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 symptom triad of fever, splenomegaly and cytopenia, the parameters ferritinemia, triglyceridemia and/or hypofibrinogenemia, increased soluble interleukin (IL)-2 receptor, decreased natural killer (NK) cell activity and evidence of hemophagocytosis in bone marrow, lymph nodes or CSF are included. If at least 5 of the 8 criteria are present, a diagnosis of HLH can be made (Henter JI et al 2007). Sensitivity and specificity of the HLH criteria have been studied mainly in pediatric patients. However, there are also studies in critically ill adult patients that showed sensitivity between 70% and 95% and 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 peripheral blood):

• Hemoglobin < 9 g/dl
• Platelets < 100 × 109/l
• Neutrophils < 1.0 × 109/l

4. hypertriglyceridemia and/or hypofibrinogenemia.

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

5. hemophagocytosis 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 of particular importance as a screening and follow-up parameter (Knaak C et al. 2020).

Immunosuppression: In addition to supportive intensive 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 cornerstone of therapy is the use of high-dose corticosteroids. Treatment beyond this depends on the triggering event and the severity of the disease.

Treatment of infections: If a viral infection is the trigger, it should be treated if possible. In Epstein-Barr virus (EBV)-associated HLH, the administration of rituximab is useful in many cases. Therapy 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 seems to lead to an improvement in 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 therapeutic option in the adult patient (Henter JI et al 2006). It is generally worth noting that, counterintuitively, some infections require initial priority immunosuppressive treatment to prevent irreversible organ damage because of the autoaggressive inflammatory event.

COVID-19: Furthermore, the occurrence of HLH-like symptomatology was also observed in patients critically ill with "coronavirus disease 2019" (COVID-19). Here, however, preliminary data suggest that despite evidence of hyperinflammation, findings clinically and laboratory characteristic of HLH are very rarely encountered and, according to HScore, few patients have a high probability of presenting with HLH. Nevertheless, for patients with severe COVID-19 disease and strong inflammatory response, immunosuppressive therapy has been shown to favorably influence the course (11 Horby P et al. (2020). Therefore, administration of dexamethasone is recommended in patients with COVID-19 disease who require oxygen or are on invasive ventilation.

Malignancy-associated HLH: Malignancy-associated HLH occurs most frequently in patients with hematologic neoplasms. In particular, various lymphoma subtypes appear to be clustered with HLH. HLH associated with a solid tumor is rarely encountered. The therapy of malignoma-associated HLH is challenging because the general condition in a relevant proportion of patients does not allow the actually indicated chemotherapeutic treatment of the HLH-causing malignancy.

Autoimmune diseases: Patients with autoimmunological or rheumatological underlying diseases as triggers represent the third major group of patients with HLH in the ICU.

MAS-HLH: Patients with MAS-HLH initially receive high doses of corticosteroids, followed by cytokine-directed biologics depending on the trigger disease. For example, in MAS-HLH, there is increasing evidence for the efficacy of the IL-1 receptor antagonist anakinra (Zhou S et al. (2018). The doses used in this setting are above the range of approval in other indications. Likewise, hyperinflammatory events associated with cellular and antibody-based immunotherapies have been increasingly reported in recent years. However, it rarely reaches the stage of HLH. 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).

Other treatment options

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

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

Plasmapheresis: In patients in multiorgan failure, cytokine elimination by plasmapheresis or adsorption column can be performed in individual cases to bridge the time until possible pharmacotherapy, especially 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.

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