SUDANESE JOURNAL OF PAEDIATRICS

2023; Vol 23, Issue No. 2

ORIGINAL ARTICLE

Paediatric haemophagocytic lymphohistiocytosis: clinical presentation and outcome of 20 patients at a single institution

Haifa Ali Bin Dahman (1), Ali Omer Aljabry (2)

(1) Associate Professor, Pediatric Department, Hadhramout University College of Medicine (HUCOM), Al-Mukalla, Yemen

(2) Pediatric Neuro-Psychiatry, Care Hospital, Nairobi, Kenya

Correspondence to:

Haifa Ali Bin Dahman

Associate Professor, Pediatric Department, Hadhramout University College of Medicine (HUCOM), Al-Mukalla, Yemen.

Email: Bin_Dahman.H [at] hotmail.com

Received: 30 July 2020 | Accepted: 18 February 2023

How to cite this article:

Dahman HAB, Aljabry AO. Paediatric haemophagocytic lymphohistiocytosis: clinical presentation and outcome of 20 patients at a single institution. Sudan J Paediatr. 2023;23(2):199–213.

https://doi.org/10.24911/SJP.106-1659160002

ABSTRACT

Paediatric haemophagocytic lymphohistiocytosis (pHLH) is a potentially life-threatening condition with significant diagnostic and therapeutic difficulties. The purpose of this study was to describe the clinical presentation, the diagnostic challenges, and the outcomes of haemophagocytic lymphohistiocytosis (HLH) in children assessed at Mukalla Hospital, Yemen. Data from 20 medical records of HLH patients admitted between January 2010 and May 2022 were retrospectively analysed. The median age at presentation was 3.5 ± 5.1 years. Male: female ratio was 1:1. The median time for referral to the hospital was 30 ± 64 days. The most common clinical manifestations were fever and pallor in 95% of cases, and splenomegaly (85%). Hepatomegaly, chest, renal and neurological manifestations were detected in 80%, 45%, 15% and 20% of cases, respectively. Bone marrow haemophagocytosis was detected in 60% of cases. Sixteen patients fulfilled the HLH diagnostic criteria, and 11 patients (55%) received the HLH 2004 protocol. Out of the 20 patients, three (15%) patients are alive. Fourteen patients died, with overall mortality of 82.35%. All mortalities were due to HLH disease with multi-organ failure. Relapse was noticed in five patients either during treatment or after full recovery. pHLH is a challenging emergency with a high mortality rate. High clinical suspicion is essential for early detection and intervention to improve the prognosis.

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KEYWORDS:

Cytokine; Familial; Ferritin; Haemophagocytosis; Haemophagocytic lymphohistiocytosis; Pancytopenia.

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INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition associated with infections (viral, bacterial, and parasitic), malignancies, rheumatologic conditions and immune deficiencies [1,2]. It is classified into primary (familial) and secondary (reactive) disease. Sharing the same spectrum of non-specific symptoms between these two subtypes raises the challenge of accurate diagnosis and rapid treatment initiation [3].

About 1 in 100,000 children under the age of 18 are thought to have HLH. However, this estimation is likely to be low [2], and now it is increasingly recognised [4].

Despite recent advances in research, a lot of curiosity surrounds the pathogenesis of HLH [5]. The aetiology of HLH is attributed chiefly to defective (low or absent) cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells’ Ag-mediated cytotoxicity [6]. This dysfunction results in a cytokine storm, causing damage to the vascular endothelium and myelosuppression [7,8].

The systemic infiltration of activated lymphocytes and macrophages causes hematologic cytopenias, liver dysfunction, coagulopathy, lymph node enlargement, splenomegaly, skin rash, oscillating fevers and central nervous system (CNS) manifestations ranging from seizures and/or localised deficits to encephalopathy [9]. High mortality risk accompanies the acute stage of the disease [7]. Delay in diagnosis and initiation of immunosuppression results in a rapid progression to multi-system organ failure (MOF) [10]. Allogeneic bone marrow (BM) transplantation is indicated in familial, relapsing, or severe/persistent cases [11].

In this study, we retrospectively describe the clinical features, diagnostic issues, and treatment outcomes of children with HLH at a single institution in Yemen over 12 years. To the best of our knowledge, this is the first case series of paediatric HLH (pHLH) from Yemen reported in the literature.

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MATERIAL AND METHODS

A retrospective study was conducted at Mukalla Maternity and Childhood (MCH) Hospital, in Mukalla City, Hadhramout Province, Yemen, from January 2010 through May 2022. The criteria for diagnosis were based on the proposed 2004 HLH diagnostic criteria of the Histiocyte Society (Table 1) [11,12].

Case records of children diagnosed with HLH were reviewed. The following details were collected and analysed: age at presentation, sex, relevant family history, presenting clinical features (fever, hepatosplenomegaly, lymphadenopathy, skin rash, bleeding tendency, jaundice, oedema, chest manifestations, CNS manifestations and renal impairment), laboratory investigations, aetiology, the referral time, which is the lag period between disease onset and first presentation to the hospital, treatment used, and outcomes. Primary HLH was highly suspected in patients with a younger age group, positive parent consanguinity, and a family history of the same presentation. However, genetic studies were needed for confirmation as the viral infection might trigger both primary and secondary HLH (sHLH). Fibrinogen, sCD25, and NK cell function were done in a few patients who could travel abroad for further evaluation. Genetic studies were not available in our country. Some patients in our study did not meet defined diagnostic criteria. However, they were still diagnosed and treated as HLH at our institution. They were included in the current study as the clinical course supported the diagnosis. On the day of diagnosis, therapeutic options included the use of supportive treatment, corticosteroids (dexamethasone, methylprednisolone) alone or with intravenous immunoglobulin (IVIG), etoposide, cyclosporine (CSA), mycophenolate mofetil (MMF), and methotrexate (MTX). Relapse was defined as disease reactivation after clinical and laboratory remission; the patient develops ≥3 of 8 diagnostic criteria or new CNS symptoms. MOF was defined as a disease requiring resuscitation, mechanical ventilation, or inotropic support.

Statistical methods

All collected data were entered and analysed using SPSS 24. Descriptive statistics, including frequencies, percentages, medians, SDs and graphs, were applied.

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RESULTS

During the study period of 12 years, 20 patients (2010–2015=6, 2016–2022=14) were diagnosed and treated for HLH. The age ranged from 0.14 to 14 years, with a 1:1 male: female ratio. The median age at diagnosis was 3.5 ± 5.2 years. Fever of unknown origin was the most common presentation on admission (65%). The median time for referral was 30 ± 64 days (2010–2015=90 ± 58.9 days, 2016–2022=21 ± 59 days).

Table 1. HLH-2004 diagnostic criteria.

The diagnosis HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular diagnosis consistent with HLH

(2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below)

(A) Initial diagnostic criteria (to be evaluated in all patients with HLH)

Fever

Splenomegaly

Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood): haemoglobin <90 g/l (in infants <4 weeks: haemoglobin <100 g/l), platelets <100 × 109/l, neutrophils <1.0 × 109/l

Hypertriglyceridemia and/or hypofibrinogenaemia: fasting triglycerides ≥3.0 mmol/l (i.e., ≥265 mg/dl) Fibrinogen ≤1.5 g/l.

Haemophagocytosis in BM or spleen or lymph nodes. No evidence of malignancy

(B) New diagnostic criteria

Low or absent NK-cell activity (according to local laboratory reference)

Ferritin ≥500 mg/l

Soluble CD25 (i.e., soluble IL-2 receptor) ≥2,400 U/ml

Other abnormal clinical and laboratory findings consistent with the diagnosis are: neurologic symptoms, lymphadenopathy, jaundice, oedema, skin rash. Hepatic enzyme abnormalities, hypoproteinaemia, hyponatremia, increase VLDL, decrease HDL. HDL, high-density lipoprotein; HLH, haemophagocytic lymphohistiocytosis; VLDL, very low density lipoprotein.

HLH was attributed to different aetiologies including infection (leishmania=2, Dengue=1, non-specific infection=4), haematology/oncology (leukaemia=1, sickle cell anaemia=1), rheumatology (systemic lupus erythematosus (SLE)=1, systemic juvenile idiopathic arthritis (sJIA)=1), and primary immunodeficiency (Griscelli syndrome (GS2)=2, Chediak-Higashi (CHS)=2, severe combined immunodeficiency (SCID)=1). The underlying cause was not identified in four cases. Parental consanguinity was detected in 11 (55%) cases and a family history of sibling death with a similar presentation was noticed in seven (35%) cases (Tables 2 and 3).

The most common clinical and laboratory manifestations are shown in Figures 1 and 2.

Treatment and outcomes

IVIG and steroids (dexamethasone or IV methylprednisolone) were used in 11 (55%) and 13 (65%) cases, respectively. Chemotherapy was initiated in nine children with HLH who did not respond to IVIG and steroids; etoposide in four (44.4%) patients, CSA in eight (88.9%) patients, and MMF in one (11.1%) patient. Intrathecal MTX was used in one patient with encephalopathy. One patient was critically ill; he was not fit for chemotherapy. Four patients did not start a specific HLH protocol as they were lost to follow-up. The use of biologics and hematopoietic stem cell transplantation (HSCT) was not a practical option for our patients. Out of 20 children with HLH, two (10%) recovered completely, and one is still on treatment. 14 patients died, giving overall mortality of 82.35%. During hospitalisation, extensive flesh-eating infection, intestinal obstruction, transfusion-associated graft versus host disease, and gastrointestinal bleeding (upper and lower) were noticed. Five patients died after relapse. One patient relapsed during treatment and four patients relapsed 2–10 months after full recovery; one patient had progressive encephalopathy (hemiplegia, left-sided facial palsy, and loss of consciousness), and another patient was not compliant with maintenance treatment of SLE. She presented with a history of recurrent blood transfusion and died with intractable heart failure. The last two presented with progressive HLH that was complicated with convulsions and coma. All deaths were attributed to disease reactivation with MOF (Tables 2 and 3).

Table 2. Clinical and laboratory parameters of HLH cases at Mukalla MCH Hospital, Yemen.

No.	1	2	3	4		5	6	7	8	9
Year	2012	2012	2013	2013	2014	2014	2016	2016	2018
Clinical parameters
Age	14 years	8 months	4 years	8 years		3 years	14 years	3.5 months	10 years	12 years
Sex	M	M	F	F		M	F	M	F	F
Fever >1 week	Yes	Yes	yes	Yes		Yes	Yes	Yes	No	Yes
pallor	Yes	Yes	Yes	Yes		yes	Yes	Yes	No	Yes
Jaundice	Yes	No	No	No		No	No	No	No	Yes
Splenomegaly	Yes	Yes	Yes	Yes		Yes	No	Yes	Yes	Yes
Hepatomegaly	Yes	Yes	Yes	Yes		Yes	No	Yes	No	Yes
Lymphadenopathy	Yes	No	No	No		No	No	No	No	Yes
Rash	No	Yes	yes	Yes		No	Yes	No	No	No
Bleeding tendency	Yes	No	No	Yes		No	No	Yes	No	No
oedema	Yes	No	No	Yes		Yes	No	No	No	No
CNS manifestation	No	No	No	No		No	No	seizure	seizure	No
Chest manifestation	Crepitation	No	No	Crepitation		No	(pain, SOB)	No	No	No
Renal impairment	No	No	No	No		No	Yes	Yes	No	No
Special features	Loss of weight Loss of appetite					Flesh eating infection	Vasculitic rash Bradycardia Mouth ulcer arthralgia	Intestinal obstruction	Rec. encephalitis Papilledema Hemiplegia Lt sided facial palsy
Laboratory parameters
WBC	Low	Low	Low	Low		Low	Low	Low	N	Low
Haemoglobin	Low	Low	Low	Low		Low	Low	Low	N	Low
Platelets	Low	Low	Low	Low		Low	N	Low	N	Low
Fibrinogen	-		-				-	-	-	-
Triglyceride	High	N	High	High		High	High	High	High	High
Ferritin	High	High	High	High		High	High	High	High	High
ALT/AST	High	N	High	N		N	N	High	N	High
LDH	High	N	High	N		High	N	High	N	High
PT/PTT/INR	N	N	N	N		N	N	High	N	N
sCD 25	-	-	-	-		-	-	-	-	-
NK activity	-	-	-	-		-	-	-	-	-
BM haemoph- agocytes	Yes	Yes	Yes	Yes		Yes	No	Yes	Not done	Yes
Treatment, causes and outcome
Initial diagnosis on admission	FUO	FUO	FUO		FUO	SCA	FUO	Griscelli	Griscelli + encephalitis	FUO
possible cause	Leukaemia	Not identified	Leishmania		Viral infection	SC crisis	SLE	Accelerated phase	(Accelerated phase)	Viral induced
Lag period from first presentation	6 months	6 months	3 months		3 months	3 months	4 weeks	10 days	2 weeks	3 weeks
Family History	No	Yes	No		No	No	No	Yes	Yes	No
consanguinity	No	Yes	Yes		No	Yes	No	yes	Yes	No
treatment	ALL Induction therapy	HLH2004 protocol (Dexa/IVIG/ CSA/etopside)	Pentostam		None	HLH2004 protocol (Dexa/IVIG/ CSA/ etopsid)	HLH 2004 protocol (Dexa/IVIG/MMF)	HLH2004 Protocol (IVMP/CSA/IVIG)	HLH 2004 protocol Dexa/CSA/IVIG/ ITMTX)	None
Outcome	Died	Relapse (Died)	Died		Loss FU	Died	Relapse (Died)	Relapse (Died)	Relapse (Died)	Loss FU

ALL, Acute lymphoblastic leukaemia; CSA, cyclosporine; Dexa: dexamethasone; FUO, fever of unknown origin; FU, Follow up; ITMTX; Intra thecal methotrexate; IVIG, intravenous immunoglobulin; IVMP, intravenous methyl prednisolone; MMF, Mycophenolate mofetil; N, normal; SCA, Sickle cell anaemia; SLE, Systemic lupus erythematosus; SOB, shortness of breath.

Table 3. Clinical and laboratory parameters of HLH at Mukalla MCH Hospital, Yemen.

No.	10	11		12		13		14		15		16	17	18		19	20
Year	2018	2018	2019	2019	2020	2020	2020	2021	2021	2021	2022
Clinical parameters
Age	7 months	11 years		10 months		4 years		11 years		15 months		52 days	3 months	3 years		3 months	4 years
Sex	M	M		F		F		F		M		M	F	F		M	M
Fever >1 week	Yes	Yes		Yes		Yes		Yes		Yes		Yes	Yes	Yes		Yes	Yes
pallor	Yes	Yes		Yes		Yes		Yes		Yes		Yes	Yes	Yes		Yes	Yes
Jaundice	Yes	No		No		No		No		Yes		Yes	No	No		Yes	No
Splenomegaly	Yes	No		Yes		Yes		Yes		Yes		Yes	Yes	Yes		No	Yes
Hepatomegaly	Yes	No		No		Yes		Yes		Yes		Yes	Yes	Yes		Yes	Yes
Lymphadenopathy	Yes	No		Yes		Yes		No		No		No	No	Yes		No	Yes
Rash	Yes	No		No		No		No		Yes		Yes	Yes	No		Yes	No
Bleeding tendency	Yes	Yes		No		No		Yes		No		No	No	No		Yes	No
oedema	Yes	No		No		No		No		No		No	No	No		No	No
CNS manifestation	No	No		No		No		No		No		Seizure	No	No		Seizure	Headache neck stiffness
Chest manifestation	Yes	No		No		Pleural effusion crepitation		cough		No		No	Pleural effusion	Wheezing		Crepitation	No
Renal impairment	Yes	No		No		No		No		No		No	No	No		No	No
Special features									Relapse (seizure and coma)				Ascites		Upper and lower GIB		Papilledema blindness
Laboratory parameters
WBC	Low	Low		High		N		Low		N		Low	Low	Low		Low	Low
Haemoglobin	Low	Low		Low		Low		Low		Low		Low	Low	Low		Low	Low
Platelets	Low	Low		Low		Low		Low		Low		Low	Low	Low		Low	Low
Fibrinogen	-	-		N		-		-		-		-	-	-		-	-
Triglyceride	High	High		High		High		High		High		High	High	High		High	High
Ferritin	High	High		High		High		High		High		High	High	High		High	High
ALT/AST	High	N		N		N		High		High		High	N	High		N	High
LDH	High	High		-		High		N		High		High	N	High		High	High
PT/PTT/INR	High	N		N		N		N		High		High	N	N		High	N
sCD 25	-	-		High		-		-		High		-	-	-		-	-
NK activity	-	-		-		-		-		N		-	-	-		-	-
BM haemophagocytes	Yes	No		No		Not done		Yes		Yes		Yes	Not done	No		No	Yes
Treatment, causes and outcome
Initial diagnosis on admission	FUO	FUO		FUO		CHS		Dengue		FUO		FUO	SCID	FUO		FUO	CHS
possible cause	Not identified	Viral infection		Not identified		CHS		Dengue		SJIA		Not identified	SCID	Leishmania		Viral infection	CHS
Lag period from first presentation	2 weeks	5 months		4 weeks		3 weeks		3 weeks		7 months		4 weeks	3 weeks	2 months		3 weeks	2 months
Family history	Yes	No		No		Yes		No		No		Yes	No	No		No	Yes
consanguinity	Yes	Yes		No		Yes		No		Yes		Yes	Yes	No		No	Yes
Treatment	None	HLH2004 protocol (IVMP/ IVIG/CSA		HLH2004 protocol (Dexa /IVIG/ CSA /etopside		supportive		Dexa		HLH 2004 protocol (Dexa/ IVIG /CSA etopside		Dexa IVIG	Dexa	Amphotricin B		HLH2004 protocol (Dexa/IVIG /CSA)	Dexa IVIG
Outcome	Died	Died (TA GVHD)		Alive		Died		Loss FU		Relapse (Died)		Died	Died	Alive		Died	Alive

CHS, Chediak-Higashi syndrome; CSA, cyclosporine; Dexa, dexamethasone; FUO. fever of unknown origin; GIB, Gastrointestinal bleeding; IVIG, intravenous immunoglobulin; IVMP, Intravenous methyl prednisolone; Loss FU, lost to follow up; N, normal; SCID, severe combined immunodeficiency; SJIA, systemic juvenile idiopathic arthritis; TAGVHD, transfusion associated Graft-versus-host disease.

Figure 1. Clinical manifestations of pHLH patients. CNS, Central nervous system.

Figure 2. Laboratory manifestations of pHLH patients. ALT, Alanine aminotransferase; AST, Aspartate aminotransferase, BM, Bone marrow; INR, International normalised ratio; LDH, Lactate dehydrogenase, NK, Natural killer cells; PT, Prothrombin time; PTT, Partial thromboplastin time; WBC, White blood cell count.

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DISCUSSION

HLH is a severe, sometimes fatal hyper-inflammatory condition brought on by an overstimulated, inefficient immune response. As a result, uncontrolled production of activated lymphocytes and macrophages could result in MOF [13].

One in 100,000 children under the age of 18 is thought to have HLH, regardless of race or ethnicity [2]. According to estimates from Sweden, familial HLH (FHLH) affects 0.12 out of every 100,000 children [12,14]. These findings were most likely understated either because there were unpublished cases [2] or because the diagnosis was challenging [4,15]. Recent advancements in diagnosis and case detection have led to an increase in the observed overall incidence [4]. It is frequently seen in infants, although it can occur at any age [4,16,17]. From in utero with hydrops fetalis up to the age of 70, Weitzman [5] described a main primary HLH presentation. A male-to-female ratio of around 1:1 was reported [18]. In line with the earlier reports, our results showed that the age of our patients ranged between 0.14 and 14 years (median 3.5 ± 5.2 years) with a 1:1 male-to-female ratio.

Primary HLH is an autosomal recessive [11,19], or X-linked [20] disease. Nine genetic mutations controlling CTLs/NK cells cytotoxicity have been connected to primary HLH advancement to further subdivisions into (FHLH 1–FHLH 5) and HLH associated with GS2, CHS, Hermansky–Pudlak syndrome type 2, and X-linked lymphoproliferative disease types 1 and 2 [1,13]. Immunodeficiency syndromes including X-linked SCID and X-linked hypogammaglobulinaemia, as well as inborn metabolic abnormalities, can also manifest with HLH [1,5,13,21].

sHLH is usually acquired (no inheritance). It is triggered by bacterial, viral, fungal and parasitic (mainly leishmaniasis) infections [22], malignancy (particularly non-Hodgkin’s lymphoma), drugs [23,24], and autoimmune diseases such as sJIA and SLE [6,25]. In the latter cases, it is often called macrophage activation syndrome (MAS) [5,9,11]. Sawhney et al. [26] reported a 6.8%–7% association between MAS and sJIA. In China, no aetiological cause was identified in 56.2% of pHLH [16].

Epstein-Barr virus was reported as a significant trigger for primary and sHLH in Asian countries [1,5,16,19,22,27]. Nandhakumar et al. [4] and Ellis et al. [28] reported dengue contribution of the total infection-induced sHLH in 52% and 67%, respectively. Other viral infections, such as hepatitis A, parvovirus 19, varicella, coxsackie, cytomegalovirus [23,24], avian flu (H5N1) [29], adenoviruses, and herpes viruses, may also trigger sHLH [27].

In our study, variable aetiologies were detected, including primary immunodeficiency in five (25%) cases; infection in seven (35%) cases; rheumatological causes in two (10%) cases; and hematology/oncology in two (10%) cases. The underlying cause was not identified in four cases. Positive consanguinity and family history of similar cases were detected in 11 (55%), and 7 (35%) cases, respectively. Previous studies reported sporadic cases of FHLH with no apparent family inheritance [7,16,25]. In our institution, it was difficult for us to differentiate between primary and sHLH as no genetic study was available.

Diagnostic recommendations for HLH considering clinical highlights, research facilities, and histopathological examinations were conceived by the Histiocyte Society in 1991 and were refreshed in 2004 [11,12,30]. HLH patients could present other biochemical parameters, including elevated transaminases, bilirubin, lactate dehydrogenase (LDH), D-Dimers, and elevated cerebrospinal fluid cells or protein [5]. In 2009, hepatitis was included as a diagnostic criterion (modified 2009 HLH criteria) [19]. As specific HLH criteria may not be applied to patients with sJIA, modified diagnostic criteria specific to MAS were suggested by Ravelli et al. [31].

The sensitivity of HLH diagnostic criteria for early HLH is unknown [9]. None of these eight criteria are specific for HLH diagnosis, and they might be found in disseminated infections and several systemic and inflammatory conditions [8–10]. HLH diagnoses are known to follow an atypical course; some may have severe systemic symptoms [1,32] and others may not have fulfilled the diagnostic criteria on presentation [3,12], including newborns [33]. All these factors might explain the difficulty and delay in recognition and referral as reflected by the long lag time between disease onset and diagnosis [4,7]. Hence, the progression of the criteria should alert physicians of the possible presence of HLH [33] as the disease manifestations may evolve [4,21]. In our current study, 16 patients fulfilled HLH diagnostic criteria at presentation, and we noticed an improvement in the referral time during the last 7 years (2016–2022) with a median time of 21 ± 59 days in comparison to 90 ± 58.9 days in the period from 2010 to 2015. This was attributed to the early referral of any patient with unexplained prolonged fever, pancytopenia and hepatosplenomegaly.

It is evident from the variety of presentations that primary care physicians, intensivists, and different subspecialists, all need to recognise the early signs of HLH and pursue appropriate diagnostic evaluations [10].

Fever and splenomegaly are early markers of pHLH (except in newborns) [8,34], although both are not specific to HLH [35]. In our study, prolonged fever and splenomegaly were documented in 95% and 85% of HLH cases at the time of presentation, respectively. Previous reports documented fever in 91% [18] and 100% of cases [4,7,20,23] and splenomegaly in 85.7% [7] and 84% [18] of pHLH cases at the initial presentation.

CNS involvement is a significant independent prognostic factor for pHLH [36]. It represents a late stage of disease and is the primary cause of morbidity in long-term survivors [36]. Neurologic symptoms, either isolated or associated with systemic findings [37], were seen in up to 37%–75% of pHLH cases [14,16,18,24,25,36,38]. These symptoms include lethargy, irritability, disorientation, headache, hypotonia, nerve palsies (VI–VII), seizures, dysarthria, dysphagia, coma, blindness, ataxia, hemiplegia/tetraplegia, signs of increased intracranial pressure, and encephalitis like presentation [8,9,20,30,36]. Unfortunately, even in the absence of neurological abnormalities, mononuclear cell pleocytosis (lymphocytic meningitis)/albuminocytologic dissociation [8] or abnormal brain computerized tomography or magnetic resonance imaging findings can be observed at the onset or during the progress of the disease [11]. In our study, seizures were noticed in four patients (20%); one patient with Griscelli syndrome presented with recurrent encephalitis and papilledema. Later on, she developed hemiplegia, left-sided facial palsy, and loss of consciousness. In our study, other general and systemic involvement was similar to previous studies [1,18,21,23,25,30,38,39].

Bi/pancytopenia may not be present in the early stage of the disease [31,40], and severe pancytopenia requiring repeated transfusions may emerge as the disease progresses into HLH [41]. During cytopenic events, patients’ BM aspirates have been observed to be hypo-cellular, normo-cellular, or even hyper-cellular [40]. Patients’ leukocyte counts at diagnosis vary, but most have anaemia and/or thrombocytopenia [38,41]. Nandhakumar et al. [4] reported anaemia and thrombocytopenia in 51% and 73% of cases, respectively. Chan et al. [7] reported pancytopenia in 100% of patients. In comparison, our current study showed variable leucocyte counts among HLH patients. Anaemia and thrombocytopenia were present in 95% and 90% of cases, respectively.

Although not specific [16], ferritin is considered an important marker for diagnosing and evaluating HLH disease activity [42]. Ferritin level above 500 µg/l is 84% sensitive [12] and high levels >10,000 µg/l in children have 90% sensitivity and 96% specificity for HLH [42]. However, some HLH patients might have ferritin levels slightly above normal [5]. A rapid reduction in ferritin levels after treatment initiation is correlated with better survival in patients with pHLH [43]. Hyperferritinaemia was detected in 100% of our patients compared to 96% [4] and 66.7% [23] of pHLH cases reported previously.

Identifying haemophagocytosis in tissue biopsies is not essential to diagnose pHLH if the clinical presentation and additional diagnostic test results strongly implicate HLH [5,35,44]. Previous studies reported variable results ranging between normal BM cytology [4,25,38,45] and haemophagocytosis in 30%–40% up to 96.8% of pHLH patients either at initial presentation or during disease progression [4,30,32,33,44]. In the current study, BM haemophagocytosis was detected in 60% of cases, while 25% of cases had normal BM cytology.

High levels of triglycerides (95%), transaminases (45%) and LDH (65%) in our patients were consistent with previous studies [1,3,17,18,25,32,33].

The HLH Study Group of the Histiocyte Society designed an HLH (1994/2004) treatment protocol (based on etoposide [VP-16], dexamethasone and cyclosporine) suitable for the initial treatment of all forms of HLH (except MAS) [5,11,12,40]. Nandhakumar et al. [4] adopted a simplified algorithm to guide the evaluation and management of pHLH in resource-limited settings.

HLH treatment aims to suppress cytokine storms and to control CTLs/NK defective cytotoxicity, causing life-threatening consequences [13,22]. Not all patients with pHLH need to be started on the full HLH 2004 protocol. The majority of children with sHLH improve with supportive care alone [4]. Patients with MAS may respond to corticosteroids alone or a combination of corticosteroids, cyclosporine, and/or IVIG [5] even for cases severe enough to warrant intensive care unit attention care [24,46]. Patients with CNS HLH should generally receive intrathecal steroids and MTX [37]. In the case of infection-related HLH, treatment of the causative agent alone is insufficient, and a conventional HLH regimen should be used [13]. Only leishmania-associated HLH necessitates exclusive amphotericin B treatment [47]. In our study, treatment included steroids and IVIG+/-chemotherapy. Eleven (55%) patients received the HLH 2004 protocol. Intrathecal MTX was used in one patient with progressive CNS manifestations. One patient with leishmania was treated successfully with amphotericin B (not in our institution).

In some cases, anti-thymocyte globulin (ATG) combined with steroids may be a viable option for etoposide [48]. Ruxolitinib, emapalumab, anakinra, and alemtuzumab have been suggested as salvage therapies for patients with refractory disease [13]. HSCT was indicated in patients with FHLH, relapsing, severe persisting disease [7], and CNS progression [36] with survival improvement ranging from 50% to 92% [1,11,38]. Unfortunately, the options of ATG, biologics, and HSCT were not available and expensive for our patients.

The survival rate of children with HLH was poor [2,5]. Advances in therapeutic protocols improved the 5-year survival for pHLH from 5%–22% to 55%–63% [1,12,14,48]. However, pHLH is still associated with high morbidity and mortality [32] of approximately 33%–63% [2,14,20,44], up to 70%–85% in certain subtypes [27]. In our study, the mortality rate during 2010–2015 was 100% (5/5) in comparison with 75% (9/12) during the period from 2016 to 2022. The overall mortality over the study period was 82.35%, mostly related to disease reactivation with MOF. Several risk factors associated with increased disease resistance, mortality, adverse outcomes, and poor prognosis in pHLH patients have been previously reported [32,35,39,49].

Diagnosis of pHLH is considered a challenge for clinicians (especially in developing countries). This might be due to:

• The similarity in phenotype and the presence of a possible genetic predisposition to sHLH cause difficulty in differentiating between primary and sHLH [4,9].
• When the disease first develops, some patients may not have all of the HLH characteristics [3].
• Most pHLH patients will be acutely ill at presentation and present with symptoms identical to those of patients with sepsis or systemic inflammatory response syndrome [6,13,24].
• Laboratory testing has the potential to produce false negative results, lack specificity, or require a longer processing time that is not practical in an emergency situation [9].
• Cytopaenia is a challenging issue. It might result from hemophagocytosis or as a manifestation of the underlying disease or the treatment of the underlying condition that triggered pHLH [35].
• The variable, non-specific clinical presentation, laboratory investigations and non-specific diagnostic criteria are present in many other conditions (infections, neoplastic and autoimmune diseases) that might trigger the disease or co-occur with pHLH [35].
• Strict adherence to the HLH criteria may also prevent the diagnosis of pHLH; some clinicians may feel hesitant to diagnose pHLH in the absence of haemophagocytosis, although it may not be present early in the disease. Moreover, haemophagocytosis is falsely considered a specific indicator of pHLH when it is not [44].
• When infection is suspected, it is essential to differentiate HLH from infection because the treatment of HLH involves immunosuppressive therapy, which might have disastrous effects on the patient if given for infection [21,35].

It is worth mentioning that despite our restricted sample size, limited access to advanced diagnostic tests, and the retrospective nature of the study, it was possible to concentrate on the significance of HLH as a challenging emergency in a paediatric population.

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CONCLUSION

pHLH diagnosis is a big dilemma for physicians because of its vague and variable presentations; patients may be critically ill or not fulfilling the diagnostic criteria at early presentation. Thus, early diagnosis requires a high clinical suspicion, a thorough awareness of the clinical manifestations of pHLH, and careful evaluation and follow-up of a child who doesn’t yet present the whole picture of HLH. Early detection and effective treatment will optimise the prognosis.

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LIST OF ABBREVIATIONS

ATG Anti thymocyte globulin

BM Bone marrow

CHS Chediak–Higashi syndrome

CNS Central nervous system

CSA Cyclosporine

CTL Cytotoxic T lymphocytes

FHLH Familial haemophagocytic lymphohistiocytosis

GS2 Griscelli syndrome type 2

HLH Haemophagocytic lymphohistiocytosis

HSCT Haematopoietic stem cell transplantation

IVIG Intravenous immunoglobulin

LDH Lactate dehydrogenase

MAS Macrophage activation syndrome

MMF Mycophenolate mofetil

MOF Multisystem organ failure

MTX Methotrexate

NK Natural killer

pHLH Paediatric haemophagocytic lymphohistiocytosis

SCID Severe combined immunodeficiency

sHLH Secondary haemophagocytic lymphohistiocytosis

sJIA Systemic juvenile idiopathic arthritis

SLE Systemic lupus erythematosus

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CONFLICT OF INTEREST

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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FUNDING

None.

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ETHICS APPROVAL

The study is a record retrospective study. No names were used for data collection. Participants consent is not required according to the approved research guidelines of Hadhramout University (Ethical Committee of Hadhramout University College of Medicine). Confidentiality was maintained by omitting any personal identifying information from data collection.

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REFERENCES

1. Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4(47):1–9. https://doi.org/10.3389/fped.2016.00047
2. Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 2010;54(3):424–8. https://doi.org/10.1002/pbc.22359
3. Brisse E, Matthys P, Wouters CH. Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options. Br J Haematol. 2016 Jul;174(2):175–87. https://doi.org/10.1111/bjh.14144
4. Nandhakumar D, Loganatha A, Sivasankaran M, Sivabalan S, Munirathnam D. Hemophagocytic lymphohistiocytosis in children. Indian J Pediatr. 2020 Jul;87(7):526–31. https://doi.org/10.1007/s12098-020-03190-6
5. Weitzman S. Approach to hemophagocytic syndromes. Hematol Am Soc Hematol Educ Program. 2011;2011:178–83. https://doi.org/10.1182/asheducation-2011.1.178
6. Janka GE, Lehmberg K. Hemophagocytic syndromes – an update. Blood Rev. 2014 Jul;28(4):135–42. https://doi.org/10.1016/j.blre.2014.03.002
7. Chan JS, Shing MM, Lee V, Li CK, Yuen P. Haemophagocytic lymphohistiocytosis in Hong Kong children. Hong Kong Med J. 2008;14(4):308–13.
8. Astigarraga I, Gonzalez-Granado LI, Allende LM, Alsina L. Haemophagocytic syndromes: the importance of early diagnosis and treatment. An Pediatr (Engl Ed). 2018;89(2):124.e1–124.e8. https://doi.org/10.1016/j.anpede.2018.05.002
9. Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139(6):713–27. https://doi.org/10.1309/AJCP4ZDKJ4ICOUAT
10. Risma KA, Marsh RA. Hemophagocytic lymphohistiocytosis: clinical presentations and diagnosis. J Allergy Clin Immunol Pract. 2019;7(3):824–32. https://doi.org/10.1016/j.jaip.2018.11.050
11. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. https://doi.org/10.1002/pbc.21039
12. Henter JI. Treatment protocol of the Second International HLH study 2004. Haemophagocytic lymphohistiocytosis study group. Stockholm, Sweden: Histiocyte Society; 2004.
13. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332–43. https://doi.org/10.1182/blood.2019000936
14. Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer. 2015;62(2):346–52. https://doi.org/10.1002/pbc.25308
15. Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019;66(11):e27929. https://doi.org/10.1002/pbc.27929
16. Zhang Z, Wang J, Ji B, Greenwood TB, Zhang Y, Wang Y, et al. Clinical presentation of hemophagocytic lympho-histiocytosis in adults is less typical than in children. Clinics. 2016;71(4):205–9. https://doi.org/10.6061/clinics/2016(04)05
17. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007;166(2):95–109. https://doi.org/10.1007/s00431-006-0258-1
18. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428–35. https://doi.org/10.1111/j.1651-2227.1991.tb11878.x
19. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Program. 2009;2009(1):127–31.
20. Rodrigues JB, Nasr BB, Cypriano MS. Hemophagocytic lymphohistiocytosis: presentation and outcome of twenty-one patients at a single institution. Hematol Transfuse Cell Ther. 2022;44(4):485−90.
21. Si SJ, Tasian SK, Bassiri H, Fisher BT, Atalla J, Reema Patel R, et al. Diagnostic challenges in pediatric hemophagocytic lymphohistiocytosis. J Clin Immunol. 2021;41(6):1213–18. https://doi.org/10.1007/s10875-021-01025-3
22. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1):4–14. https://doi.org/10.1046/j.1365-2141.2003.04726.x
23. Singh S, Chandrakasan S, Ahluwalia J, Suri D, Rawat A, Ahmed N, et al. Macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis: clinical experience from northwest India. Rheumatol Int. 2012;32(4):881–6. https://doi.org/10.1007/s00296-010-1711-z
24. Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology. 2001;40(11):1285–92. https://doi.org/10.1093/rheumatology/40.11.1285
25. Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. Indian Pediatr. 2011;48(1):31–5. https://doi.org/10.1007/s13312-011-0020-2
26. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421–6. https://doi.org/10.1136/adc.85.5.421
27. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–22. https://doi.org/10.1016/S1473-3099(07)70290-6
28. Ellis EM, Sharp TM, Pérez-Padilla J, González L, Poole-Smith BK, Lebo E, et al. Incidence and risk factors for developing dengue-associated hemophagocytic lymphohistiocytosis in Puerto Rico, 2008-2013. PLoS Negl Trop Dis. 2016;10(8):e0004939. https://doi.org/10.1371/journal.pntd.0004939
29. Henter JI, Chow CB, Leung CW, Lau YL. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006;367(9513):870–3. https://doi.org/10.1016/S0140-6736(06)68232-9
30. Stabile A, Bertoni B, Ansuini V, La Torraca I, Sallì A, Rigante D. The clinical spectrum and treatment options of macrophage activation syndrome in the pediatric age. Eur Rev Med Pharmacol Sci. 2006;10(2):53–9.
31. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13(4):289–98. https://doi.org/10.1038/gene.2012.3
32. Luo ZB, Chen YY, Xu XJ, Zhao N, Tang YM. Prognostic factors of early death in children with hemophagocytic lymphohistiocytosis. Cytokine. 2017;97:80–5. https://doi.org/10.1016/j.cyto.2017.03.013
33. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46. https://doi.org/10.1146/annurev-med-041610-134208
34. Suzuki N, Morimoto A, Ohga S, Kudo K, Ishida Y, Ishii E. HLH/LCH Committee of the Japanese Society of Pediatric Hematology. Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan. J Pediatr. 2009;155(2):235–8. https://doi.org/10.1016/j.jpeds.2009.02.050
35. Otrock ZK, Daver N, Kantarjian HM, Eby CS. Diagnostic challenges of hemophagocytic lymphohistiocytosis. Clin Lymphoma Myeloma Leuk. 2017;17S:S105–10. https://doi.org/10.1016/j.clml.2017.02.017
36. Horne A, Trottestam H, Aricò M, Egeler RM, Filipovich AH, Gadner H, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327–35. https://doi.org/10.1111/j.1365-2141.2007.06922.x
37. Horne A, Wickstrom R, Jordan MB, Yeh EA, Naqvi A, Henter JI, et al. How to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis? Curr Treat Options Neurol. 2017;19(1):3. https://doi.org/10.1007/s11940-017-0439-4
38. Ishii E, Ohga S, Tanimura M, Imashuku S, Sako M, Mizutani S, et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol. 1998;30(5):276–83. https://doi.org/10.1002/(SICI)1096-911X(199805)30:5<276::AID-MPO3>3.0.CO;2-C
39. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120:172–9. https://doi.org/10.1016/j.jfma.2020.03.025
40. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–52. https://doi.org/10.1182/blood-2011-03-278127
41. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221–30. https://doi.org/10.1007/BF00443367
42. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35. https://doi.org/10.1002/pbc.21423
43. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154–5. https://doi.org/10.1002/pbc.22774
44. Lao K, Sharma N, Gajra A, Vajpayee N. Hemophagocytic lymphohistiocytosis and bone marrow hemophagocytosis: a 5-year institutional experience at a tertiary care hospital. South Med J. 2016;109(10):655–60. https://doi.org/10.14423/SMJ.0000000000000546
45. Yasumi T, Hori M, Hiejima E, Shibata H, Izawa K, Oda H, et al. Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. Br J Haematol. 2015;170(4):532–8. https://doi.org/10.1111/bjh.13461
46. Tristano AG, Casanova-Escalona L, Torres A, Rodriguez MA. Macrophage activation syndrome in a patient with systemic onset rheumatoid arthritis: rescue with intravenous immunoglobulin therapy. J Clin Rheumatol. 2003;9(4):253–8. https://doi.org/10.1097/01.rhu.0000081259.61370.eb
47. Cancado GG, Freitas GG, Faria FH, de Macedo AV, Nobre V. Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis in late adulthood. Am J Trop Med Hyg. 2013;88(3):575–7. https://doi.org/10.4269/ajtmh.12-0563
48. Mahlaoui N, Ouachée-Chardin M, de Saint Basile G, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622–8. https://doi.org/10.1542/peds.2006-3164
49. Kaya Z, Bay A, Albayrak M, Kocak U, Yenicesu I, Gursel T. Prognostic factors and long-term outcome in 52 Turkish children with hemophagocytic lymphohistiocytosis. Pediatr Crit Care Med. 2015;16(6):e165–73. https://doi.org/10.1097/PCC.0000000000000449