Haemophagosytic limphohistiosytosis (HLH) in adults - clinical features, triggering diseases, prognostic factors and outcomes: Report of thirty-three cases

*Corresponding Author:

Liliya Yankova Komsalova
Hospital Marina Salud
Dénia, Alicante, Spain
E-mail: li_kom04@yahoo.es

Abstract

Objective: To analyse clinical features, triggering diseases, treatment strategies and prognostic factors in patients with secondary haemophagosytic limphohistosytosis (SHLH).

Methods: We retrospectively analysed thirty-three patients with positive haemophagocytosis bone marrow biopsies, all collected between 1995 and 2015 from two different hospitals.

Results: The average age was 44.39 years with a man/women ratio 1.06/1. The underlying diseases were as follows: Autoimmune diseases (n=11), liver or kidney transplant (n=9), haematological malignancies (n=5) infection (n=5) and solid organ cancer (n=3). The average time from hospitalisation to death was 49.95 days (49.95 ± 39.608). Three different prognostic factors were separately analysed: overall mortality, severe disease (less than two months to death) and extremely severe disease (less than one month to death). Risk factors associated to overall mortality were age >35 years (p<0.011), severe cytopenias such as anaemia (p<0.002), bicytopenia (p<0.007) and pancytopenia (p<0.025), ongoing lung involvement (p<0.012) and sepsis (p<0.044). Risk factors for severe disease were underlying treatment with corticosteroids alone (p<0.013), severe anaemia (p<0.002), neutropenia (p<0.027) and pancytopenia (p<0.016). Severe hypofibrinogenemia (p<0.039), ongoing lung involvement (p<0.022) and a late start to specific treatment (p<0.047) were highly indicative for severe disease, whereas underlying autoimmune disorder (p<0.003) and the simultaneous use of immunosuppressant at the onset (p<0.007) seemed to act as a protective factor for severe disease. Risk factors for extremely severe disease were underlying solid organ cancer (p<0.043), severe cytopenias such as thrombocytopenia (p<0.016), bicytopenia (p<0.016) and pancytopenia (p<0.009), and a late start to specific treatment (p<0.043).

Conclusions: Patients with secondary HLH might have a different prognosis according to the triggering disease. Underlying autoimmune disorder might be related to a better prognosis and malignancy might indicate high mortality. Early recognition and specific treatment is essential for the patient’s survival whereby tight suspicion is necessary for an attempt at curative therapy to be made.

Keywords

haemophagosytic lymphohistiosytosis, macrophage activation syndrome, haemophagositosis, autoimmune diseases, prognostic factors, adults

Introduction

Haemophagocytic lymphohistiosytosis (HLH) is the clinical manifestation of a wide array of different entities, which include primary or familial haemophagocytic lymphohistiocytosis (FHLH) and secondary forms. The hallmark is haemophagocytosis, appearance of activated macrophages that have engulfed other haematopoietic elements. FHLH, mainly documented in early infancy, is related to familiar inheritance or genetic causes [1]. Secondary forms (SHLH), also called reactive HLH, are frequently diagnosed in adults and refer to cases with underlying infection, malignancy or autoimmune disease [2]. Over the last decade immunosuppression, immunodeficiency, auto inflammatory diseases and inborn errors of metabolism have been also described as triggering diseases [3]. Macrophage activation syndrome (MAS) is a secondary form, recently reported in patients with autoimmune or auto inflammatory diseases, especially patients with systemic juvenile idiopathic arthritis (SJIA), Systemic lupus erythematosus (SLE), and adult onset systemic Still’s disease (AOSD) [4]. Our study reports 33 adult cases and we try to analyse triggering diseases, prognostic factors, treatment strategies and outcomes.

Patients and methods

This study includes thirty-three patients from two hospitals, Doce de Octubre, Madrid and Marina Salud, Denia.

All patients were diagnosed positive for haemophagocytosis by bone marrow biopsy reviewed by expert pathologists between 1995 and 2015. Patients without positive biopsy were not included. All patients were diagnosed with HLH according to HLH-diagnostic guidelines during the time of their hospitalisation. We also collected the following chart for each patient: age, gender, underlying triggering disease or infection, underlying treatment with corticosteroids, immunosuppressant or mycophenolate mofetil (MFM). Clinical features such as long-lasting fever, splenomegaly, ongoing liver, central nervous system (CNS) or lung involvement, and sepsis were also reported. Underlying and ongoing infection were separately evaluated. The laboratory data collected from each patient were: haemoglobin, neutrophil and platelet count, as well as ferritin, fibrinogen and triglyceride levels, and NK cell counts (if available). We separately evaluated three outcomes: overall mortality (OM), severe disease (SD) (less than two months to death) and extremely severe disease (ESD) (less than one month to death). Quantitative variables such as age were evaluated by T Student test for simple independent variables. For the rest of the qualitative variables we used Chi square test. Statistical significance was set at P<0.05. Associations were expressed using Odds ratios (ORs) with 95% confidence interval (95% CI).

Results

This study includes thirty-three patients from two hospitals, Doce de Octubre, Madrid and Marina Salud, Denia.

All patients were diagnosed positive for haemophagocytosis by bone marrow biopsy reviewed by expert pathologists between 1995 and 2015. Patients without positive biopsy were not included. All patients were diagnosed with HLH according to HLH-diagnostic guidelines during the time of their hospitalisation. We also collected the following chart for each patient: age, gender, underlying triggering disease or infection, underlying treatment with corticosteroids, immunosuppressant or mycophenolate mofetil (MFM). Clinical features such as long-lasting fever, splenomegaly, ongoing liver, central nervous system (CNS) or lung involvement, and sepsis were also reported.

Clinical features and underlying diseases

The average age was 44.39 years (range 18- 78 years) Table 1. 17 (51.5%) patients were male and 16 (48.5%) were female, with male/ female ratio 1.06/1. 11 (33.3%) patients were diagnosed as having autoimmune disease at the onset, 9 (27.3%) had liver or kidney transplant, 5 (15,2%) haematological malignancies, 5 (15.2%) underlying infection and three (9.1%) solid organ cancer. 23 (69.7%) patients had infection at the onset and in five of those patients the infection was the only known trigger, while for the rest infection and other triggers were simultaneously presented. 17 (51.5%) patients received corticosteroids at the onset, but only six of them had long-term treatment with corticosteroids alone. 20 (60.6%) patients received any immunosuppressant at the onset (including corticosteroids). 10 (90.9%) of the 11 patients with autoimmune disorder had immunosuppressant at the onset and 5 corticosteroids alone. The autoimmune disorders collected in our study were: systemic lupus erythematosus (SLE) (n=5), rheumatoid arthritis (RA) (n=3), adult onset systemic Still’s disease (ASD) (n=2) and Sjögren´s syndrome (SS) (n=1). Haematological malignancies were: Non-Hodgkin Lymphoma, 2 patients, T cell lymphoma, 2 patients and Myelodysplastic syndrome, 1 patient. The most frequent infectious agents were Epstein Barr virus (EBV) (n=8), Mycobacterium tuberculosis (n=2), Leishmania (n=2), Cytomegalovirus (CMV) (n=2), Toxoplasma gondii (n=2), Aspergillus fumigatus (n=3), Staphylococcus aureus (n=1), Human Herpesvirus type 6 (n=1), Pseudomonas aeruginosa (n=1) and HIV (n=1). All patients had long-lasting fever. Splenomegaly was present in 24 (72.7%) patients and liver dysfunction in 19 (59.4%). Central nervous system (CNS) manifestations such as convulsions had 2 patients, meningoencephalitis 3, encephalopathy 6 and 2 had cephalea. 17 (51.5%) patients developed pulmonary disorders during the disease course, such as pneumonia (n=7), pleural effusions (n=5) and acute respiratory failure (n=5). Severe haemorrhage was reported in 4 patients, significant skin rash in 1 patient and arthralgia in 4. Severe ongoing infection or sepsis was developed by 6 patients.

Table 1. Clinical features and underlying diseases

Laboratory tests

All values were fixed at the time of diagnosis. Haemoglobin (Hgb) levels were available in all patients, with median haemoglobin nadir 84 +/- 1.703 g/L (range 29.0-139.0). 19 (57.6%) patients had severe anaemia (Hg<to 85 g/L), 13 (39.4%) had severe neutropenia (neutrophils <0.5 × 10*9/L) and 15 (45.5%) had severe thrombocytopenia (platelets <35 × 10*9/L). 9 (27.3%) patients had severe bicytopenia such as anaemia and neutropenia, and 11 (33.3%) had anaemia with thrombocytopenia. Severe pancytopenia was detected in 7 (21.2%) patients. 16 (48.5%) patients had high triglyceride levels (TG>265 mg/dL). Hypofibrinogenemia (<1.5 g/L) was detected in 10, and severe hypofibrinogenemia (<1.0 g/L) in 6 patients. NK cell count was available in 8 patients. 7 of them had a very low NK cell count (range 0-10) and one had normal NK values (99). Ferritin levels were available in 19 patients. 16 of those patients had ferritin levels higher than 500 ng/ mL, and 5 had ferritin levels higher than 5000 ng/mL (Table 2).

Table 2. Laboratory tests

Treatment

In order to evaluate the outcome of the used therapies we divided the patients into 4 sets;

• Patients without specific treatment, 3 (9.1%).

• Corticosteroids alone, 10 (30.3%).

• Corticosteroids with another immunosuppressant (and immunoglobulin in 3 cases), 10 (30.3%).

• Corticosteroids, cyclosporine and Etoposide, 10 (30.3%) patients.

Two patients with NHL (Non-Hodgkin Lymphoma) also received Cyclophosphamide, Vincristine and Adriamycin, and another two patients who had T cell lymphoma received Rituximab. Antibiotics were administered in all cases with bacterial or mycobacterial infection (n=15) and Acyclovir in eight patients. Three patients received intravenous immunoglobulin. The immunosuppressant drugs widely used were cyclosporine, 11 patients, tacrolimus 4, and azathioprine 1 patient.

Bone marrow biopsy

The biopsy images were uniformly presented by benign histiocytes hyperplasia, independently of the associated infections or co morbidities. In nine of those cases, the haematopoietic bone marrow cellularity was significantly erased by the histiocytes hyperplasia. The haemophagocytosis was a common event in each biopsy and in some cases accompanied by cellular debris.

Outcomes

Table 3 Overall mortality: 19 (57.6%) patients from the 33 in our study died (overall mortality rate 57.6%). The average period from time of hospitalisation to death was 49.95 days (49.95+/- 39.608), range 14-180 days. The overall mortality for the patients with underlying autoimmune disorder (MAS) was lower, 36.3% (4 patients died and six survived). The consecutive monitoring of one of those patients was lost after one year. According to time of death, 7 patients (21.2%) died in less than one month, and 15 (45.5%) died in less than two months. Only one patient with MAS died in less than one month, while the remaining patients had a higher rate (six). Risk factors significantly associated to overall mortality were age >35.08 (p<0.009), underlying treatment with MFM (p<0.028), severe anaemia (p<0.007), severe bicytopenia (anaemia and neutropenia) (p<0.007), severe pancytopenia (p<0.025), ongoing lung involvement (p<0.012) and severe ongoing infection or sepsis (p<0.044). Risk factors for extremely severe disease were underlying solid organ cancer (p<0.043), severe thrombocytopenia (p<0.016), severe bicytopenia such as anaemia and thrombocytopenia (p<0.016), and anaemia with neutropenia (p<0.046), severe pancytopenia (p<0.009) and a late start to specific treatment (p<0.043). Severe hypofibrinogenemia (<1.0 g/L) showed a trend towards a significance (p<0.057) for extremely severe disease. Risk factors for severe disease were underlying treatment with alone (p<0.013), severe anaemia (p<0.002), severe neutropenia (p<0.027) and severe pancytopenia (p<0.016). Severe hypofibrinogenemia (p<0.039), ongoing lung involvement (p<0.022) and a late start to specific treatment (p<0.047) were highly indicative of severe disease. Infection at the onset showed a trend towards a significance for severe disease (p<0.053).

Table 3. Overall mortality

Patients with MAS had a better prognosis (p<0.003) and the simultaneous use of immunosuppressant typical for those patients, seemed to act as a protective factor (p<0.007), corresponding odds ratios (OR)=0.057(0.006- 0.532) CI 95%, and Odds 0.71(0.008-0.664) CI 95%. Statistically significant outcomes for variables such as gender, splenomegaly, haepatopathy, ferritin or triglyceride levels as well as treatment strategies 2, 3 or 4 were not found.

Discussion

HLH is a rare, potentially life threatening immune disorder which includes a long lasting fever, haepatoslnomegaly and laboratory findings such as cytopenias, hyperferritinaemia, hypertriglyceridemia and/ or hypofibrinogenaemia. Pathogenesis remains unknown; nevertheless, impaired T and natural killer (NK) cell cytotoxicity seem to be involved [5]. Over the last few decades a variety of genetic disorders have been discovered in patients with FHLH, all responsible to encode proteins participating in the granule-dependent cytotoxic function of natural killer (NK) and T cells [6]. All cytotoxic cells are equipped with cytotoxic granules, called lysosomes, where perforin and granzym B are stored. Upon activation of natural killer (NK) cells and cytotoxic lymphocytes (CTLs), perforin is inserted into the plasma membrane and starts polymerisation. This results in perforin forming pores in the cell membrane and granzym B enters the target cell, giving the start signal for the programmed cell death [7]. The presence of defects in the granule dependent cytotoxic activity may result in that NK and CTLs fail to kill target cells and remove the source of antigenic stimulation. The persistent antigenic stimulation leads to continuous antigen driven activation and proliferation of new cytotoxic T cells with overproduction of inflammatory cytokines, such as interferon γ (IFR γ). In response to this continuous stimulation, macrophages become haemophagocytic. In 2010, Grom and Mellins showed that cytolytic function in patients with MAS was found to be profoundly depressed [8]. Low NK cytolytic activity has been also reported in patients with SJIA, and that data was used to differentiate those patients from the other forms of childhood arthritis. It appears that multiple factors; genetic abnormalities and acquired factors might lead to abnormal cytolytic function in patients with SJIA and MAS. Later, in 2012, Canna and Behrens presented IFN gamma as a critical pro-inflammatory mediator, which delivered via osmotic pump is sufficient to cause haemopahgocytosis and anaemia [9]. The same reviewers described the mechanisms by which the combination of viral infection and abnormal cytolytic function might result in HLH, suggesting that MAS and HLH are overlapping diseases.

An important finding in our study is that, that patients with MAS have a lower risk of severe disease. To date, several studies have confirmed that data Table 4. Dhote, in a study of twentysix cases with underlying autoimmune disorder found overall mortality 38.5% [10]. Fukaya, in a study of 30 similar cases reported overall mortality 20% [11]. Takahashi, in a study of 52 cases (including lymphoma, virus, bacteria and autoimmune associated HLH) showed that prognosis depended on the underlying disease and found that patients with lymphoma associated HLH had a lower survival rate [12]. Otroch, in a similar study of 73 cases (including Infection, malignancies, primary immunodeficiency, post solid organ transplantation, idiopathic and autoimmune associated HLH) pointed out malignancy as a risk factor [13]. Our study confirmed that patients with underlying solid organ cancer had a worst prognosis. We also discovered that patients with MAS and those who had simultaneous immunosuppressive treatment seemed to have less severe disease. That data was not confirmed by other studies where underlying immunosuppressive treatment was more likely associated with a worst prognosis Table 4. Factors such as younger age and lower association with comorbidities might act as biases. Future studies are necessary in order to clarify that data.

Table 4. Risk of severe diseases in MAS patient

Overall mortality in our study was higher (57.6%) and closer to studies focused on malignancies, virus and post transplantation associated HLH. Karras, in a study of 17 patients with renal transplantation associated HLH reported overall mortality 47% [14]. Shabbir, in a study of 18 patients with haematological malignancies, post-transplantation, sepsis, and autoimmune diseases associated HLH reported 67%, and Warley, in a similar study, 53.4% [15,16]. Our study highlighted that younger patients (<35.08 years) had a better survival rate. This data was confirmed by several authors. In 1997, Kaito reported age >30 years as a significant factor for the patients survival [17]. In 2008, Fukaya pointed out age >50 years and later, in 2015, Otrock, age >30 years associated with a worst prognosis Table 4. Cytopenia involving >2 cell lines was defined as a diagnostic criterion according to Haemophagocytic Limphohistiocytosis guidelines 2004. Over the last 10 years, several authors pointed out bicytopenia, usually attributed to hypercitokinemia, as important factor for the patient’s survival. Lehmberg, in a review of sensibility and specificity of HLH guidelines 2004 exposed that bicytopenia was fulfilled in most cases and neutrophils were frequently the last cell line to drop [18]. Our study found a close relationship between severe anaemia, bicytopenia and pancytopania and patient survival. Such data was confirmed by a wide variety of studies. Takakashi and Kaito reported anaemia and thrombopenia, Fukaya, leucopenia and thrombocytopenia, and Dhote, thromcytopenia related to a poor prognosis Table 4. The excess of ferritin usually reflects macrophage activation and suggests that high levels of ferritin, and more important, a failure of ferritin to fall dramatically after specific treatment, highly indicative of a worse prognosis. Unfortunately, our study did not demonstrate a significant relationship between ferritin levels and prognosis, probably because of the low sampling size. Nevertheless, that data was confirmed by authors such as Takakashi, Otrock and Kaito Table 4. Hypofibrinogenemia is not always present at the beginning of HLH, even if in some cases it could be a normal fibrinogen level. This abnormality usually is due to the fibrinogen property to act as acute phase protein. However, a normal fibrinogen range in patients with long lasting fever should be suspicious. Our study highlighted severe hypofibrinogenemia (fibrinogen levels <1.0 g/L) as an important risk factor for a worst prognosis and that date was confirmed by Karras and Kaito Table 4. Underlying treatment with corticosteroids and/ or immunosuppressant was reported by Dothe as a risk factor for a worst prognosis Table 4. In our study, we tried to analyse that data and we confirmed that patients who had received corticosteroids alone had a worse prognosis. Having an infection at the onset was found statistically significant for patient´s survival. Infection and/ or high C reactive protein levels, as risk factors for poor prognosis were reported by Fukaya Table 4. We tried to analyse that data and we found that underlying infection showed a trend towards a significance for a worse prognosis. Furthermore, we separately analysed patients with ongoing infection or sepsis and we found strong relationship with mortality. Our study also discovered that patients with ongoing lung involvement had a higher mortality rate. Such data has not been analysed by other authors and should be cautiously interpreted because of the fact that patients with lung involvement usually have a severe ongoing infection. Micophenolate mofetil (MFM) as a possible cause of haemophagocytic syndrome was mentioned by Raffray in 2010 [19]. We analysed four patients with underlying MFM treatment and obtained similar results. Nevertheless, such data should be cautiously interpreted because of the small sampling size and other confounding factors.

Therapeutic strategy: HLH treatment remains challenging

Suppression of the severe hyper inflammation and reduction of the storm of cytokines is the main and immediate aim of HLH treatment. Identifying triggering infections and elimination of the stimulus for the rapid but ineffective T-cell activation is the second but not less important point in this management. The first achievement in the treatment of HLH in adults has been reported in 2 protocols, the HLH-94, and the HLH-2004 [20]. Both recommend the use of etoposide in combination with corticosteroids and cyclosporine A (CSP) as a successful treatment to achieve remission. Corticosteroids, which are cytotoxic for lymphocytes and inhibit cytokines expression, are one of the most important therapeutic agents [21]. Dexamethasone (DXA) crosses the blood brain barrier better than prednisolone and is the preferred glucocorticoid for less severe cases [22]. CSP, which inhibit T lymphocyte activation, and immunoglobulin infusions (IVIG), which act by providing cytokines and pathogen-specific antibodies, are also frequently used. IVIG could be successfully used if started early in HLH treatment [23]. Etoposide is an effective drug for monocytic and histiocytic disease usually preserved for more severe cases. Etoposide has also been reported as a lifesaving, especially in patients with EBV associated HLH [24]. The HLH 94 protocol should not be used at all in patients with MAS where methylprednisolone pulse for 3 days, followed by methylprednisolone 2-3 mg/kg is the preferred drug [25]. Recently the interleukin-1 receptor antibody Anakinra has been successfully applied in patients with MAS, showing promising results [26]. Several case reports describe the use of Rituximab (anti cd- 20 monoclonal antibody) in patients with HLH secondary to Hodgkin lymphoma [27]. Patients with MAS were also successfully treated with Rituximab [28,29]. Drugs such as Alemtuzumab, infliximab, daclizumab and haematopoietic cell transplant have been also used as salvage therapies. Remission of the triggering disease might increase efficiency of immunosuppressive therapy [30]. Anecdotal case with successful MMF treatment has been recently reported [31].

However, despite the fact that prognosis of HLH has improved over the last 10 years; it is essential not to delay specific treatment [32]. Our study demonstrates that early recognition and specific treatment is essential for the patient’s survival. Unfortunately, we did not found relationships between the use of corticosteroids, CSP or Etoposide and prognosis. However, we confirmed that tight suspicion from the beginning remains lifesaving, and the use of new strategies might change the disease prognosis.

References

1. Gholam C, Grigoriadou S, Gilmour KC et al. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin. Exp. Immunol. 163(3), 271–83 (2011).
2. George MR. Hemophagocytic lymphohistiocytosis: rewiew of ethiologies and managemet. J. Blood. Med. 5, 69–86 (2004).
3. Bode SF, Ammann S, Al-Herz W et al. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica. 100(7), 978–88 (2015).
4. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch. Dis. Child. 85(5), 421–6 (2001).
5. Grom AA. Natural Killer Cell Dysfuntion: A common pathway in sistemic-onset juvenile rheumatoide arthritis, macrophage ativation syndrome, and Hemophagocytic lymphohistiocytosis? Arthritis. Rheum. (2004).
6. Jordan MB, Allen CE, Weitzman S et al. How I treat hemophagocytic lymphohistiocytosis. Blood. 118, 4041–4052 (2011).
7. Aricò M, Danesino C, Pende D et al. Pathogenesis of haemophagocytic lymphohistiocytosis. Br. J. Haematol. 114, 761–769 (2001).
8. Grom AA, Mellins ED. Macrophage activation syndrome: advances towards understanding pathogenesis. Curr. Opin. Rheumatol. 22(5), 561–6 (2010).
9. Canna SW, Behrens EM. Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes. Curr. Opin. Rheumatol. 24(1), 113–118 (2012).
10. Dhote R, Simon J, Papo T et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis. Rheum. 49(5), 633–9 (2003).
11. Fukaya S, Yasuda S, Hashimoto T et al. Clinical features of hemophagocytic síndrome in patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology. 47(11), 1686–91 (2008).
12. Takahashi N, Chubachi A, Kume M et al. A clinical analysis of 52 adult patients with hemophagocytic síndrome: the prognostic significance of the underlying diseases. Int. J. Hematol. 74(2), 209–13 (2001).
13. Otrock ZA, Eby CS. Clinical characteristics, prognosis factors, and outcomes of adult patiens with hemophagocytic lymphohistiocytosis. Am. J. Hematol. 90(3), 220–4 (2015).
14. Karras A, Thervet E, Legendre C. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation. 77(2), 238–43 (2004).
15. Shabbir M, Lucas J, Lazarchick J et al. Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and review of literature. Hematol. Oncol. 29(2), 100–6 (2011).
16. Warley F, Bonella BM, Odstrcil-Bobillo MS et al. Hemophagocytic limphohistiocytosis. Experience in 27 patients. Rev. Med. Chil. 145(3), 344–350 (2017).
17. Kaito K, Kobayashi M, Katayama T et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur. J. Haematol. 59(4), 247–53 (1997).
18. Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemopahagocytic limphohistiocytosis. Br. J. Haematol. 160(3), 275–87 (2013).
19. Raffray L, Couzi L, Viallard JF et al. Mycophenolate mofetil: a possible cause of hemophagocytic syndrome following renal transplantation. Am. J. Transplant. 10(10), 2378–9 (2010).
20. Henter JI, Horne AC, Aricó M et al. HLH-2004: Diagnosis and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood. Cancer. 48(2), 124–31 (2007).
21. Janka G, Stadt UZ. Familial and acquired Hemophagocytic Lymphohistiocytosis. Hematology. Am. Soc. Hematol. Educ. Program. 2005, 82–8 (2005).
22. Janka G, Lehmberg K. Hemophagocytic Lymphohistiocytosis: pathogenesis and treatment. Hematology. Am. Soc. Hematol. Educ. Program. 2013, 605–11 (2013).
23. Emmenegger U, Frey U, Reimers A et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am. J. Hematol. 68(1), 4–10 (2001).
24. Imashuku S, Kuriyama K, Tramura T et al. Requirement for etoposide in the treatment of Ebstein- Barr- associaed Hemophagocytic Lymphohistiocytosis. J. Clin. Oncol. 19(10), 2665–73 (2001).
25. Roseé PL. Treatment of Hemophagocytic Lymphohistiocytosis in adults. Hematology. Am. Soc. Hematol. Educ. Program. 2015, 190–6 (2015).
26. Miettunen PM, Narendran A, Jayanthan A et al. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 50(2), 417–419 (2011).
27. Hu S, Bansal P, Lynch D et al. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature. J. Med. Case. Rep. 10, 365 (2016).
28. Bakshi J, Hassan S, D'Cruz D et al. Rituximab therapy in refractory macrophage activation syndrome secondary to systemic lupus erythematosus. Lupus. 22(14), 1544–6 (2013).
29. Junga Z, Stitt R, Tracy C et al. Novel use of rituximab in macrophage activation syndrome secondary to systemic lupus erythematosus. BMJ. Case. Rep. 2017 (2017).
30. Karlsson T. Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital. Ups. J. Med. 120(4), 257–62 (2015).
31. Nawata T, Kubo M, Shiragami K et al. Succssful treatment of Hemophagocytic limphohistiocytosis associated with lupus nephritis by using mycophenolate mofetil. Case. Rep. Rheumatol. 2017, 4159727 (2017).
32. Olivera C, Chacim S, Ferreira I et al. Secondary hemophagocytic syndrome: The importance of clinical suspicion. Case. Rep. Hematol. 2014, 958425 (2014).