key: cord-0872423-uz4vahvc
authors: Salama, Hind Abdin; RahmanJazieh, Abdul; Alhejazi, Ayman Yahya; Absi, Ahmed; Alshieban, Saeed; Alzahrani, Mohsen; Alaskar, Ahmed; Gmati, Giamal; Damlaj, Moussab; Abuelgasim, Khadega A.; Alghamdi, Abdulrahman; Alahmari, Bader; Almugairi, Areej; Alzahrani, Hazza; Bazarbachi, Ali; Musa, M.O.H.; Goyal, Gaurav
title: “Highlights of the Management of Adult Histiocytic Disorders: Langerhans cell histiocytosis, Erdheim-Chester disease,Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis”
date: 2020-08-18
journal: Clin Lymphoma Myeloma Leuk
DOI: 10.1016/j.clml.2020.08.007
sha: 1841c55fd067ba607ae2ac19a9bed4bf7261e8be
doc_id: 872423
cord_uid: uz4vahvc

Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and paucity of approved treatments, thereby, leading to various challenges in their diagnosis and management. With the development of novel molecular targets and the incorporation of targeted agents in the management of different categories of adult histiocytic disorders, their management has become increasingly complex. In an attempt to improve the clinical management of common adult histiocytic disorders (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis), we created this document based on existing literature and expert opinion.

Histiocytic disorders are an exceptionally rare group of diseases characterized by tissue infiltration of histiocytes and dendritic cells. These disorders can involve one or more organ, and due to their rarity, diagnosis is usually delayed or missed. Recommendations for the management of adult histiocytic disease are sparse. In 2018 our first set of local guidelines were published 1 , however, due to the discovery of new molecular data and targeted therapies, these guidelines were in need of refinement and updating for the different categories of histiocytic diseases. This document will provide highlights for management of the most encountered histiocytic diseases; these were mainly developed through literature reviews and experts' opinions 2 .

LCH is a clonal disorder with MAPK-ERK mutations present in most patients. BRAFV600E is present in more than 50% of cases 2 . LCH is characterized by tissue infiltration with dendritic cells. Presumptive diagnosis of LCH is usually made on radiological and clinical findings without tissue diagnosis e.g. typical lesions on chest computed tomography (CT) or the typical lytic lesions seen on bone images (motheaten or punched out appearance; Figure 1 ). 2 Definite diagnosis of LCH requires the presence of CD68/163+ histiocytes that are positive for CD1a and/or langerin (CD207) on immunohistochemical stain (IHC). Electron microscope examination is not required for diagnosis if langerin is positive as this correlates with the presence of Birbeck granules. Mutational analysis of BRAFV600E or MAPK-ERK mutations is required, as this will influence the treatment decision process.

LCH can involve single system or organ (SS LCH) or multiple systems (MS-LCH). LCH with risk organ (RO LCH) is identified when there is an infiltration of vital organs e.g. Bone marrow, spleen, liver, and central nervous system (CNS).

The clinical presentation of adult LCH (a-LCH) varies and will depend on the site of involvement. Bone involvement is common, with the skull being the most commonly seen boney site involved having an incidence of 60%. Vertebral involvement with or without soft tissue involvement and cranial fossa involvement with intracranial soft tissue extension can occur. Patients usually present with bone pain, fractures, or cord compression. For bones, LCH Fluorodeoxyglucose-Positron Emission Tomography-Computed Tomography (FDG-PET-CT) is the most sensitive functional test used in identification of the lesions and measurement of response to therapy. If (FDG-PET-CT) is not available, a technetium 99m bone scan should be performed in addition to a skeletal survey.

Thirty percent of adult LCH present with diabetes insipidus (DI) secondary to pituitary fossa involvement.

In children, isolated lung involvement is rare, whilst in adult's lung involvement can occur as an isolated lesion mainly in smokers. Typical lesions found by a high-resolution CT in the form of nodules, cavitated nodules and cysts coexist mainly in the upper and middle J o u r n a l P r e -p r o o f lungs. Pulmonary function tests may show reduced diffusion capacity, exhibiting a restrictive or obstructive pattern. 2 Tissue biopsy is recommended to diagnose atypical lung lesions.

Central nervous system (CNS) involvement Incidence is 5% 2 . Lesions are either in the form of the tumor involving most commonly the hypothalamic-pituitary region, or nontumorous involvement of cerebellum or brain stem. 3 Some can present with neurodegenerative manifestations including cognitive function impairment. Skin involvement occurs in 15-30% of patients. 2 Any form of rash could occur and should be documented by histological examination.

Liver involvement usually represented by the occurrence of hepatomegaly of greater than three centimeters below the costal margin or abnormal liver function tests (LFT). Indicators include Gamma-glutamyl transferase (GGT) that is greater than two times the upper limit of normal and/or alanine aminotransferase(ALT)/aspartate aminotransferase (AST) that is greater than three times the upper limit of normal, a bilirubin level greater than three times the upper limit of normal, ascites, edema or an intrahepatic mass. Life-threatening sclerosing cholangitis can occur because of hepatic infiltration. Less commonly observed LCH could involve the ears, eyes, mucus membranes, gastrointestinal tract, spleen, and bone marrow.

Approach to diagnose and manage a-LCH is mostly based on general agreement between experts. 2, 3 To diagnose LCH an involved tissue should be examined for specific (IHC) and (BRAFV600E) mutation testing. 4 For patients with MS-LCH who are BRAF-V600E negative; consider next generation sequencing for MAPK/ERK pathway mutations. (FDG-PET-CT) is the gold standard image for pretreatment evaluation and follow-up. High resolution CT should be performed if pulmonary LCH is suspected followed by bronchoalveolar lavage (BAL) if a lesion identified. The presence of greater than 5% CD1a positive cells in the fluid is diagnostic in nonsmokers (CD1a), as the stain can be positive in the BAL of smokers without lung disease; lung biopsy is needed if BAL is not conclusive. 5, 6 If DI is suspected, a Pituitary MRI should be performed. A spinal MRI should be performed in all patients with vertebral bone involvement in order to exclude cord compression.

LCH with isolated bone disease can regress spontaneously. Indications to treat LCH are: the presence of MS LCH, multifocal bone lesion, single lesion in CNS, single lesion with RO or the risk of CNS involvement (e.g. craniofacial lesions, ears or eye involvement that is not amenable to local therapy), and isolated pulmonary LCH that is not responsive to smoking cessation.

Single system-unifocal bone disease will need treatment if the lesions are at a weight bearing area, if it causes disfigurement, if there is a risk of spinal cord compression, if the bone lesions are at areas with CNS risk e.g. skull or if the lesion affects functionality.

The type of treatment of SS-unifocal bone lesion would depend mainly on the lesion size. For lesions <5 cm curettage would be sufficient for diagnosis and treatment. Radical excision should be avoided as it might cause permanent disfigurement. Intraregional injection of steroid may allow rapid healing, and the dose varies between 40 and 160 mg of methyl prednisolone. Radiation may be considered for single lesions that have recurred after surgery or cannot be surgically excised. Systemic therapy is indicated for lesions (>5 cm) or lesions at risk of transferring to the CNS or lesions at critical areas.

Multifocal bone lesion is treated as MS LCH (Figure 2 ). Single system LCH other than bone is treated according to the location. For the skin, LCH usually topical nitrogen mustard ointment 20% can be sufficient to control the disease. If not successful or the involved areas are extensive, other options would include: steroid with or without vinblastine, low doses oral methotrexate (MTX) 20 mg weekly alone or in combination with prednisolone and azathioprine, single agent azathioprine at dose of 2 mg/kg PO daily, thalidomide at a dose of 100 mg daily (especially if multifocal skin lesion or mucous membrane involvement or psoralen with ultraviolet-A (PUVA)).

Isolated lung LCH is rare, mainly occurring in smokers, and can lead to recurrent pneumothorax or cardiorespiratory arrest. In most cases, smoking cessation is sufficient to cause disease regression. 6 If not, options would include: single agent cladribine or vinblastine and steroids. However, the later did not show efficacy in adults with pulmonary LCH. 5 Severe cases of pulmonary LCH might need lung transplant.

Isolated pituitary involvement does not require therapy. However, desmopressin (DDAVP) should be used for symptomatic patients. Neurodegenerative disease and cognitive impairment are not uncommon. There is currently no optimal treatment available. Some pediatric studies suggest benefit with early initiation of targeted therapies such as BRAF and MEK inhibitors 7 . Therefore, these agents may be considered over conventional agents such as: retinoic acid, cladribine, vincristine + cytarabine, and IV immunoglobulin.

There is no standard front line regimen for adults as there is for pediatrics. In children, the standard protocol is one or two cycles of vinblastine (VBL) and steroids followed by maintenance 4 . This approach is recommended for adults with MS-LCH or SS-LCH with RO up to the age of 20 years (Figure 2 ). For older adults it was found to be less effective and more toxic. Therefore, single agent chemotherapy or a novel agent is preferred.

Cytarabine at a dose of 100 mg/m 2 intravenously (IV) for 5 days every 28 days is a preferred option for symptomatic MS-LCH with no RO, and for patients with CNS involvement. If the patient is in complete or partial remission (CR or PR) after the first cycle, it is advisable to continue maintenance cytarabine 100 mg/m 2 for 6-12 months.

Another effective single agent is cladribine, as it is a preferred option for MS LCH with RO. Cladribine is usually given at dose of 6 mg/m 2 or 0.14 mg/kg IV for 5 days every 28 days. If the patient is in CR or PR after two cycles it is recommended to continue until the completion of four cycles. If there is an ongoing partial response and the treatment has been well tolerated, six cycles can be given. Recently, a group from Mayo clinic published their outcomes with single agent cladribine used to treat 37 patients with LCH, and found that single agent cladribine has high ORR and most of the patients achieved PR regardless of the mutation of BRAFV600E. 8 Etoposide as a single agent can be used at dose of 100 mg/m 2 for 5 days every 28 days, up to 6 cycles.

Combination chemotherapy, for instance the MACOP-B regimen (Table 1) , was found to be effective and resulted in a long lasting response without a need for maintenance after the induction course was completed, however, it should only be considered only in cases with aggressive LCH 9 .

For MS LCH with mild symptoms and no RO-LCH, either methotrexate 20 mg IV/PO weekly or azathioprine 2 mg/kg PO daily can be given.

For refractory or relapsed LCH, the general concept is to use different agents rather than induction therapy. Options would include combination of vincristine, prednisolone and cytarabine. 10 Cladribine as a single agent, with a dose of (6 mg/m 2 ) IV infused over 2 hours daily for 5 days if not used as induction.

Vemurafenib may be considered in relapsed or refractory cases with V600E BRAF mutations. 11 MEK inhibitor (cobimetinib) can be considered in severe organ involvement or refractory non-BRAF-V600E mutated LCH. A phase II trial using cobimetinib in 18 patients with histiocytosis regardless of their genotype showed an overall response rate (ORR) of 89%. 12 Cytarabine and cladribine combination is a toxic regimen and is associated with increased risk of infection. Therefore, it should be reserved for severe cases or refractory RO-LCH.

Autologous or allogeneic stem cell transplant may be considered for relapse refractory transplant eligible patients. In children, the preferred conditioning chemotherapy regimen which involves either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC), remains unclear. For adults, (RIC) is the preferred salvage option due to the lower post-transplant associated morbidity and mortality, however, relapse rate is higher after RIC. The role of HSCT in the era of targeted therapies is unclear and may even become obsolete in adults, as these therapies are uniformly effective.

Erdheim-Chester disease (ECD) is a clonal disorder marked by recurrent BRAFV600E mutations in more than 50% of patients, moreover, nearly 100% of ECD patients have the mutation if sufficiently sensitive testing techniques are used. Other mutations involving MAPK/ERK or PI3K-AKT pathway can be frequently detected in those patients 13 . A characteristic histopathological finding of ECD includes: tissue infiltration with foamy histiocytes, IHC staining is positive for CD68, CD163, negative for CD1a and langerin (CD207).

ECD can involve any organ, however, it is seen especially in: bones, CNS, and the cardiovascular system.

The finding of symmetrical osteosclerosis of the meta-diaphysis of long bones in the legs (around knees) is present in almost 90% of ECD patients with or without bone pain 2 .

Cardiovascular manifestations affect more than 50% of ECD patients 2 . The most common abnormality is circumferential soft tissue sheathing of the thoracic and abdominal aorta seen on a CT scan as a "coated aorta". Other manifestations include pseudo tumor infiltration of the right atrium visualized clearly on MRI as a mass lesion. Furthermore, hypertension, coronary artery disease, and pericardial disease can also occur. However, valve lesions and conduction defects are rare.

Lung involvement is usually asymptomatic or can present with a cough, dyspnea, lung infiltrates, and an observation of restrictive patterning on spirometry. Fluid from BAL might show lipid-laden macrophages. The central nervous system is involved in 40% of the patients 2 , mainly in the form of cerebellar and pontine involvement, thereby, causing progressive cerebellar symptoms. Unilateral or bilateral peri-orbital involvement resulting in exophthalmos, eye pain, or blindness can also occur.

Sixty percent of ECD patients present with abdominal and pelvic involvement including infiltration of perinephric tissues leading to the characteristic "hairy kidney". Hydronephrosis, retroperitoneal fibrosis, and mass like soft tissue infiltration can occur.

Skin manifestations such as Peri-orbital xanthelasmas and xanthomas may present. Additionally, endocrine manifestations can present in LCH, as 25% of ECD patients can present with DI, erectile dysfunction and gonadotrophin insufficiency.

Pre treatment evaluation History should include symptoms of bone pain, abnormal gait, weakness, decreased vision, polyuria, and polydipsia. Constitutional symptoms in the form of fever, weight loss, fatigability, and sweating were found in 28% of ECD patients. 14 We reported a case of ECD with a 50 kg weight loss and no skeletal bone involvement. 15 Complete physical examination looking for skin lesions, soft tissue swelling, xanthelasmas, fundoscopy, in addition to: cardiovascular, chest, cognitive, and neurological examinations. Pretreatments work up should include full blood counts, liver function, renal function, sodium level, C reactive protein, serum and urine osmolality, and gonadotropin levels. In addition to the IHC and morphology examination of the involved tissue, mutation analysis and next generation sequencing for BRAF V600E and MAPK/ERK pathway should be processed. PDG-PET-CT scans are recommended for every patient. Cardiac MRI and MRI brain are requested upon clinical suspicion.

In general, therapy is initiated for all patients diagnosed with ECD except asymptomatic patients with only bone disease or those who present only with DI. 15 Treatment options ( Figure  3 ) include: Interferon Alpha at a dose of 3-9million IU via IV route three times per week or pegylated interferon(PEG-IFN) at a dose of 135mcg/week subcutaneously. Higher doses at 180 mcg/week may be needed for suboptimal responses or cardiac/CNS involvement. Interferon should be continued until: disease progression, lack of response, or intolerance due to side effects. Common side effects include: fever, flu like symptoms, myalgia, arthralgia, neuropsychiatric manifestations, transaminitis, and pruritus.

Vemurafenib (BRAF kinase inhibitor) 11,16 is indicated as a first line therapy for stable patients with mutated BRAF V600E ECD or as a second line therapy for those who are refractory to the conventional first line therapy. The recommended dose is 480 mg orally twice per day, until disease progression or intolerance. Dose reductions may be required based on toxicities and/or side effects. Common toxicities include: fatigue, arthralgia, headaches, multiple skin lesions, QTc prolongation, peripheral edema, and diarrhea. Prolonged exposure to vemurafenib could rarely cause squamous cell carcinoma.

Single agent cladribine should be considered for BRAF negative cases that are unresponsive or intolerant to interferon at a dose of 0.14 mg/kg or 6 mg/m2 via IV infusion for two hours daily for D1-5 days on a 28-day cycle. If the patient is responding after two cycles, up to 2-4 additional cycles may be provided. All patients should be given PCP, anti viral, and anti fungal prophylaxis for 1 year after completing cladribine therapy.

PET-CT should be performed every 3 months for all patients following the initiation of treatment, afterwards, the interval between scans can be increased once the disease has stabilized . Organ specific images should be performed after 3 months of initial therapy and then every 6 months. Once disease stabilization is achieved, scans should be repeated only as indicated by changes in clinical status or laboratory values.

Rosai Dorfman Disease (RDD) is a rare type of non-Langerhans histiocytosis. Histological examination typically showed peri-capsular fibrosis and dilated sinuses heavily infiltrated with large histiocytes, lymphocytes, and plasma cells. The engulfment of lymphocytes and plasma cells by histiocytes that express S 100 is considered diagnostic of RDD. IHC stains of RDD cells are also positive for CD68, CD163, whereas CD1a is typically negative. Recent studies have raised the possibility of a clonal origin due to the presence of KRAS, NRAS and MAP2K1 genes 17 . Unlike LCH and ECD, the BRAFV600E mutation is typically undetected. Gene sequencing is recommended especially in refractory cases.

RDD usually presents as painless and massive lymphadenopathy that is mainly cervical, accompanied by a fever, night sweats and weight loss. Cutaneous manifestations occur in 10% of cases 17 , usually with erythematous brownish or erythematous yellowish papules, localized or disseminated, without a fixed site. Isolated extra nodal involvement is present in 67% of cases mainly in the skin, soft tissues, upper respiratory tract, retro orbital and bones. 18 CNS and ophthalmic manifestations is present in 10 %of cases 2 . Normochromic normocytic anemia is not uncommon. Additionally, there are reported cases of RDD presenting with autoimmune hemolytic anemia 18, 19 .

Asymptomatic patients can be observed and followed closely. Patients with constitutional symptoms or sudden enlargement of lymph nodes need to be treated. Treatment options include: prolonged course of low dose prednisone (1mg/kg of prednisone equivalent for 2-3 weeks followed by prolonged taper over 2 months), high dose steroids for patient with compression to vital organs or systemic disease. Sirolimus at dose of 2.5mg/m 2 for 18 months, is recommended by some authors. 19 Rituximab 375mg/m 2 once a week x 4 doses is recommended for those with immune-related RDD. Low dose methotrexate combined with 6-mercaptopurine or single agent cladribine are recommended for patients J o u r n a l P r e -p r o o f with severe RDD. Lenalidomide or thalidomide have been tried with success for refractory cutaneous RDD 17 . Clofarabine was used on three patients with relapsed refractory RDD, two patients achieved CR and one achieved PR. 17 Cobimetinib is recommended for refractory RDD with mutations involving MAP2K1 pathway, therefore, NGS is recommended at diagnosis 17 .

HLH is a hyperinflammatory immune response syndrome driven by T-cells. It could be either primary or secondary to a trigger. Secondary HLH accounts for the majority of adult HLH. Secondary HLH is mainly due to inability of the hosts' immune system to restrict the stimulatory effects of different triggers. HLH was previously understood as a pediatric disease, with most of the HLH-guidelines being based on the HLH-94 and HLH-2004 pediatric trials. However, over the past 10 years a-HLH has been diagnosed more frequently. As a result, recent HLH publications have explored adult HLH in greater detail.

Adult-HLH is frequently misdiagnosed as acute sepsis. The accurate and timely diagnosis is crucial due to the high mortality rate. HLH2004 diagnostic criteria ( Table 2) was developed for children, and it is not validated in adults, however, it is still widely used to diagnose a-HLH.

Serum ferritin greater than 10,000 ng/ml was found to be 96% specific and 90% sensitive for diagnosis in children; 22, 23 however, this is not the case in adults. Soluble CD25 (sCD25 or interleukin-2) activity is a more sensitive tool to suggest a-HLH rather than serum ferritin. A high transaminase is a common presentation in a-HLH, but is not part of HLH2004 diagnostic criteria. Therefore, there is a need for another scoring system in adults.

The H-Score (Table 3) is an online scoring calculator, it incorporates clinical and laboratory data, with the cumulative score ranged between 0-300 24 . In a multicenter trial, the performance of HLH2004 diagnostic criteria was compared to the H-Score in 147 children and adults with suspected HLH. The authors concluded that the H-score is more efficient in diagnosing HLH for both children and adults 25 . If the chemical and clinical markers are suggestive of a-HLH, a bone marrow or tissue biopsy should be performed to look for evidence of hemophagocytosis. However, morphologic evidence of hemophagocytosis in bone marrow may not always be captured on a biopsy and is not a mandatory criteria for making a diagnosis of HLH. HLH should be considered in the differential diagnosis of patients with otherwise unexplained fevers, bicytopenia, and elevated ferritin levels, especially in combination with elevated sCD25 receptor assay.

Mutation analysis for the genes involved in familial HLH (PRF1, UNC13D, Munc18-2,  Rab27A, STX11, SH2D1A, BIRCC4) should be sent as well as other tests to look for the trigger such as Epstein Barr virus (EBV) PCR, cytomegalovirus (CMV) PCR, HIV1/2 antigen assay and blood and urine culture, autoimmune screen, in addition to a PET-CT looking for an underlying lymphoma or malignancy. Brain MRI and CSF examination should be performed for those with neurological symptoms.

Due to the high mortality of HLH and delays in specialized test results like sCD25 assay, treatment with dexamethasone or another corticosteroid should be initiated at initial suspicion. The management approach of a-HLH follows two strategies: suppressing the cytokine storm and treating the underlying trigger. The HLH-94 (Table 4 ) is widely used for HLH in children. Due to the heterogenicity of a-HLH, a one size protocol does not fit all. Offering HLH-94 protocol to primary or refractory HLH is a recommendation of this paper. This protocol consists of extensive cytotoxic medications given in two phases for a total duration of one year. 26 Adult tolerability to etoposide is less than in children, therefore, the etoposide dose can be modified to 50-100 mg/m 2 , in addition to administering it on a weekly schedule when compared to the twice per week protocol seen in children. Once a-HLH is suspected IVIG 1-2gm/kg for one to two days with or without steroids may be given, as this will temporarily control the cytokine storm until the specific cause is identified. (Figure 4) 

Mal-HLH is the most aggressive subtype and carries a high mortality rate. It accounts for 40-70% of a-HLH. 27 50% of S-HLH in adults is a result of hematological malignancies. Lymphoma is the most common cause especially NK-cell and peripheral Tcell lymphoma (35%), followed by B-cell lymphomas (32%), leukemias 6%, Hodgkin lymphomas (6%), and solid malignancies (3%). 28 Diagnosis of underlying malignancy can be challenging and repeated biopsies may be needed to confirm a diagnosis. There is some evidence to suggest that a high sCD25/ferritin ratio suggests lymphomas as an underlying cause for HLH rather than other secondary causes. 28 Treatment initiation with immunoglobulin and steroid therapy is crucial. Whenever possible, tissue biopsy should be obtained prior to the initiation of steroids. In severe HLH with risk of organ damage, etoposide 50-100 mg/m 2 can be added to control the HLH before the start of specific chemotherapy. It is reasonable to add etoposide to lymphoma treatment using CHOP if the patient is fit enough to tolerate the additional drug. For a-HLH secondary to Tcell lymphoma, it is usually recommended to offer autologous or allogeneic HSCT as consolidation post-chemotherapy.

Familial HLH is extremely rare in adults. Familial HLH should be considered in young males with a family history of HLH, who are EBV positive, or young patients with CNS disease or albinism. The PRF1 gene mutation has been detected in 10% of healthy caucasians. 29 For familial HLH and HLH with an unknown trigger, we recommend using the HLH-94 protocol. Allogeneic stem cell transplantation is offered for familial and relapse refractory HLH. In children, reduced intensity conditioning (RIC) is the preferred conditioning regimen showing 3 years OS with myeloablative vs. RIC at 43% and 92% respectively. In adults, RIC did not show superiority based on a retrospective EBMT study 30 . The underlying trigger as well as the patient's comorbidity index and age should guide the decision on which conditioning chemotherapy is appropriate.

HLH secondary to infection is usually associated with intracellular organisms that trigger the immune response such as: tuberculosis, malaria, leishmaniasis, and rickettsia 31 . HLH secondary to (EBV) can occur at any age, and it may be associated with X-linked immunodeficiency disorder, which is characterized by Tcell deficiency, and a genetic predisposition to EBV infection, additionally, some patients may present with HLH during adulthood. Other infectious triggers HLH include: HIV CMV, use of medicinal herbs, simplex virus, fungal infection, and influenza. The treatment usually incorporates IVIG and specific antimicrobials with or without corticosteroids. Etoposide is reserved for severe cases where no response has been achieved with other treatment options. For EBV-HLH, rituximab should be added.

HLH secondary to autoimmune disease (MAS) is reported more frequently in children and can be misdiagnosed in adults. It has been reported in 10-15% of adult-onset juvenile rheumatoid arthritis and in 0.9-9% of Systemic lupus erythrematosis. 32 An adult rheumatologist should be involved in the diagnosis and management of MAS.

Management options included combinations of immunosuppressants with corticosteroids as a backbone. Recent evidence showed excellent response of anakinra, an IL1 inhibitor in MAS associated with adult juvenile rheumatoid arthritis. 33

Immunotherapeutic agents that target CD19 such as chimeric antigen receptor (CART), bispecific antibodies (blinatumomab), and PD1 check point inhibitors can induce HLH as a part of cytokine release syndrome (CRS). 22 The anti IL6 antibody, tocilizumab is often used to control drug induced cytokine storm. Etoposide may be considered in cases that do not respond appropriately to tocilizumab. 

There are reported cases of idiopathic or secondary HLH during pregnancy, in which early steroid initiation resulted in improved outcomes. 34, 35 

The COVID-19 pandemic has resulted in approximately 700,000 deaths according to the most recent data. A cytokine release syndrome that resembles s-HLH with release of IL6 , IL1 and other inflammatory markers has been associated with severe COVID-19 cases. 36, 39 A recent multicenter study from Wuhan, China, on 150 COVID-19 patients revealed that high serum ferritin and high IL6 predicted for worse mortality, suggesting that COVID-19 mortality might be related to CRS/s-HLH like disease 36 . A few authors suggested the possibility of applying the H-Score for all severe COVID-19 patients in an attempt to classify those who could benefit from immunosuppression. 37, 39 Furthermore, a case series found that the use of anakinra in COVID-19 patients with positive H-score resulted in an improved respiratory function. 38 Tocilizumab has been used with success in China for patients with COVID-19 induced pneumonia and high IL6. 39, 40 Therefore, there are several overlaps between s-HLH and the CRS associated with COVID-19 infection. Moreover, the RECOVERY trial has shown that, dexamethasone administration to COVID-19 patients who required respiratory support resulted in reduction of mortality. 41 These data suggest that patients with COVID-19 who develop CRS and s-HLH like illness may benefit from dexamethasone in conjunction with anti-cytokine therapy. There are ongoing trials with etoposide and dexamethasone for severe CRS related to COVID. 42

Relapsed refractory HLH has a dismal outcome. If the HLH-94 protocol is not used initially, it is can be used followed by allogeneic hematopoietic cell transplantation as a primary option. Alemtuzumab (antiCD52 antibody) has been used in 22 pediatric patients with refractory HLH at median dose of 1 mg/kg divided over a duration of 2-10 days, 77% of the patients survived to undergo allogeneic hematopoietic cell transplantation. 43 Other options would include Janus kinase inhibitors (ruxolitinib). 22 Plasmapheresis can be used in critically ill patients.

Anti-INF-Ɣ monoclonal antibody emapalumab has been recently approved for refractory primary HLH in children and adults and there are ongoing trials in secondary HLH 22, 44 .

In addition to HLH directed therapy, supportive therapy is warranted. Patients usually present with cytopenia, disseminated intravascular coagulopathy, as well as defective T cell immunity and risk of fatal infection.

Correction of any cytopenia and coagulopathy is imperative to safe management. Furthermore, repeated blood transfusions as well as prompt infection management protocols are mandatory. Antivirals are recommended for prophylaxis for all patients, fungal and pneumocystis carinii prophylaxis is given to those patients on the HLH-94 protocol, as well as those with prolonged neutropenia or long-term steroid use. GCSF and GMCSF have been reported to cause capillary leak syndrome and experts advise to avoid their use in active HLH, however, risk versus benefit should be assessed carefully. For patients with Mal-HLH on an intensive chemotherapy protocol it can be utilized to support patients throughout the treatment process.

We would like to thank Dr Ronald Go. Division of hematology, Mayo Clinic for his input in formulation of these guidelines.

Nothing to disclosed

The manuscript has no fund.

Hind Abdin Salama manuscript writer

Gaurav Goyal reviewed and edited the manuscript (as an international expert in histiocytic disease)

• Table 1 : Methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOPP)

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Why tocilizumab could be an effective treatment for severe COVID-19?

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

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The authors have no conflicts of interest to declare J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f