Journal of Applied Hematology

: 2018  |  Volume : 9  |  Issue : 4  |  Page : 111--119

Guide lines for management of adult histiocytic disease

Hind Abdin Salama1, Ayman Yahya Alhejazi2, Ahmed Absi3, Saeed Alshieban4, Mohsen Alzahrani2, Ahmed Alaskar2, Giamal Gmati2, Moussab Damlaj2, Khadega A Abuelgasim2, Osama Ali1, Abdulrahman Alghamdi5, Bader Alahmari1, Areej Almugairi6, Hazza Alzahrani7, Hanni ALhashmi8, Abdul Rahman Jazieh2,  
1 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, Department of Oncology, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia
2 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, Department of Oncology, King Abdul-Aziz Medical City; King Saud bin Abdul-Aziz University for Health Science, College of Medicine, Riyadh, Saudi Arabia
3 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, Princess Nora Oncology Centre, King Abdul-Aziz Medical City, Jeddah, Saudi Arabia
4 King Saud bin Abdul-Aziz University for Health Science, College of Medicine; Department of Pathology and Clinical Laboratory, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia
5 Department of Clinical Pharmacy, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia
6 Department of Pathology and Clinical Laboratory, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia
7 Section of Adult Hematology and Stem Cell Transplant, Department of Oncology, King Faisal Specialist and Research Centre, Riyadh, Saudi Arabia
8 Section of Adult Hematology and Stem Cell Transplant, Department of Oncology, King Faisal Specialist and Research Centre, Dammam, Saudi Arabia

Correspondence Address:
Dr. Hind Abdin Salama
Adult Hematology Section, Department of Oncology, King Abdulaziz Medical City, Riyadh
Saudi Arabia


BACKGROUND: Histiocytic disease is a diverse disease, characterized by multisystem involvement, diagnosis and management can be challenging. Guidelines are important tool to provide evidence-based management; however, guidelines for management of adult histiocytic disease are scarce. METHODOLOGY: A multidisciplinary team from Saudi Arabia developed guidelines to manage the adult histiocytic disease with an intention to provide standard of care for diagnosis and management of the most frequently encountered subtypes of adult histiocytic disease in the region. RESULTS: Detailed guidelines to different categories of histiocytic disease were finalized after review of many international guidelines and extensive literature review. CONCLUSION: Local guidelines for adults histiocytic disease was developed and can be shared with different hematology centers.

How to cite this article:
Salama HA, Alhejazi AY, Absi A, Alshieban S, Alzahrani M, Alaskar A, Gmati G, Damlaj M, Abuelgasim KA, Ali O, Alghamdi A, Alahmari B, Almugairi A, Alzahrani H, ALhashmi H, Jazieh AR. Guide lines for management of adult histiocytic disease.J Appl Hematol 2018;9:111-119

How to cite this URL:
Salama HA, Alhejazi AY, Absi A, Alshieban S, Alzahrani M, Alaskar A, Gmati G, Damlaj M, Abuelgasim KA, Ali O, Alghamdi A, Alahmari B, Almugairi A, Alzahrani H, ALhashmi H, Jazieh AR. Guide lines for management of adult histiocytic disease. J Appl Hematol [serial online] 2018 [cited 2021 Jul 24 ];9:111-119
Available from:

Full Text


Histiocytic disease is a diverse disease characterized by tissue infiltration of dendritic cells. It can involve one or more organ or system.

Histiocytic disease subtypes are rare, however, can be life-threatening if not properly and timely managed.

Guidelines are important tool to provide evidence-based management; unfortunately, guidelines for the management of the adult histiocytic disease are scarce.

To this date, there are no published guidelines from the middle east; furthermore, most of the international published guidelines are by the histiocytic society group, and they are mainly based on pediatric clinical trials.

In our institutions, we treat young adolescents from 14 to 18 years as adults; however, knowing that this age group was considered as pediatrics in all international histiocytic guidelines, we have adjusted our guidelines to use similar protocols to treat patients up to 18 years. As for older patients, we will use an individualized strategy based on extensive literature review and expert opinions.

In this manuscript, we are presenting our locally developed guidelines for the management of the adult histiocytic disease.

We distributed the guidelines into three parts, guidelines for Langerhans cell histiocytosis (LCH), Non-LCH (N-LCH) and hemophagocytic histiocytosis (HLH).


Histiocytic guidelines were developed by multidisciplinary team members including hematologists, pathologists, and clinical pharmacists.

Our recommendations were based mainly on histiocytic society guidelines for patients age 14–18 years, whereas for older patients we created our guidelines based on extensive literature review and expert opinions.

 Langerhans Cell Histiocytosis Guidelines


LCH is a heterogeneous disease characterized by tissue infiltrations of dendritic cells. Any organ or system can be affected.

For diagnosis of LCH examination of tissues for morphology and immunohistochemistry (IHC) stains IHC is required.

Definite diagnosis of LCH mandates positive IHC for CD1a and or langerin (CD207) or presence of characteristic Birbeck granules on the electron microscope.

Electron microscope examination is not needed for diagnosis if langerin is positive as this correlate to the presence of Birbeck granules.

Presumptive diagnosis is usually made only on radiological and clinical finding without tissue diagnosis e.g., typical lesions on chest computed tomography (CT).


Single system involvement LCH (SS-LCH), the involvement of only one system or organ. Multisystem disease LCH (MS-LCH), involvement of more than one organ or systemLCH with risk-organ (RO-LCH) bone marrow, spleen, liver, and central nervous system (CNS) involvement.

Lung involvement is not considered by some group as RO.

Definition of organ involvement in (langerhans cell histiocytosis)

Hematopoietic involvement – Severe involvement if (hemoglobin) Hb <7 g/dL and platelet <20 × 109

Mild involvement Hb between 7 g/dL and 10 g/dL and platelet between 20 × 109

Bone involvement – Craniofacial bone involvement, for example, orbital, mastoid, ethmoid, maxilla or paranasal sinuses. All skull bone lesions except the vault are considered the risk for CNS

Cranial fossa with intracranial soft-tissue extensionVertebral involvement with or without soft tissue involvementAll other radiologically documented bone lesionsPositron-emission test (PET) scan has proven to be the most sensitive functional test used in the identification of LCH lesions and in evaluating patient response to therapy, if it is not available bone scan should be performed in addition to the skeletal survey.

Central nervous system involvement – Intracerebral expansive lesions affecting the brain or meninges or magnetic resonant imaging (MRI) compatible with neurodegenerative disease or cerebral atrophy.

Ears involvement – Recurrent/refractory otitis externa or otitis media.

Eyes involvement – Ptosis, exophthalmos.

Liver involvement:

Hepatomegaly >3 cm below costal margin or abnormal liver function test (LFT), GTP >2T normal, alanine aminotransferase/aspartate aminotransferase >3T normal bilirubin >3T normal, ascites, edema or intrahepatic massLiver infiltration can result in sclerosing cholangitis.

Lung involvement:

Typical lesions by high resolution CT in form of nodules, cavitated nodules and cysts coexist mainly in the upper and middle lungsAtypical lung lesions confirmed by histopathology.

Spleen involvement – Enlargement of 3 cm below the coastal region.

Skin involvement – Any rash documented by histological examination.

Pituitary involvement – Presence of diabetes insipidus (DI).

Mucosal involvement – Oral mucosal lesion or genital lesion.

Gastrointestinal tract involvement (GIT):

Rare, can appear as a solitary colorectal polyp or multiple granulomatous lesions in upper or lower GITSolitary lesion usually asymptomatic, infiltrative lesions can present with diarrhea.

 Guidelines For Langerhans Cell Histiocytosis Management

Grades of recommendation

Grade of recommendations based on levels of evidence

Level A: Meta-analyses or randomized controlled trials[1]Level B: Systematic reviews of case-control or cohort studies[1]Level C: Nonanalytic studies based on case reports, case series, or small retrospective studies[1]Level D: Expert opinion.[1]

Grade of recommendations based on levels of agreement between experts

Grade 2: General agreement between experts[1]Grade 1: Discussed recommendations but no formal objections between experts[1]Grade 0: Divergence of opinions.[1]



History should include pain, fever, weight loss, night sweats, rash, lumps, constitutional symptoms, polyuria, polydipsia, history of learning difficulties, smoking history, respiratory symptoms, and family history.

Physical examination

Complete physical examination, including weight, temperature, lymphadenopathy, and hepatosplenomegaly, and skin lesion, tenderness over bones, soft-tissue swelling, neurological examination, and cognitive function assessment.

Laboratory and radiological examinations


Blood test should include full blood counts, liver function, renal function, Serum sodium, serum and urine osmolality, gonadotropins, coagulation profile, viral serology, HIV, and serum ferritin.[1]Tissue biopsy for specific (IHC) and ( BRAFV600E) mutation.[2]

Radiological examination

Chest X-ray and PET scan.

Other Investigations as per certain indications

Bone marrow biopsy (BMA) if there are abnormal blood countsHigh-resolution CT for suspected lung lesions, bronchoalveolar lavage (BAL) if a lesion identified

The presence of >5% CD1a positive cells in the fluid is diagnostic in nonsmokers (CD1a stain can be positive in BAL of smokers without lung disease).[2] Lung biopsy if BAL is not conclusive.

Pituitary MRI if suspicion of DIBrain MRI for neurological symptoms, spinal MRI to exclude cord compression for patients with vertebral bone involvementEndoscopy, audiogram, liver ultrasound, and other tests based on suspected sites of involvement.

Treatment recommendations

Indications for systemic treatment

MS-LCHMultifocal bone lesionSingle lesion in CNS or at an area with risk for CNS involvement e.g., (craniofacial lesions, ears or eye involvement)Single bone lesion >5 cmsingle vertebral lesionSingle lesion in the oral mucous membrane.

Treatment of Single system langerhans cell histiocytosis

Treatment of SS-unifocal bone disease – Isolated bone disease can regress spontaneously.

Indications to treat SS-unifocal bone disease

Lesions at weight-bearing areaCosmetic, for example, a lesion that causes disfigurementRisk of spinal cord compressionIf the lesion affects functionBone lesion at areas with risk to CNS, for example, skull.


For lesions <5 cm curettage would be enough to diagnose and treatAvoid radical excision as it might cause permanent disfiguring. Intraregional injection of steroid may allow rapid healing dose varies between 40 and 160 mg of methyl prednisoloneLarger lesions or lesions at risk of CNS or at critical areas are indications for systemic therapyRadiation might be considered (Grade C, 2) However, most experts do not recommend it due to the long-term sequelae.

Treatment of SS-multifocal bone lesions

Treat as MS-LCH see section (1.3.8).

Treatment of single system-skin langerhans cell histiocytosis

Involve dermatologyTopical 20% nitrogen mustard ointmentIf failed or extensive area, therapy options would include:

Steroid with or without vinblastineLow doses oral methotrexate (MTX) dose of 20 mg weekly can be used alone or in combination with prednisolone and azathioprineAzathioprine 2 mg/kg PO dailyThalidomide 100 mg daily, especially if multifocal skin lesion or mucous membrane involvement (Grade C2)Psoralen plus UVA, not indicated in scalp and penile lesions.

Treatment of single system-Langerhans cell histiocytosis of the lung

Rare, mainly in smokers, can lead to recurrent pneumothorax or cardiorespiratory arrestInvolve pulmonologyStop smoking. In some cases, this is enough to cause disease regression.

Treatment options:

Purine analog (cladarabine)vinblastine (VBL) + steroidsSevere cases might need lung transplant for this reason avoid pleurectomy.

Treatment of Isolated pituitary involvement

No indication for systemic therapyInvolve endocrinology to consider DDAVP (Desmopressin).

Treatment of neurodegenerative complications

No optimal treatment option yet.

Options include:

Retinoic acid, cladribine, vincristine + cytarabine, and IV immunoglobulin.

Treatment of multisystem-langerhans cell histiocytosis

There is no standard front-line regimen for adults as pediatrics where the standard for children up to 18 years is induction with one or two cycles of VBL/steroids followed by maintenance, for older adults this protocol did not show enough effectiveness, single-agent cytarabine or cladribine were found to be less toxic and more effective.

Treatment for patients from 14 to 18 years

We recommended treating patients from 14 to 18 years with VBL/Prednisolone Paediatric LCH protocols.[3]

Vinblastine/prednisolone protocol

One cycle of VBL and prednisolone (6 weeks course) is recommended for patients from 14 to 18 years with MS-LCH regardless of RO involvement, the second cycle should be given if based on the response and RO.

Prednisolone 40 mg/m2 day orally in three divided doses, after 4 week start reducing it taper off at 6 weeks.

VBL 6 mg/m2 IV bolus weekly ×6 weeks.

Assess after 6 weeks if in CR and no RO, start maintenance. If in PR or in CR, but RO give another induction with VBL/Prednisolone then proceed to maintenance.

Maintenance protocol

VBL 6 mg/m2/d IV bolus q 3 weeks + prednisolone 40 mg/m2 PO on D1–D5 every 3 weeks6 MP 50 mg/m2 orally daily, for 1 year should be added to those with RO, (round down to the nearest 50 mg).

Maintenance duration is 1 year.

Treatment options for patients >18 years


Preferred option for symptomatic MS-LCH with no RO or patients with CNS involvement (Grade C1)Cytarabine 100 mg/m2 D1–D5Assess after the first cycle if in CR, PR or stable diseases give maintenance cytarabine 100 mg/m2 D1–D5 monthly × 6–12 months (Grade D2).


The preferred option for MS-LCH with RO (Grade C2)Cladribine (CDA) 6 mg/m2 q 4 weeks IV for 5 daysAssess after the first cycle if in CR, PR or stable diseases give maintenance Cladribine monthly ×6 months (Grade D2).


The preferred option for symptomatic MS-LCH with no RO (Grade D1)Etoposide 100 mg/m2 D1–D5 q4w IV.Assess after the first cycle if in CR, PR or stable diseases give maintenance etoposide monthly ×6 months (Grade D2).

Intensive chemotherapy:

Combination chemotherapy, for example, MACOP-B[5] was found to be effective and resulted in long-lasting response with no need for maintenance after course completion but should be considered only in cases with aggressive LCH (Grade C1)MACOP-B consists of short course of chemotherapy combinations that can be given as outpatient, [Table 1].{Table 1}


For MS-LCH with mild symptoms and no RO, the following are acceptable options:

MTX 20 mg IV/PO weekly (Grade C1)Azathioprine 2 mg/kg PO daily (Grade D1).

Second line treatment

For patients failed first-line therapy, it is recommended to contact LCH expert.

General concept is to use different agents than induction therapy.


Combinations of cladribine + cytarabine especially for cases with CNS involvement.Vincristine + prednisolone + cytarabineCladribine as single agent, dose of (6 mg/m2) IV infusion for 2 h daily for 5 days if not used as inductionSome case reports responded to tyrosine kinase inhibitors (imatinib)Vemurafenib should be used within the contest of clinical trial in relapsed refractory cases with BRAF V600E mutations.

Hematopoietic stem cell transplant

Hematopoietic stem cell transplant (HSCT) should be considered for relapse refractory transplant-eligible patients.

In pediatric studies, there were no conclusion about the preferred conditioning chemotherapy, whether myeloablative conditioning (MAC) or reduced intensity conditioning (RIC).

In one study, relapse rate was higher with RIC.[6]

For adults due to the high toxicity with MAC we elected to give RIC for all our patients who are transplant candidate; however, this should be assessed case by case.


Radiotherapy should be limited only to patients with risk of neurological deficit and high risk for surgery.


All patients need PCP prophylaxisGCSF for neutropenia patientsBlood and blood products should be irradiated and leukoreducedZolendronic acid can be used for multifocal bone LCH (Grade C2).

Assessment of treatment response and follow up

After the end of first cycle patients should have full assessment by history, examination, laboratory and images, (All positive original testing should be repeated).

Then reassess every 3–6 months for 3 years. Then assess annually for 5 years.

After 5 years annual follow-up and images only per clinical suspicion.

 Nonlangerhans Histiocytosis Guidelines

Erdheim Chester disease


Erdheim Chester disease (ECD) is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, nearly 100% ECD patients have the mutation if sufficiently sensitive techniques are used.

Diagnosis requires the presence of certain histopathological and clinical features.

Characteristic finding of ECD is tissue infiltration with foamy histiocytes, IHC staining is positive for CD68, CD 163, negative for CD 1a and langerin (CD207).

Organs involvement

Skeletal manifestations

Symmetrical finding of osteosclerosis of long bones in the legs present in almost 95% of ECD patients with or without bone pain

Cardiovascular manifestations

The most common abnormality is circumferential soft-tissue sheathing of the thoracic and abdominal aorta on CT scan “coated aorta”

HypertensionCoronary artery diseasePericardial diseasPseudo-tumor infiltration of the right atrium visualized clearly on MRI as a mass lesion, rarely causing valve dysfunction and conduction abnormalities.

Lung manifestations

Usually asymptomatic, can present with cough, dyspnea, lung infiltrates, restrictive pattern on spirometry, fluid from BAL might show lipid Leiden macrophages.

Central nervous system

Mainly cerebellar and pontine involvement, causing progressive cerebellar symptomsUnilateral or bilateral Periorbital involvement resulting in exophthalmos, eye pain, or blindness.

Abdominal and pelvic involvement

Infiltration of perinephric tissues leading to the characteristic “hairy kidney” is commonHydronephrosis, retroperitoneal fibrosis, and mass-like soft-tissue infiltration can occur.

Skin manifestations

Xanthelasmas and xanthomas

Endocrine manifestations

DI, erectile dysfunction and gonadotropin insufficiency.

Guidelines for management of Erdheim Chester disease

Pre-treatment evaluation

Complete history

History should include history of bone pain, abnormal gait, weakness, decrease vision, polyuria, polydipsia, and constitutional symptoms.

Complete physical examinations

Complete physical examination looking for Skin lesions, soft-tissue swelling, xanthelasmas, fundoscopy, cardiovascular, chest, cognitive, and neurological examinations.

Laboratory and radiological examinations

Full blood counts, liver function, renal function, sodium level, C-reactive protein, serum and urine osmolality, and gonadotropinsTissue biopsy for morphology, IHC and BRAFV600 mutation analysisFor all patients CT chest, abdomen and pelvis, PET scan cardiac electrocardiogram, cardiac MRI and MRI brainFor selected patients orbital MRI, electromyography.

Treatment options[7]

Interferon a or pegylated interferon α

Dose of Interferon α (IFNα) 3 million unit 3T/week, for patients with high burden disease e.g., cardiac or CNS involvement higher doses as 18 million unit 3T/week should be used.

Pegylated IFNα dose is 180 mg/week.

Interferon should be continued till disease progression, lack of response, or intolerance due to side effects.

Side effects: Fever, flu-like symptoms, myalgia, arthralgia, neurophyscatric manifestations, transaminitis, and pruritus.

Vemurafenib (BRAFV600E inhibitor)[7],[8]

Indicated as a first line therapy for ok patients with mutated BRAF V600E ECD or as second line for those who are refractory to first lineDose is 480 mg orally twice daily, till disease progression or intoleranceCommon toxicities include fatigue, arthralgia, headache, and multiple skin complications.

Patients need to sign informed consent as there is rare risk of squamous cell carcinomas after prolong exposure to vemurafenib.


Cladarabine should be considered for BRAF negative cases that are unresponsive or intolerant to interferon.

Dose (0.14 mg/kg) IV infusion 2 h daily for 5 days on a 28 days cycle, Up to 6 cycles.

All patients should be given anti-PCP (pneumocystis pneumonia), anti-viral, and anti-fungal prophylaxis for 1 year after completing therapy.

Assessment of treatment response

All patients must be followed regularly by a hematologistNeurologist, endocrinologist, psychiatrist, and cardiologist may be involved as per affected organs; physiotherapy and occupational therapy are needed for those with weaknessAssessment should include history, improvement, or deterioration of previous symptoms, compliance and side effects of the medicationsPET should be performed every 3 months for all patients following the initiation of treatment then the interval between scans can be increased once disease has stabilized[7]Organ-specific images should be performed after 3 months of initial therapy then every 6 months. Once disease stabilization is achieved, should be repeated only as indicated by changes in clinical status or laboratory values.

 Sinus Histiocytosis With Massive Lymphadenopathy Rosai Dorfman Disease

Clinical manifestations

Painless, massive lymphadenopathy, mainly cervical, usually accompanied by fever, night sweats and weight lossCutaneous manifestations occur in 10% of cases, usually with erythematous brownish or erythematous yellowish papules, localized or disseminated, with no fixed siteExtra nodal involvement in 43% of cases mainly skin, soft tissues, upper respiratory tract, retro-orbital and bones.

Laboratory and radiological examinations

Full blood counts they might have neutrophilia and normochromic normocytic anemiaLiver function, renal function, and CRPImmunoglobulin level (polyclonal hypergammaglobulinemia)Tissue biopsy shows pericapsular fibrosis and dilated sinuses heavily infiltrated with large histiocytes, lymphocytes, and plasma cellsThe engulfment of lymphocytes and erythrocytes by histiocytes that express S-100 is considered diagnostic of rosai dorfman disease (RDD). IHC stains of RDD cells are also positive for CD68, CD163, whereas CD1a is typically negativeCT chest, abdomen, and pelvis.


Asymptomatic patients can be observed and closely followedPatients with constitutional symptoms or sudden enlargement of lymph nodes need to be treated.

Options include

Prolonged course of low-dose prednisoneHigh dose steroids for patient with compression to vital organsSurgical resection is the most successful treatment for prevention of relapse in extra nodal RDDRadiotherapy should be considered for bulky lesions with underlying organ risk in case of refractory to high dose steroids or extra nodal RDD when surgery cannot be doneChemotherapy for patients with life-threatening lymphadenopathy and risk of organ damage usually combination of low-dose MTX and 6MP, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) like chemotherapy can be usedCladribine for patients with severe RDD or relapsed refractory patientsTyrosine kinase inhibitors (imatinib) should be used in the context of clinical trial.

 Hemophagocytic Lymphohistiocytosis Guidelines


The hallmark of hemophagocytic lymphohistiocytosis (HLH) is immune dysregulation either familial or sporadic secondary to many triggers, the accurate and timely diagnosis is crucial due to the high mortality rate.

Most of HLH guidelines were based on HLH-94 and HLH-2004 trials, the patients were mainly children up to 18-year-old with familial, sporadic or secondary HLH.

HLH-2004 is an updated version of HLH-94, in HLH-2004 cyclosporine was added earlier with the initiation phase, both HLH-2004 and HLH-94 were not tested in adults but given the increased neurotoxicity with cyclosporine most adult experts recommended the use of HLH-94 protocol.

After chemotherapy completion patients with familial or relapse refractory HLH were considered for Allogeneic stem cell transplantation if a donor is identified.

Adults HLH (a-HLH) is more diverse, HLH-94 protocol might not fit all cases, there is no guidelines to treat a-HLH, and most recommendations are based on expert opinions.

In these local guidelines, we will treat all patients from 14 years to 18 years with HLH-94 as well as some selected older adults, for the rest we will use individualized strategy as below.

Diagnostic criteria (from hemophagocytic lymphohistiocytosis 2004)

Presence of either

Molecular diagnosis consistent with HLH: Mutations of PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4


Five of the 8 criteria listed below:

Fever ≥38.5°CSplenomegalyCytopenias (affecting at least 2 of 3 lineages in the peripheral blood):

Hemoglobin <9 g/dLPlatelets <100 × 103/mLNeutrophils <1 × 103/mL

Hypertriglyceridemia (fasting >265 mg/dL or >3mmol/L) and/or hypofibrinogenemia (<1.5 g/dL)Hemophagocytosis in bone marrow, spleen, lymph nodes, or liverLow or absent natural killer-cell activity.Ferritin >500 ng/mLElevated sCD25 (α-chain of sIL-2 receptor).

 Guidelines For Management Of Hemophagocytic Histiocytosis

Pretreatment evaluation


Detailed history including fever, family history, recent infection, weight loss, rheumatologic disease, or history of malignancy should be obtained.


Full physical examination including weight, temperature, lymphadenopathy, skin lesions, hepatosplenomegaly, and neurological examination should be performed.


Tests to diagnose hemophagocytic histiocytosis

Full blood counts, reticulocytes, LFT, renal function, basic screen, coagulation, fibrinogen, triglyceride, ferritin, sCD25BMA for evidence of HLHMutational analysis for familial HLHPRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, BIRC4Abdominal ultrasound.

Tests to identify the cause

CT neck, chest, abdomen, and pelvisPeripheral blood flowcytometryEBV-PCR, cytomegalovirus (CMV)-PCR and HIVAutoimmune screen, blood, and urine culturesTissue or lymph node biopsy if malignancy suspected.

Other tests

Brain MRI and CSF examination for those with neurological symptomsImmunoglobulin levelHLA typing for the patient.

Treatment recommendations

Treatment for patients from 14 to 18 years

Patients with a diagnosis of HLH up to 18 years should be treated with HLH-94 protocol

This protocol consists of extensive cytotoxic medications given in two phases for total duration of 1 year.[12]

Initiation phase (8 weeks) duration

Consists of dexamethasone, etoposide and weekly intrathecal chemotherapy starting from the 3rd week for patients with progressive neurologic symptoms and/or abnormal cerebrospinal fluid findings[Figure 2].{Figure 2}

Continuation phase (44 weeks)

Patients with nonfamilial HLH who optimally responded to initiation therapy should not receive continuationThose with familial or refractory relapse cases should continue therapy until ALLO-SCT is feasibleContinuation phase consists of combination of etoposide, pulse dexamethasone, and cyclosporine [Figure 2]All patients on HLH-94 should be on PCP and fungal prophylaxis as well as proton pump inhibitors.

Treatment for patients >18 years

Adult HLH is life threatening condition can lead to multi-organ failure if not treated properly, the type of HLH, i.e., primary or secondary does not affect induction therapy hence delaying the therapy for this reason is not justified. Identifying the cause is very crucial to choose the optimal therapy.

Causes of secondary a-HLH:

1-InfectionEBV, CMV, HIV, influenza, fungal, bacterial infection, and leishmaniasis2-Malignancy work up for malignancy, especially lymphoma is mandated3-Auto immune disease.

Treatment recommendations based on etiology

Start immunoglobulin (1–1.6 g/kg for 2–3 days) with or without cyclosporine, this is enough to control transient HLHTreating physician should not wait till the cause is identifiedSearch for the trigger.

Once a cause is identified treat accordingly as follows:

NO identified cause identified or familial HLH give HLH-94 protocol [Table 2]HLH secondary to EBV, treat with cyclosporine and rituximab 375 mg/m2 weekly for four weeks + immunoglobulin[10]

HLH secondary to Lishmaniasis, treatment with liposomal amphotericin B revert HLH effectivelyHLH secondary to malignancy start cyclosporine + immunoglobulin[10]

In severe HLH with risk of organ damage, etoposide 50–100 mg/m2 can be added to control the HLH before the start of the specific chemotherapyIt is reasonable to add etoposide to lymphoma cases treated with CHOP if they are fit. Consider Auto-SCT for lymphoma in CR1.

For idiopathic aHLH give αIL6R (tocilizumab)For relapse aHLH give HLH-94 followed by SCTFor HLH secondary to auto-immune disease treat withPulse methyl prednisolone + cyclosporine + αIL1R (anakinara)For HLH secondary to bacterial infection give antimicrobials and Immunoglobulin.{Table 2}

Supportive therapy

Correct coagulopathyCorrect anemia and thrombocytopenia (keep platelet >50)Avoid GCSF in active HLH (reported to cause capillary leak syndrome)Treat infection, revaluate any new fever and give PCP, fungal and viral infection prophylaxis.

Hematopoietic stem cell transplant

HSCT for HLH is recommended for all cases of familial HLH and recurrent or refractory cases despite chemo immunotherapy[11]Use of HSCT as consolidation in a-HLH, should be decided case by caseRIC is the preferred conditioning regimen, 3 years survival with (MAC) VRS (RIC) was 43% and 92%, respectivily.[13]RIC protocol commonly used by by HLH experts is fludarabine, melphalan, and alemtuzumabFor familial HLH, HLA matched siblings should have genetic testing as screening tool before accepting them as potential donorsRemission before transplant is a major prognostic factorIf patient not in remission after induction, treatment with alemtuzomab 1 mg/kg total dose, divided over 4 days found to induce remission before SCTFor aHLH secondary to lymphoma it is recommended to offer autologous-HSCT as consolidation postchemotherapy.[14],[15]

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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