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A rare case of secondary hemophagocytic lymphohistiocytosis with severe acute malnutrition in an infant

 Department of Pediatrics, Kalinga Institute of Medical Sciences, KIIT Deemed to be University, Bhubaneswar, Odisha, India

Date of Submission23-Aug-2021
Date of Decision04-Oct-2021
Date of Acceptance25-Nov-2021

Correspondence Address:
Nirmal Kumar Mohakud,
Department of Paediatrics, Kalinga Institute of Medical Sciences, KIIT Deemed to be University, Bhubaneswar - 751 024, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_693_21


Hemophagocytic lymphohistiocytosis (HLH) is a rare hematological entity in children that presents with unremitting fever, organomegaly, cytopenias, hemophagocytosis by activated macrophages, and results in a fatal outcome in untreated cases. Other biochemical abnormalities include hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, increased soluble interleukin-2 receptor levels, histological evidence of benign hemophagocytic macrophage, and impaired natural killer cell activity. It is the result of an aberrant hyper inflammatory response that usually does not respond to conventional treatment. Secondary HLH is mostly associated with infection, malignancy, and autoimmune diseases and usually resolves on the treatment of the primary condition. Severe acute malnutrition (SAM) causing secondary HLH is rare, although hemophagocytosis in bone marrow without other diagnostic features of HLH is seen in many deficiency states including SAM. Here, we present a 1-year-old female child with SAM and secondary HLH focusing on clinical manifestation, diagnosis and treatment.

Keywords: Hemophagocytic lymphohistiocytosis, hyperferritinemia, Hypertriglyceridemia, severe acute malnutrition

How to cite this URL:
Mohakud NK, Sahu SK. A rare case of secondary hemophagocytic lymphohistiocytosis with severe acute malnutrition in an infant. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2023 Mar 20]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=339735

  Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a rare hematological disorder in the pediatric population with a potentially fatal outcome in untreated cases. The incidence is about 1.2 cases in every 1 million pediatric populations below 15 years.[1] It is the consequence of an atypical hyper-inflammatory condition due to impaired natural killer (NK) cell and cytotoxic T cell function. Corticosteroids are the mainstay of therapy as they suppress the excessive immune response by inhibiting cytokine expression. However, intravenous immunoglobulin (IVIG) is used more commonly due to its broader action of cytokine neutralization, modulation of T cell and Fas/fas ligand pathway, and downregulation of complement activation.[2] After an extensive literature search, no data on secondary HLH caused by severe acute malnutrition (SAM) was found. The dilemma in diagnosis and management of a child with SAM and HLH is challenging. We present our experience of a case of a 1-year-old female infant diagnosed with SAM and secondary HLH.

  Case Report Top

A 1-year-old female child presented with chief complaints of intermittent fever and abdominal fullness for 1 month, bilateral swelling of feet for 4 days, and red spots on the right foot for 1 day. She had a history of blood transfusion 2 days before admission to our hospital. There was no history of any chronic illness. The child was delivered at home, at term with birth weight 2.4 kg, cried immediately after birth, and no history of hospitalization thereafter. She had a 6-year-old elder sister doing well.

On examination, the child was febrile, having severe pallor, bilateral pedal edema, enlarged cervical lymph node, and distended abdomen with hepatosplenomegaly. Anthropometry revealed weight 6 kg and length 67 cm (z-score <−3 SD) indicating SAM. The child was admitted with a provisional diagnosis of lymphoreticular malignancy and congenital hemolytic anemia with SAM. Routine hematological parameters revealed low hemoglobin with dimorphic anemia (microcytic, hypochromic, and macrocytic), low red blood cell count, low platelets, increased reticulocyte count, and no atypical cells in peripheral smear. C-reactive protein was 92 mg/L and erythrocyte sedimentation rate was 48 mm in 1st h [Table 1]. Infections such as malaria, typhoid, dengue, and scrub typhus were excluded by appropriate investigation. In view of the ongoing pandemic real time polymerase chain reaction for SARS-CoV-2 was done which was negative and antibody level was 1.55 signal to cut off ratio (geometric mean of SARS-CoV-2 neutralizing antibodies expressed relative to the candidate International Standard; >1 is considered as protective). Urine and blood culture was sterile. High-performance liquid chromatography showed sickle cell trait and direct Coombs test was negative. Markers for EpsteinBarr virus, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, and rubella were negative. Ultrasonography of the abdomen revealed hepatosplenomegaly with mild ascites.
Table 1: Observed values of various hematological and biological parameters

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Biochemical investigations revealed increased serum transaminases, low serum protein, normal renal function, low Vitamin B12, folic acid, serum ferritin, and normal serum triglyceride [Table 1]. In view of fever, splenomegaly, and bicytopenia (low hemoglobin and low platelets), the diagnosis of HLH was thought of and serum fibrinogen and bone marrow study was done. Serum fibrinogen was 149 mg/dL (low) and in bone marrow biopsy there were features of erythroid hyperplasia, phagocytosis of erythroid precursors, and platelets by macrophage, without any evidence of malignancy [Figure 1]. As it fulfilled the 5 out of 8 diagnostic criteria, the child was diagnosed as a case of secondary HLH with SAM with sickle cell trait.
Figure 1: Bone marrow biopsy showing haemophagocytosis of erythroid precursors and platelets by macrophage (arrow)

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  Management and Outcome Top

The treatment of SAM was started as per WHO protocol. Apart from packed red blood cell transfusion (10 ml/kg) and other supportive measures, the child was treated with a pulse dose of methylprednisolone (20 mg/kg/day) for three days followed by oral prednisolone (1 mg/kg/day for 7 days and tapered over next 7 days). Considering the immunocompromised condition in SAM and administration of pulse dose of methylprednisolone, empiric broad-spectrum antibiotic (ceftriaxone 75 mg/kg/day) was given for 5 days in spite of sterile urine and blood culture.[3] The mother was counseled regarding the feeding, the child was started on F75 formula followed by F 100 along with multivitamin supplements. Iron and folic acid were started after 7 days. The child responded well with defervescence of fever within 48 h and gradually her counts improved. She was discharged in a stable condition after 14 days of admission with a progressive weight gain of 20 g/day.

  Discussion Top

HLH is a rare hyperinflammatory hematological condition due to the abnormal functioning of NK cells and cytotoxic T cells. Transformed macrophages (hemophagocytic histiocytes) invade bone marrow, spleen, lymph nodes, liver, and skin leading to the manifestations of multiorgan failure. The presenting features are unremitting fever, hepatosplenomegaly, cytopenias, haemophagocytosis by activated macrophages along with hyperferritinemia, hypertriglyceridemia, hypofibrinogemia, increased soluble interleukin-2 (IL-2) receptor levels, histological evidence of benign hemophagocytic macrophage, and impaired NK cell activity on flow cytometry.[4] Hypercytokinemia and hyperchemokinemia due to hyperactivation of antigen-presenting cells (macrophages, histiocytes) and CD8+ T cells cause progressive organ dysfunction. Overproduction of IL-1, IL-6 and tumor necrosis factor leads to unremitting fever.[5] Upregulation of heme-oxygenase in response to hypercytokinemia causes hyperferritinemia, whereas inhibition of lipoprotein lipase causes hypertriglyceridemia.[6] The activation of macrophages and secretion of plasminogen activator leads to hypofibrinogemia.[7] Peripheral cytopenia is due to phagocytosis of blood cells in the bone marrow. HLH is categorized into two types: Primary (inherited) and secondary (associated with infection, malignancy, autoimmune diseases, etc.). Despite diagnostic guidelines being available (Revised Diagnostic Guidelines for HLH 2004), it is often under-diagnosed.[1] The overall mortality has been documented to exceed 50% and most of the patients have been reported to die within the first 2 months of treatment.[8]

The association of SAM with HLH has been hardly reported in literature and this is the maiden instance of secondary HLH in a SAM infant to be reported. Although at admission, it was suspected to be a case of lymphoreticular malignancy and congenital hemolytic anemia, investigation revealed it to be a case HLH. There are certain studies that mention the presence of hemophagocytes in bone marrow in malnutrition and some deficiency states such as low serum hydroxycobalamin levels and iron deficiency anemia.[9],[10] Micronutrients act as cofactors and immune modulators in immune function and various immune reactions. Their deficiency may be responsible for aberrant immune reactions. Although hyperferritinemia and hypertriglyceridemia are important features of HLH, normal serum ferritin, in this case, is due to iron deficiency as evidenced by microcytic, hypochromic anemia, and depletion of iron stores as evidenced by iron profile. Although the biochemical parameters would have been influenced by the history of recent blood transfusion, not the case for serum ferritin and folic acid level.[11] Normal serum triglyceride may be attributed to deficiency of protein and lipids especially lipoproteins in SAM.

  Lessons Learnt Top

HLH should be a differential diagnosis in children presenting with prolonged fever, organomegaly with cytopenias, not responding to routine management modalities. As the signs, symptoms, and abnormalities of laboratory parameters in HLH evolve over time, children may not manifest all the findings at a particular point of time. In case of non-availability of IVIG, pulse methylprednisolone is good enough to treat HLH. It is time for the health care professionals to think beyond infections in children with prolonged fever.


We are grateful for the co-operation of parents and the KIMS Hospital. Our special thanks to Dr. Ranjana Giri, MD pathology for providing the photograph and Dr. Mirabai Das, MO, KISS University for her helps in data collection and counseling the parents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 1
Freeman B, Rathore MH, Salman E, Joyce MJ, Pitel P. Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome. J Pediatr 1993;123:479-81.  Back to cited text no. 2
Szabados F, Michels M, Kaase M, Gatermann S. The sensitivity of direct identification from positive BacT/ALERT™(bioMérieux) blood culture bottles by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is low. Clin Microbiol Infect 2011;17:192-5.  Back to cited text no. 3
Janka GE. Hemophagocytic syndromes. Blood Rev 2007;21:245-53.  Back to cited text no. 4
Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis 1999;179:S294-304.  Back to cited text no. 5
Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: Unleashing the protective properties of heme. Trends Immunol 2003;24:449-55.  Back to cited text no. 6
Freeman HR, Ramanan AV. Review of haemophagocytic lympho histiocytosis. Arch Dis Child 2011;96:688-93.  Back to cited text no. 7
Sahu SK, Behera JR, Das P. Managing pediatric haemophagocytic lymphohistiocytosis (HLH) in a resource limited setting – A 3 years experience. Int J Res Pharm Sci 2020;11:5965-70.  Back to cited text no. 8
Dokmanović L, Krstovski N, Lazić J, Rodić P, Milosević G, Janković S, et al. Extreme hypertriglyceridemia in an infant with hemophagocytic lymphohistiocytosis and hydroxycobalamin deficiency. Srp Arh Celok Lek 2015;143:744-7.  Back to cited text no. 9
Kotwal J, Singh V, Kotwal A, Dutta V, Nair V. A study of haematological and bone marrow changes in symptomatic patients with human immune deficiency virus infection with special mention of functional iron deficiency, anaemia of critically ill and haemophagocytic lymphohistiocytosis. Med J Armed Forces India 2013;69:319-25.  Back to cited text no. 10
Ho CH. The effects of blood transfusion on serum ferritin, folic acid, and cobalamin levels. Transfusion 1992;32:764-5.  Back to cited text no. 11


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