Iran J Pediatr. 2015 June; 25(3):e339. DOI: 10.5812/ijp.25(3)2015.339 Letter Published online 2015 June 27.

Secondary Hemophagocytosis in Propionic Acidemia

1,* 2 3 4 Cigdem Seher Kasapkara ; Murat Kangin ; Banu Oflaz Ozmen ; Mehmet Nuri Ozbek ; 2 2 5 5 5 Remezan Demir ; Mustafa Karatas ; Leyla Tumer ; Fatih Suhey Ezgu ; Alev Hasanoglu

1Department of Pediatric Metabolism and Nutrition, Diyarbakir Children’s Hospital, Diyarbakir, Turkey 2Pediatric Intensive Care Unit, Diyarbakir Children’s Hospital, Diyarbakir, Turkey 3Department of Pediatric Hematology and Oncology, Diyarbakir Children’s Hospital, Diyarbakir, Turkey 4Department of Pediatric , Diyarbakır Children’s Hospital, Diyarbakir, Turkey 5Department of Pediatric Metabolism and Nutrition, Gazi University Hospital, Ankara, Turkey *Correspanding author : Cigdem Seher Kasapkara, Department of Pediatric Metabolism and Nutrition, Diyarbakir Children’s Hospital, Diyarbakir, Turkey. E-mail: [email protected] Received: ; Accepted: February 1, 2014 November 11, 2014

Keywords: Propionic Acidemia; Secondary Hemophagocytosis

Dear Editor,

Propionic acidemia is one of the intoxication type or- were decreased. He was dehydrated. He was not oriented ganic acidemias, which often present in the neonatal and did not cooperate but was able to localize the pain- period with lethargy, feeding difficulties, , ful stimuli. During the follow up in intensive care unit, and coma if not identified and treated appro- his consciousness deteriorated progressively, and he priately. Patients with propionic acidemia can decom- was intubated. Serum level was elevated (280, pensate during periods of increased metabolic demand normal range 31 - 123 µg/dL) and hyper-ammonemia re- (1, 2). Hemophagocytic lymphohistiocytosis (HLH) is a sponded dramatically to a single dose of oral carglumic life threatening disorder that can rapidly deteriorate acid. Over the following 6 hours, the plasma ammonia and lead to multiple organ failure and death. It can be level dropped to 81 µg/dl and remained normal thereaf- classified as primary (familial) or secondary (acquired) ter. Serum uric acid level was 9.4 mg/dL. Complete (3, 4). Secondary HLH is associated with infections es- count revealed hemoglobin 12.7 g/dL, leucocyte count pecially viral, malignant disorders, inborn errors of 3.1 × 109/L and platelets 96 × 109/L. Blood gas analysis metabolism such as multiple sulphatase deficiency, ly- showed pH: 7.52, pCO2 10.8 and HCO3 8.7 mmol/L. Plasma sinuric protein intolerance, , Gau- lactate was 6,77 mmol/L. Urine was positive for . cher disease and galactosialidosis (5-8) In this report, we He was put on broad spectrum antibiotic treatment af- present a case of a 3 year old boy with propionic acide- ter several sets of cultures were taken. On the third day mia who experienced secondary HLH during his meta- of admission, pancytopenia was prominent with hemo- bolic attack and was successfully treated with intrave- globin 8.2 g/dL, leucocyte 2.1 × 109/L, and platelet count nous gammaglobulin, broad spectrum antibiotics and 4 × 109/L. The peripheral smear showed leukopenia, dexamethasone therapy. normocytic normochromic anemia, and thrombocy- A 3-year-old boy who had been followed up with the topenia. Serum ferritin level was 1753 ng/mL. Although diagnosis of propionic acidemia from the neonatal pe- he was not on parenteral nutrition, serum triglyceride riod presented with respiratory distress, somnolance, level was > 1420 mg/dL. Plasma fibrinogen level was 87 fever and diarrhea to pediatric metabolic unit. His par- mg/dL (normal range 160 - 400 mg/dL). Lactate dehy- ents were first degree cousins. Carboxylase activities in drogenase level was 1376 IU/L. With the diagnosis of sec- cultured fibroblasts confirmed the diagnosis of isolated ondary HLH, bone marrow aspiration was performed. propionyl COA carboxylase deficiency. He had been ad- On light microscopic examination of bone marrow as- mitted to hospital several times due to metabolic at- pirate, increased histiocytes, lipid laden macrophages, tacks. On his last admission, body temprature was 39°C. and prominent hemophagocytosis were observed. Viral He was tachypneic and tachycardic and capillary refill- testing was negative. Based on diagnostic criteria, our ing time was longer than normal. Skin turgor and tonus patient fulfilled 5 of the 8 criteria and was diagnosed

Copyright © 2015, Growth & Development Research Center. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non- Commercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. Kasapkara CS et al. as HLH. Intravenous gamma globulin was given im- WBC mediately and dexamethasone added to treatment as 10000 ordered in the treatment protocol for Hemophagocytic 8000 IVIG Lymphohistiocytosis (HLH-2004) (Figures 1 - 3). 6000 He became better in terms of clinical picture and labo- 4000 Dexamethasone IVIG ratory findings. Fever decreased strikingly. The blood 2000 count normalized day by day. We tapered the steroid 0 day 1 day 3 dose according to HLH 2004 protocol. Two months after day 4 day 5 day 7 day 8 the beginning of HLH 2004 protocol, dexamethasone day 9 day 10 WBC: White Blood Cell day 11 day 12 dosage was decreased. Now he is on regular outpatient IVIG: Intravenous gamma globulin clinic visits for propionic acidemia and had no relapse DoH: Day of Hospitalization DoH during follow up. Hemophagocytic lymphohistiocytosis is a potentially Figure 1. fatal hyperinflammatory condition caused by a highly Shows the White Blood Cell Count Levels Variation With the Treatment Protocol stimulated but ineffective immune response. HLH can be classified according to the underlying etiology into either primary or secondary. HLH may also occur PLT(103/mm3) as a secondary disorder in association with severe in- 120000 fections, malignancies, rheumatologic disorders and 10000 some metabolic diseases (1). The mechanism is not 80000 60000 clear how the metabolites trigger HLH in inborn errors Dexamethasone , IVIG 40000 IVIG of metabolism. The HLH-2004 diagnostic criteria sug- 20000 gests that to make a diagnosis of HLH, five of the follow- 0 day 1 ing criteria are required: 1) fever for 7 days, 2) Spleno- day 3 day 4 day 5 day 6 day 7 day 8 megaly, 3) unexplained progressive cytopenia of two or PLT: Platelet day 9 3 day 10 day 11 more of three lineages: ANC < 1 × 10 /µL, hemoglobin < 9 IVIG: Intravenous gamma globulin DoH g/dL, platelet count < 100 × 103/µL, 4) hypertriglyceride- DoH: Day of Hospitalization mia > 265 mg/dL or hypofibrinogen-emia, 5) hyperfer- ritinemia > 500 µg/L, 6) increased soluble CD25 > 2400 Figure 2. Shows the Platelet Levels Variation With the Treatment Protocol U/mL, 7) reduction of natural killer cell activity and 8) pathology showing hemophagocytosis (2). Our patient met five of the eight criteria: fever, cytopenia, hypertri- Hb (gr/dl) glyceridemia, hypofibrinogenemia, elevated ferritin, and pathology showing hemphagocytosis. No infec- 15 IVIG IVIG, Dexamethasone tious agent was demonstrated from multiple cultures and by serological evaluations. Our patient did respond 10 to dexamathasone and intravenous gammaglobulin therapy. Removal of cytokines with plasma exchange 5 can help to maintain patients until other therapies have a chance to work. Plasma exchange could not be 0 done effectively in our center. However we recommend day 1 day 3 day 4 initiation of the treatment with steroid and immune day 5 day 6 day 7 day 8 Hb: Hemogolobin day 9 day 10 globulin and if the HLH cannot be taken under control, DoH: Day of Hospitalization day 11 other drugs such as etoposide and cyclosporin A should IVIG: Intravenous gamma globulin DoH be added to the therapeutic regimen. Also in resistant secondary HLH cases, plasma exchange may be consid- Figure 3. ered in terms of removing cytokines and toxins from Shows the Hemoglobin Levels Variation With the Treatment Protocol circulation if available (3, 4). In conclusion this experi- ence suggests that steroid and immune globulin could be considered as a first line therapy in patients with secondary HLH associated by metabolic diseases. Of References course, awareness of the clinical symptoms and diag- 1. Gokce M, Unal O, Hismi B, Gumruk F, Coskun T, Balta G, et al. nostic criteria for hemophagocytic syndrome is crucial Secondary hemophagocytosis in 3 patients with organic acide- Pediatr Hematol Oncol. mia involving propionate metabolism. to start timely lifesaving therapy. The efficacy of thera- 29 2012; (1):92–8. Blood Rev. peutic measures and prognosis depends on degree of 2. Janka GE. Hemophagocytic syndromes. 2007; 21 hypercytokinemia-associated organ failure at disease (5):245–53. onset and underlying disorders. 3. Imashuku S. Differential diagnosis of hemophagocytic syn-

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