OBJECTIVE: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice.
METHODS: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure.
RESULTS: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS.
CONCLUSIONS: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare complication of dengue fever with potentially life-threatening consequences and high mortality. Therefore, this study aims to investigate the prevalence, management and outcome of HLH in dengue fever.
METHODS: The major electronic databases, including PubMed, ScienceDirect and Ovid SP, were searched from inception until 31 January 2024 to identify relevant studies. Pooled prevalence and mortality were calculated using the random-effects generic inverse variance model with a 95% CI. All the statistical analysis was conducted using R programming.
RESULTS: A total of nine studies with 157 patients with HLH, 576 patients with severe dengue and 5081 patients with dengue fever were included in this meta-analysis. The prevalence of HLH in severe dengue (22.1%, 95% CI 8.07 to 48.0%) was significantly higher than the prevalence in dengue fever (3.12%, 95% CI 0.37 to 21.9%). The prevalence of HLH in severe dengue was higher in the paediatric population (22.8%, 95% CI 3.9 to 68.4%) compared with the adult population (19.0%, 95% CI 3.0 to 63.9%). The overall mortality rate was 20.2% (95% CI 9.7 to 37.2%).
CONCLUSIONS: The prevalence of dengue-associated HLH was low in patients with dengue fever but is significantly higher in patients with severe dengue and a high mortality rate.

UNASSIGNED: An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments.
UNASSIGNED: Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases.
UNASSIGNED: Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26-86). The mean time to the onset of symptoms was 10.3 weeks (7 days-14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described.
UNASSIGNED: HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.

We report a case of an adult female with disseminated tuberculosis, cytomegalovirus viraemia and haemophagocytic-lymphohistiocystosis syndrome associated with neutralizing anti- interferon gamma (IFNγ) autoantibodies demonstrated by absent IFNγ stimulated STAT1 phosphorylation in the presence of patient sera. A brief review of immunodeficiency caused by anti-IFNγ autoantibodies is also described.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) has a potentially high mortality rate. Anakinra, an interleukin-1 receptor antagonist, is now recommended early in HLH/MAS, with intravenous (IV) use proposed in critically unwell patients. This systematic review establishes the literature relating to IV anakinra in secondary HLH/MAS (sHLH/MAS).
METHODS: We screened Embase, PubMed, and Medline, including all reports of IV anakinra for HLH or MAS. We extracted age, HLH/MAS trigger, continuous infusion or bolus dosing, and survival.
RESULTS: Twenty-nine case reports/series identified 87 patients (median age 22 years, range 22 months to 84 years), all with sHLH. Amongst identifiable triggers, 43% were systemic infection, 33% rheumatological, 9% oncological. Children had predominantly a rheumatological trigger (48%), whilst adults were more commonly infection-driven (50%). Overall, rheumatologically triggered disease showed greater survival (83.3%), particularly compared with oncological triggers (42.9%). Children had a greater survival, particularly under 10 years (83%, vs. adults, 63%).
CONCLUSIONS: Despite IV anakinra recipients likely to be critically unwell, this cohort had similar disease triggers and survival compared to large historical cohorts, and enhances awareness of age and trigger-specific survival patterns. IV anakinra had a wide therapeutic dosing range and tolerability, regardless of trigger, demonstrating substantial utility in severe sHLH/MAS.

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory hyperferritinemic syndrome, is triggered by various etiologies and diseases and can lead to multiorgan dysfunction and death. There are two types of HLH: primary and secondary. Primary HLH (pHLH) is caused by a genetic mutation resulting in dysfunction in cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, hyperactivated immune cells, and hypercytokinemia. In secondary HLH (sHLH), an underlying etiology is the cause of the disease. Infections, malignancy, and autoimmune diseases are well-known triggers for sHLH. Infectious triggers for sHLH are most frequently viruses, where different mechanisms, including dysregulated CTLs and NK cell activity and persistent immune system stimulation, have been reported. Similarly, in severe coronavirus disease 2019 (COVID-19) patients, a hyperinflammatory mechanism leading to hypercytokinemia and hyperferritinemia has been demonstrated. A similar dysfunction in CTLs and NK cells, persistent immune system stimulation with increased cytokines production, and severe end-organ damage have been reported. Therefore, a significant overlap is present between the clinical and laboratory features seen in COVID-19 and sHLH. However, SARS-CoV-2, similar to other viruses, can trigger sHLH. Hence, a diagnostic approach is needed in severe COVID-19 patients presenting with multiorgan failure, in whom sHLH should be considered.

Scrub typhus is a natural foci disease caused by the bacteria Orientia tsutsugamushi. Symptoms of the disease range from fever to severe multiple organ dysfunction. The diagnosis is based on clinical signs and antibody serological tests, which has poor sensitivity and specificity. Scrub typhus is rarely associated with multiple organ dysfunction syndrome (MODS) and haemophagocytic lymphohistiocytosis (HLH). In this paper, we report a 17-year-old Asian male who was characterized with a persistent fever without eschar. He was diagnosed with scrub typhus using metagenomic next-generation sequencing (mNGS) of the blood after negative of routine examinations. The patient was progressed to HLH and MODS but had a good recovery following anti-rickettsial therapy, dexamethasone, and advanced life support. Besides, we present a brief overview of the literature about scrub typhus and associated complications.

Invasive mould infections are life-threatening and mainly occur in immunocompromised patients. Whereas aspergillosis is described during haemophagocytic lymphohistiocytosis (HLH), only a few cases of concomitant mucormycosis with HLH have been reported. Here, we present an uncommon coinfection of mucormycosis and aspergillosis associated with HLH probably due to a varicella zoster virus (VZV) viraemia which was unresponsive to triple antifungal therapy (liposomal amphotericin B combined with isavuconazole and caspofungin). A review of the cases of mucormycosis with HLH showed that this uncommon association was always lethal and underscored the relevance of screening for mould infections in patients with HLH.

Tuberculosis-associated haemophagocytic lymphohistiocytosis (HLH) is rare in paediatrics and can be fatal if not recognised and treated on time. A 3-month-old infant with tuberculosis and HLH is described. He was successfully treated with anti-tuberculous therapy (ATT) which comprised isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin and dexamethasone (10 mg/m2/day). On Day 28 of therapy, he developed a paradoxical upgrading reaction to ATT for which he was again treated with (oral) corticosteroids for 4 weeks. He recovered successfully and is now completely well and asymptomatic. To the best of our knowledge, this is the first case of a child having a paradoxical upgrading reaction following treatment for TB-HLH.Abbreviations ATT: anti-tuberculous therapy; CB-NAAT: cartridge-based nucleic acid amplification test; CECT: contrast-enhanced computed tomography; HLH: haemophagocytic lymphohistiocytosis; NK: natural killer, PUR: paradoxical upgrading reaction; sHLH: secondary HLH.

Disseminated toxoplasmosis associated with haemophagocytic lymphohistiocytosis (DT-HLH) is rare and difficult to diagnose compared to disseminated toxoplasmosis or HLH presenting alone. Because of the limited number of reported cases, the clinical characteristics and outcomes of DT-HLH are unknown. We report a case of DT-HLH in a human immunodeficiency virus (HIV)-infected patient who was successfully treated with early anti-toxoplasmic therapy and performed a comprehensive literature review. A 33-year-old Cameroonian woman was transferred to our hospital owing to HIV infection and encephalitis. Although she developed HLH, bone marrow biopsy did not reveal the cause. She was diagnosed as having DT-HLH via polymerase chain reaction testing of bone marrow biopsy tissue, blood, and cerebrospinal fluid. DT-HLH improved within the initial two weeks of treatment for toxoplasmosis (sulfamethoxazole-trimethoprim, trimethoprim 10 mg/kg/day and clindamycin 1,800 mg/day) before the introduction of antiretroviral therapy. To our knowledge, only eight cases of DT-HLH have been previously reported in the literature. Most patients died within three weeks of hospitalisation and were diagnosed by autopsy. Conversely, patients diagnosed antemortem were all treated and survived, including the currently reported patient. DT-HLH can lead to poor prognosis without early and proper treatment. Clinicians should consider toxoplasmosis in the differential diagnosis of HLH.