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Table of Contents   
REVIEW ARTICLE  
Year : 2018  |  Volume : 11  |  Issue : 1  |  Page : 1-7
Hemophagocytic lymphohistiocytosis in a Nigerian child: A review of the literature


1 Department of Paediatrics, Babcock University Teaching Hospital, Ilishan-Remo, Ogun State, Nigeria
2 Department of Medicine, Adelaide and Meath, National Children's Hospital, Dublin, Republic of Ireland
3 Department of Surgery, Babcock University Teaching Hospital, Ilishan-Remo, Ogun State, Nigeria
4 Department of Medicine, Babcock University Teaching Hospital, Ilishan-Remo, Ogun State, Nigeria

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Date of Web Publication10-Dec-2019
 

   Abstract 


Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, underdiagnosed hematologic disorder that occurs from unregulated immune activation, extreme inflammation, and tissue damage. The major cause of mortality in HLH is a delay in diagnosis and prompt initiation of treatment which occurs due to the variability of the clinical manifestation of this disease entity. We present a case of a 17-year-old adolescent who presented with fever, painful facial swelling that partially resolved with the initial use of intravenous dexamethasone. Diagnosis of HLH was finally made and he had complete resolution of symptoms following appropriate treatment. With careful search, there is no report of HLH in Nigeria and the possibility of missed diagnosis and underdiagnosis cannot be ruled out. This case report of HLH is the first in Nigeria and due to the rarity of the disease the need to raise more awareness is imperative as a high index of suspicion is required for diagnosis.

Keywords: Hemaphagocytosis, hemophagocytic lymphohistocytosis, Nigerian child

How to cite this article:
Solarin AU, Adekunle MO, Obaze RO, Jagun OO, Ogbaro D. Hemophagocytic lymphohistiocytosis in a Nigerian child: A review of the literature. Ann Trop Med Public Health 2018;11:1-7

How to cite this URL:
Solarin AU, Adekunle MO, Obaze RO, Jagun OO, Ogbaro D. Hemophagocytic lymphohistiocytosis in a Nigerian child: A review of the literature. Ann Trop Med Public Health [serial online] 2018 [cited 2020 May 29];11:1-7. Available from: http://www.atmph.org/text.asp?2018/11/1/1/272538



   Case Report Top


A 17-year-old adolescent boy was referred from a private hospital to our facility with complaints of fever and facial swelling of 2-week duration. Facial swelling was initially noticed around the upper and lower eyelids but progressed to involve the entire face [Figure 1]. The swelling was painful, associated with diplopia, photophobia, and blurring of vision. Fever was low grade, intermittent with associated headache, and there was no history of vomiting nor change in bowel habit. He had no significant lymphadenopathy or meningeal irritation signs. He also had no significant family or allergy history. He previously had tuberculosis (TB) in 2013.
Figure 1: (a) The periorbital swelling with conjunctival chemosis; (b) The swollen cheeks

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Initial differential diagnosis included orbital cellulitis, cavernous sinus thrombosis, and angioedema and his blood workup included complete blood count (CBC), renal profile, erythrocyte sedimentation rate, and liver function tests.

He also had a urinalysis and computed tomography (CT) brain and these tests were all unremarkable except for white cell differential showing lymphocytosis of 68%(normal range [NR] 20%–45%), neutropenia 26% (NR 40%–75%), and normal white cell count of 5.3 (NR 4.0–11.0 × 109/ L).

He was treated empirically with intravenous second-generation cephalosporin, and given a dose of an oral anticoagulant at the private hospital for 2 days with no resolution of symptoms hence, his referral to us.

On admission to our facility, marked facial swelling, bilateral periorbital edema with conjunctival chemosis was noticed. There was no proptosis and pupils were equal and reactive to light.

He had no significant lymphadenopathy. There were no cranial nerve deficits and other systemic examination was unremarkable.

He had hematological, biochemical, and radiological investigations repeated. Of note was his raised lactate dehydrogenase (LDH) of 379.2 u/L (NR 135–225 u/L), raised liver function tests with aspartate aminotransferase-114 U/L (10–42 U/L), alanine aminotransferase-150 IU/L (10–42 u/L), alkaline phosphatase-102 U/L (32–92 U/L), and low MCV-70.9 (NR 75–96 fl). His chest X-ray showed right apical fibrotic changes from a previous TB infection and electrocardiogram revealed sinus bradycardia.

Furthermore, CBC showed marginally raised lymphocytes 48.3% (20%–45%).

He was reviewed by our ophthalmology team and fundoscopy revealed no abnormality. A diagnosis of nonspecific orbital inflammation was considered, and as a result, he was commenced on IV dexamethasone 8 mg 8 h and IV ceftriaxone (third-generation cephalosporin) as well as antibiotic eye drops.

His symptoms partially resolved as evidenced by some improvement in facial and periorbital swelling and he was discharged on oral steroids following 7 days of inpatient treatment.

He represented to our institution 5 days postdischarge due to worsening of facial and periorbital swelling.

As a result, he had further re-evaluation with tests including; LDH, C-reactive protein (CRP), CBC, renal and liver profiles, peripheral blood film, autoimmune screen, virology screen (HIV), immunoglobulins, C1 esterase inhibitor levels, and iron levels.

Of note, he had a remarkable increase in his LDH to1296.6 IU/L (NR 135–225 IU/L) and his peripheral blood film showed blast cells, immature granulocytes, and nucleated red blood cells with microcytosis and anisocytosis.

Subsequently, as lymphoproliferative disorder was suspected, he had a CT thorax which showed fibrotic changes bilaterally in the upper lobes, and the lingular likely sequel to an old infective etiology with no enlargement of mediastinal lymph nodes and abdominal ultrasound was normal. Rheumatoid factor was (101 U/ml), antinuclear antibody test was negative, CRP was 2.3 mg/l, serum C3 and C4 complements were 141 mg/dl and 41.8 mg/dl which were essentially normal, anti-double-stranded DNA was negative at a value of 9.91 and serum IgG was normal (1217 mg/dl) and HIV test was negative. Other tests were pending at the time of referral.

A bone marrow biopsy and aspirate were also advised but as the patient deteriorated, his parents opted to seek specialist treatment in an overseas hospital and a detailed letter of referral was obtained from our institution.

Following extensive review in the overseas hospital, he was found to have hemophagocytosis in his bone marrow and liver biopsy. In addition, triglyceride levels were elevated at 210 mg/with ferritin and IL-2R elevated as well with values of 199,800 and 8411, respectively. He was leukopenic with a white cell count of 1.9 × 109/L and anemic as hemoglobin was 9.8 g/dL. He had elevated liver enzymes with an alanine transaminase of 328 U/L and aspartate transaminase 1134 U/L. Clotting profile was deranged with prothrombin time and partial thromboplastin time below 13.6 s and 22.4 s, respectively. He had severe coagulopathy with bleeding from the mouth and peripheral line sites. LDH was also elevated with a value of 1351 dl/L. D-Dimer was markedly elevated with a value of 10,726 ng/ml and beta-D-glucan was above 500 pg/ml. In the course of his investigations, virology screening showed CMV quantitative PCR peaked at 88,242 copies/ml. However, adenovirus and Epstein-Barr virus PCR testing were negative. No primary cause of the disease was identified. Bronchoscopy and bronchoalveolar lavage, CT brain, thorax, abdomen and pelvis, and positron emission tomography-CT scans were also done and were unremarkable. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made as six of the eight diagnostic criteria were met [Table 1].
Table 1: Diagnostic criteria for hemophagocytic lymphohistiocytosis according to the hemophagocytic lymphohistiocytosis-2004 protocol

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Gene analysis for AP3B1, BLOC1S6, ITK, LYST, magnesium transporter 1 deficiency (MAGT1), PRF1, RAB27A, SH2D1A,

SLC7A7, STX11, STXBP2, UNC13D, and XIAP were all negative. The elevated CMV PCR was the only possibility for a secondary cause of HLH.

He was initially treated with interleukin receptor antagonist (anakinra) but symptoms worsened with the development of coagulopathy and deranged liver function tests. His treatment regimen was then changed to antithymocyte globulin, etoposide, and high-dose dexamethasone according to HIT-HLH protocol. He had seven courses of etoposide weekly with marked improvement of his clinical and laboratory parameters.

Following chemotherapy, he had fungal pneumonia as a complication from high-dose dexamethasone due to immunosuppression. He was readmitted for 10 days and was treated with oral voriconazole while being weaned off steroid therapy.

He improved significantly and at discharge, facial and periorbital swelling was minimal, hepatomegaly of 4 cm reduced significantly to 1 cm, coagulopathy resolved, and marked improvement in the laboratory parameters noticed [Table 2].
Table 2: Laboratory results

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   Introduction Top


HLH is a rare but fatal hematologic disorder with a mortality rate of 95% if untreated.[1] It is a clinical condition that is underdiagnosed by the health physicians.[1] It results from excessive immune activation and tissue damage.[1] HLH also known as hemophagocytic syndrome was first reported by two Scottish pediatricians, Farquhar and Claireaux,[2] in 1952 following an autopsy finding of hemophagocytosis in organs of two infants that died from the disease. Scott and Robb-Smith[3] were scientists that first described HLH in 1939 as a syndrome with histiocyte proliferation.

Epidemiology

No racial or sex predilection to HLH, however, there disparity in its occurrence from one region to another.[4] In Sweden, the incidence is 1.2 cases/1,000,000 which is equivalent to 1 in 50,000 live births.[5] In Japan and North America, its occurrence rate is 1 in 800,000 and 1 in 3000 cases, respectively.[6],[7] A higher incidence of 7.5 in 10,000 in Turkey is due to high prevalence of perforin gene defect and consanguinity.[8] Seasonal variation of HLH with a higher occurrence in summer has also been reported.[9]


   Etiology Top


HLH is a disease caused by excessive immune activation of cytotoxic cells, Natural Killer (NK) cells, and macrophages.[9] It occurs either as a primary genetic or sporadic disease. Sporadic disease also known as secondary HLH can be triggered by a malignancy, immune suppressants, immunodeficiency, metabolic disorders, or infection.[10] It can also occur in individuals that had stem cell or organ transplantation.[11] Infection can be a trigger of both genetic and sporadic HLH.[12]

Familial HLH (FHL) which is an autosomal recessive disease usually occur before 2 years of age but late diagnosis even in adults above 60 years has been made.[4] Gene for familial HLH was first mapped out in four families with FHL to the long arm of chromosome 9.[13] However, in seventeen families with FHL, the genetic locus was found on the long arm of chromosome 10, an evidence for its heterogeneity.[14] There are five genetic causes of familiar HLH but clinical genetic testing is available for all except Type 1. FHL Type 2-5 is caused by mutation in the PRF1, UNC13D, STX11, and STXRP2 gene, respectively.[15] In general, 50%–60% of HLH in children has no identified gene defect, but in Japan, over 80% cases are caused by defect in PRF1 or UNC13D gene [Table 3].[11],[16]
Table 3: Classification of hemophagocytic lymphohistiocytosis

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Some immunodeficiency syndrome can manifest primarily as HLH. This has been documented in diseases such as Chediak–Higashi syndrome, X-linked proliferative syndrome Type 1 and 2, Griscelli syndrome Type 2, and Hermansky–Pudlak syndrome 2 and 9 involving mutation of LYST, SH2D1A, XIAP, RAB 27, AP3B1, and BLOC1S6, respectively.[17]

Epstein–Barr virus (EBV) is the most common infective cause of HLH in both genetic and sporadic diseases.[18] Increase susceptibility to EBV and lymphomas are seen in MAGT1 and IL2 inducible T-cell kinase deficiency and persons with these conditions can present with HLH.[19] Cytomegalovirus infection and histoplasmosis are the second most common cause of acquired HLH.[5] Other viral agents linked to HLH are HIV, parvovirus, and hepatitis virus.[20] Candida species and some other fungi have been linked to HLH; also, Plasmodium vivax, Leishmania sp, and Toxoplasma gondii are triggers of HLH. Solid organ transplantation can be complicated by HLH.[20] Most reported organ transplant-related HLH cases were associated with viral infection such as EBV, cytomegalovirus and herpes virus. HLH can also occur in malignancy, most especially non-Hodgkins lymphomas and leukemias of T-cell lineage.[7]


   Pathophysiology Top


HLH results from uncontrolled immune response to various stimuli.[11] Impairment in macrophages, NK-cells, and cytotoxic T-cells in response to an inflammatory cascade triggered by antigenic stimuli underlies the manifestation of HLH.[21] Dysfunctional immune response and inflammation cascade cause hypercytokinemia that leads to excessive release of IL-1, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon γ, CD25 (a soluble interleukin-2 alpha receptor).[10],[21] Cytokines released stimulates the proliferation of macrophages, cytotoxic T-cells and NK-cells. Excessive cytokines infiltrate organs and cause hyperinflammation that result in tissue destruction and multiorgan failure.[10]

Perforin granules released by NK-cells creates pore within the target cell membrane. Granzymes are also released by NK-cells and they enter the cells through the created pores by perforin to cause apoptosis.[18] Mutations in perforin with defective apoptosis have been linked to the etiology of most FHL.[22]

Clinical manifestations of HLH are due to the excessive stimulation of inflammatory cytokines. Bone marrow suppression occurs in HLH from the toxic effect of IFN-γ and TNF-α and the occurrence of hemophagocytosis. Interleukins and TNF-α induce fever and clinical manifestation of hypertriglyceridemia is due to inhibition of lipoprotein lipase by TNF-α. Direct infiltration of the liver and spleen by macrophages and lymphocytes causes hepatosplenomegaly.[23],[24]


   Clinical Manifestations Top


Clinical manifestations of HLH vary and can mimic overwhelming sepsis, Kawasaki disease, and multiple organ failure.[7] The variability of manifestations in HLH results in delay diagnosis that worsens the clinical outcome.[25] The diagnosis of HLH can be established if one of either 1 or 2 criteria is met: A molecular diagnosis consistent with HLH is an established sole criterion for diagnosis of HLH. Five out of eight criteria of the following can also be used in the diagnosis of HLH; fever, splenomegaly, cytopenias (affecting 2–3 lineages in the peripheral blood), hypertriglyceridemia and/or hypofibrinogenemia; fibrinogen ≤1.5 g/L; hemophagocytosis in bone marrow, spleen, or lymph nodes; low or absent NK-cell activity; ferritin ≥500 μg/L; and soluble CD25 (i.e., sIL2r) ≥2400 U/ml. In the index case, criteria meet for HLH diagnosis were hemophagocytosis in bone marrow biopsy, fever, hypofibrinogenemia, hyperferritinemia, and increased IL-2R.[26] [Table 2] Importantly, diagnostic criteria for HLH does encompass all the typical presentations that can occur and there is need for a high index of suspicion.[26]

Early clinical presentation of HLH is unspecific but common presentations are prolonged fever, cytopenia, and hepatosplenomegaly which can be a manifestation of many disease conditions such as acute leukemia.[7],[25] Other manifestations that can occur in HLH are severe diarrhea, lymphadenopathy, edema, and jaundice. Bleeding from various sites can occur from coagulopathy and thrombocytopenia.,[7],[24],[27] Rash occurs in 65% of cases of HLH and has been described as generalized purpuric, macular rash, or erythroderma.[28] The central nervous system involvement can present as seizure, altered consciousness, irritability, cranial nerve palsy, peripheral neuropathy, sensorineural deafness, and lymphocytic meningitis.[7],[29],[30] Neuroimaging is not specific in HLH and hypodense or necrotic area may be seen.[31]


   Laboratory Findings Top


Cytopenia involving at least two cell lines is seen in over 80% cases of HLH and its occurrence should lead to the suspicion of HLH.[22],[32]

Hemophagocytosis occurrence in the bone marrow, lymph nodes, and/or spleen without an evidence of malignancy is a manifestation of HLH. It is characterized by the presence blood cell lines or their fragments within the cytoplasm of the macrophage. Hemophagocytosis is not pathognomonic for HLH and its presence might not be seen at the onset of the illness.[33]

Hyperferritinemia above 10,000 μg/L is a sensitive and specific diagnostic marker for HLH.[34] The rate of decline of ferritin level following the commencement of therapy also is a prognostic marker. Less than 50% decline of ferritin from the initial value prior commencement of therapy was associated with more than 17 times mortality than those with a higher decline.[35] Serum ferritin is relatively accessible compared to other diagnostic markers such as IL-2R, and also, the results are usually available within 24 h; these are factors that make it a readily available diagnostic marker in HLH.[36] Elevated ferritin and LDH levels were the most consistent findings noticed by Henter et al.[26] even though LDH is not a diagnostic tool. NK-cell dysfunction and activity is also a diagnostic marker in HLH.

This study has shown that elevated soluble IL-2R is a poor prognostic marker in HLH.[37] CD25 is an inflammatory marker that correlates consistently with recent disease activity but its use compared to ferritin is limited because the test is not readily available in most facilities.[7],[37]

Coagulopathy occurrence in HLH is due impairment in hepatic function and/or disseminated intravascular coagulopathy.[38] Elevated prothrombin time, partial thromboplastin time, and/or positive D-Dimer are test done in evaluating coagulopathy.[38] Hepatitis manifestation with deranged liver function test is very common in HLH and it is a manifestation seen mostly in sporadic HLH.[18] On liver histology, histiocytes with or without hemophagocytosis are seen.[18] Elevated liver enzyme markers such as LDH, bilirubin, aminotransaminases, and hypoalbuminemia are common presentations.[7]

Cerebrospinal fluid pleocytosis can occur in HLH with CNS manifestations. Elevated CSF protein, histiocytes, and hemophagocytosis can also be seen.[39]


   Treatment Top


Modalities of treatment of HLH include immunomodulation, immunosuppression, chemotherapy, and use of biological response modifiers.[7],[23],[26] Early identification of HLH and prompt therapy is key to the survival of patients with HLH.[5] Before the recommendation of Histiocyte Society in 1994, on treatment protocols for HLH (HLH-94 protocol), the use of chemotherapy or immunotherapy alone resulted in mortality rate as high as one hundred percent.[40],[41] HLH-94 protocol[42] included the use of chemotherapy, immunotherapy with intrathecal methotrexate in patients with CNS manifestations. Induction therapy for the first 8 weeks aimed at suppression of the hyperinflammatory processes. The medications given were epipodophyllotoxin and dexamethasone with cyclosporin A which is given at the end of the induction phase. Dexamethasone is commenced at 10 mg/m2 daily for the first 2 weeks with half reduction in dosage every 2 weeks and 1.25 mg/m2 dosage in the past 2 weeks. Intravenous etoposide is given at 150 mg/m2 twice weekly for the first 2 weeks and then reduced to a weekly dose for the remaining 6 weeks. Cyclosporine is given at 6 mg/kg/day with the maintenance of blood level at 200 μg/L. The retrospective review of children treated with HLH-94 resulted in a survival rate of 37.5 months in 56%.[43] Following the successes of HLH-94 protocol, a further review to increase the survival outcome has led to HLH-2004 protocol.[26] The difference in the recent compared to HLH-94 is the commencement of cyclosporine at the onset of treatment and the addition of prednisolone to CNS therapy. Reduction in the dose of etoposide has been postulated in patients with creatinine clearance <50 ml/min and direct bilirubin above 3 mg/dl.[7]

Continuation therapy recommended for patients with familial disease, persistent sporadic disease and with relapse symptoms. This comprises of pulses of dexamethasone and intravenous etoposide which is given prior hematopoietic stem cell transplantation.[26]

The introduction of biologic agents directed specifically at the inflammatory cytokines has been shown to be effective. Alemtuzumab, a monoclonal antibody to CD52 has been shown to be useful in refractory HLH and rituximab reduces EBV viral load and circulating B-cells.[7],[44],[45]

Supportive treatments for patients with HLH include prophylaxis for Pneumocystis jirovecii, broad-spectrum antibiotics, antifungal, intravenous immunoglobulin, granulocyte colony stimulating factor, and blood products.[7]

Allogeneic stem cell transplantation (allo-HSCT) is the only curative therapeutic option in FHL.[26],[32],[42],[46] A search for an appropriate donor should be commenced and HSCT instituted as soon as there is complete resolution of symptoms. Active disease process and HLA-haploidentical HSCT are poor prognostic factors of HSCT. In a retrospective study on cases with FHL that had HSCT, overall survival rate of 5 years was 58.5%.[47] The most common complications were veno-occlusive disease and graft-versus-host-disease.


   Conclusion Top


HLH is a rare, life-threatening disease, and underdiagnosed in our environment. The outcome of HLH is dependent on early diagnosis and immediate institution of therapy. Its nonspecific clinical presentation would possibly have accounted for its underdiagnosis in our environment. There is a need for a high index of suspicion for HLH. Early diagnosis and prompt institution of therapy cannot be overemphasized.

Acknowledgment

We wish to thank the parents of our patient for consenting to our writing this report and providing us with the results of the investigations done outside the country.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Dr. Adaobi Uzoamaka Solarin
Department of Paediatrics, Babcock University Teaching Hospital, Ilishan-Remo, Ogun State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ATMPH.ATMPH_797_16

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