Secondary hemophagocytic lymphohistiocytosis D76.1

Acquired (primary) hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome classified among the histiocytoses, caused by a massive, exuberant, sepsis-like, inflammatory response of the immune system with overwhelming activation of T lymphocytes and macrophages. The disease is life-threatening.

According to a systematic review of 661 HLH patients,:

• infections (50%)
• hematopoietic malignancies (28 %) and
• autoimmune diseases (12 %)

in the ICU represent the most common precipitating factors (Knaak C et al. 2020).

The leading symptom of hemophagocytic lymphohistiocytosis (HLH) is a protracted high fever that responds inadequately to anti-infective therapy. If enlargement of the spleen and/or liver and bi- or pancytopenia are also present, HLH should be considered and appropriate diagnostic tests should be performed. The level of C-reactive protein (CRP) in HLH is usually strikingly low in relation to the clinical signs of inflammation. In MAS-HLH, on the other hand, leukocytosis and a marked elevation of CRP and fibrinogen are initially seen before the HLH criteria are gradually met with further progression. Other symptoms and laboratory chemical changes that are optional in HLH include neurologic abnormalities, enlarged lymph nodes, elevation of transaminases, and impaired hepatic synthesis capacity manifested particularly by coagulation abnormalities.

Dermatologically, panniculitis and purpuric exanthema are relevant.

The diagnosis of HLH is made using the HLH-2004 criteria (see below). In addition to the triad of symptoms:

• fever
• splenomegaly and
• cytopenia

the parameters ferritinemia, triglyceridemia and/or hypofibrinogenemia, increased soluble interleukin (IL)-2 receptor, reduced natural killer (NK) cell activity and hemophagocytosis in bone marrow, lymph nodes or cerebrospinal fluid are included.

If at least 5 of the 8 criteria are present, the diagnosis of HLH can be made (Henter JI et al. 2007). The sensitivity and specificity of the HLH criteria have mainly been investigated in pediatric patients. However, there are also studies in critically ill adult patients that showed a sensitivity between 70 % and 95 % and a specificity between 90 % and 93.6 %.

HLH-2004 criteria (Henter JI et al. 2007).

1. fever

2. splenomegaly

3. cytopenia (≥ 2 of 3 lines in the peripheral blood):

• Haemoglobin < 9 g/dl
• Thrombocytes < 100 × 109/l
• Neutrophils < 1.0 × 109/l

4. hypertriglyceridemia and/or hypofibrinogenemia

• Fasting triglycerides ≥ 265 mg/dl
• Fibrinogen ≤ 1.5 g/l

5. haemophagocytosis in bone marrow, spleen or lymph nodes

6. low natural killer (NK) cell activity

7. ferritin ≥ 500 μg/l

8. soluble interleukin-2 receptor ≥ 2400 U/ml

In the intensive care unit , the ferritin value is particularly important as a screening and follow-up parameter (Knaak C et al. 2020).

Immunosuppression: In addition to supportive intensive medical care, which may include invasive ventilation, administration of vasopressors, renal replacement therapy and other therapeutic procedures, HLH patients require immunosuppressive treatment to suppress hyperinflammation. The mainstay of therapy is the use of high-dose corticosteroids. Further treatment depends on the trigger and the severity of the disease.

Treatment of infections: If viral infections or other infections (e.g. Leishmania, tubercle bacilli, etc.) are the trigger, these should be treated specifically if possible.

In many cases of Epstein-Barr virus (EBV)-associated HLH, the administration of rituximab is advisable. Treatment of bacterial and parasitic diseases as well as fungal infections can lead to remission of HLH by eliminating the trigger. In addition, the use of immunoglobulins in patients with infectious-triggered HLH appears to improve the prognosis (Knaak C et al. 2020). A combination of dexamethasone and etoposide has been well studied in children with HLH and, in a modified form with a lower dose of etoposide, is also an effective treatment option in adult patients (Henter JI et al. 2006). It is generally worth mentioning that some infections must initially be treated counterintuitively with immunosuppressive therapy to prevent irreversible organ damage due to the autoaggressive inflammatory process.

COVID-19: Furthermore, the occurrence of HLH-like symptoms has also been observed in patients critically ill with coronavirus disease 2019 (COVID-19). However, preliminary data suggest that despite evidence of hyperinflammation, clinical and laboratory findings characteristic of HLH are very rare and, according to HScore, only a few patients have a high probability of having HLH. Nevertheless, for patients with severe COVID-19 disease and a strong inflammatory reaction, it has been shown that immunosuppressive therapy has a favorable effect on the course (11. Horby P et al. (2020). Therefore, the administration of dexamethasone is recommended for patients with COVID-19 disease who require oxygen or invasive ventilation.

Malignoma-associated HLH: Malignoma-associated HLH occurs most frequently in patients with hematologic neoplasms. Various lymphoma subtypes in particular appear to be frequently associated with HLH. HLH associated with a solid tumor is rare. The treatment of malignoma-associated HLH represents a challenge, as the general condition of a relevant proportion of patients does not permit the chemotherapeutic treatment of the malignoma causing HLH that is actually indicated.

Autoimmune diseases: Patients with autoimmunological or rheumatological underlying diseases as triggers represent the third large group of patients with HLH in the intensive care unit.

MAS-HLH: Patients with MAS-HLH initially receive high doses of corticosteroids, followed by cytokine-directed biologics depending on the trigger disease. For example, there is increasing evidence for the efficacy of the IL-1 receptor antagonist anakinra in MAS-HLH (Zhou S et al. (2018). The doses used here are above the approval range in other indications. Hyperinflammatory events in connection with cellular and antibody-based immunotherapies have also been increasingly reported in recent years. However, the stage of HLH is rarely reached. Depending on the trigger, treatment is with corticosteroids and tocilizumab, an antibody directed against IL-6. In severe cases, the administration of etoposide should be discussed (Eichenauer DA et al. 2021).

Further treatment options

Corticosteroids + etoposide: A total of 63 HLH patients with an inadequate response to first-line therapy consisting of corticosteroids and etoposide were treated with the DEP regimen (liposomal doxorubicin, etoposide, methylprednisolone) as part of a prospective study. The response rate was 76.2 %.

Ruxolitinib: Another treatment option is the Janus kinase (JAK)-2 inhibitor ruxolitinib, for whose use in HLH prospective data are also available (27. Zhang Q et al. 2020).

Plasmapheresis: In patients with multiple organ failure, cytokine elimination can be performed in individual cases using plasmapheresis or an adsorption column in order to bridge the time until possible pharmacotherapy, particularly in liver and kidney failure (Eichenauer DA et al. 2021).

Despite maximal intensive care treatment, the prognosis of critically ill patients with HLH is poor. For example, mortality among HLH patients treated in an intensive care unit was nearly 60% according to a systematic review published in 2021, but differed between different patient groups depending on the initiating trigger. Prognosis was least favorable in patients with malignancy-associated HLH (Eichenauer DA et al. 2021).

The presence of HLH should be considered differentially in patients with protracted fever, cytopenias, and enlargement of the spleen and/or liver in the absence of response to anti-infective therapy.

1. Eichenauer DA et al (2021) Hemophagocytic lymphohistiocytosis in critically ill patients. Med Clin Intensiv Med Notfmed 116: 129-134.
2. Fishman JA et al (2019) Inflammatory and infectious syndromes associated with cancer immunotherapies. Clin Infect Dis 69:909-920.
3. Henter JI et al (2006) Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet 367:870-873.
4. Henter JI et al (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer48:124-131.
5. Horby P et al (2020) Dexamethasone in hospitalized patients with Covid-19-preliminary report. N Engl J Med doi: 10.1056/NEJMoa2021436.
6. Knaak C et al (2020) Treatment and mortality of hemophagocytic lymphohistiocytosis in adult critically ill patients: a systematic review with pooled analysis. Crit Care Med doi: 10.1097/CCM.00000000004581.
7. Knaak C et al (2020) Hemophagocytic lymphohistiocytosis in critically ill patients. Shock 53:701-709.
8. Zhang Q et al. (2020) A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis. Haematologica doi: 10.3324/haematol.2020.253781.
9. Zhou S et al. (2018) Biological therapy of traditional therapy-resistant adult-onset still's disease: an evidence-based review. Ther Clin Risk Manag 14:167-171.