immunoregulatory defect that predisposes to an uncontrolled production of activated histiocytes in response to a stimulus such as a viral infection.11 Infections that have been associated with HLH have also been reported as etiologies for nonimmune hydrops fetalis.2,7,13 Although viral and bacterial studies all were negative in our patient, it is possible that an infectious process could have triggered both hydrops fetalis and HLH. However, an in utero infection would most likely have affected both infants of a twin gestation. Perinatal HLH has been reported. The presentations of previously described newborns include cutaneous manifestations with erythroderma, generalized purpuric macules and papules, and morbilliform eruptions.14 Neonates presenting with isolated thrombocytopenia or hepatic dysfunction, with other characteristic findings becoming evident subsequently, have also been reported.6 One such infant with HLH who presented with thrombocytopenia had been delivered at 33 weeks gestation because of hydrops fetalis. Only the platelet cell line was depressed at birth, and the infant demonstrated neutropenia and anemia by 8 days of age. While our infant’s pancytopenia coincided more definitively with the hydropic condition, both cases highlight the relationship between HLH and hydrops fetalis. This association is important in that it may help with the recognition of an underdiagnosed disease for which there is effective treatment. Although various chemotherapeutic regimens for HLH have had mixed success, bone marrow transplantation has resulted in much improved survival rates. The aim of current treatment protocols is to achieve remission with immunochemotherapy, followed by a cure with bone marrow transplantation.15 All three infants described by Levendoglu-Tugal et al.6 received chemotherapy and 459
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survived; two of the infants subsequently underwent bone marrow transplantation and did well. Combination treatment offers a cure for nearly two-thirds of patients and should be considered in all children with primary HLH.12 In summary, we are the first to report in the English literature the association between HLH and nonimmune hydrops fetalis. Our case emphasizes the importance of bone marrow evaluation in the presence of hydrops and/or cytopenia of unexplained etiology. References 1. Castillo RA, Devoe LD, Hadi HA, Martin S, Geist D. Nonimmune hydrops fetalis: clinical experience and factors related to a poor outcome. Am J Obstet Gynecol 1986;155:812–6. 2. Jones DC. Nonimmune fetal hydrops: diagnosis and obstetrical management. Semin Perinatol 1995;19:447–61. 3. Henter JI, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:417–33. 4. Huang F, Arceci R. The histiocytoses of infancy. Semin Perinatol 1999;23:319–31. 5. Parizhskaya M, Reyes J, Jaffe R. Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis. Pediatr Dev Pathol 1999;2:360–6. 6. Levendoglu-Tugal O, Ozkaynak MF, LaGamma E, Sherbany A, Sandoval C, Jayabose S. Hemophagocytic lymphohistiocytosis presenting with thrombocytopenia in the newborn. J Pediatr Hematol Oncol 2002;24:405–9.
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7. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29–33. 8. Henter JI. Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. Med Pediatr Oncol 2002;38:305–9. 9. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr 1993;82: 369–72. 10. Kataoka Y, Todo S, Morioka Y, et al. Impaired natural killer activity and expression of interleukin-2 receptor antigen in familial erythrophagocytic lymphohistiocytosis. Cancer 1990;65:1937–41. 11. McClain K, Gehrz R, Grierson H, Purtilo D, Filipovich A. Virus-associated histiocytic proliferations in children. Frequent association with Epstein– Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hematol Oncol 1988;10:196–205. 12. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol 2004;124:4–14. 13. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. 14. Morrell DS, Pepping MA, Scott JP, Esterly NB, Drolet BA. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol 2002;138:1208–12. 15. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100:2367–73.
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