What is the management approach for pediatric patients with macrophage dysfunction syndromes?

Management of Pediatric Macrophage Dysfunction Syndromes

Initiate high-dose intravenous methylprednisolone (15-30 mg/kg/day, maximum 1g/infusion) immediately upon diagnosis, with cyclosporine A added within 24-48 hours for severe cases or inadequate initial response. 1

Initial Diagnostic Approach

Before initiating immunomodulatory therapy, confirm the diagnosis using HLH-2004 criteria, which requires 5 of 8 parameters: cytopenias affecting ≥2 lineages, hypertriglyceridemia and/or hypofibrinogenemia, low/absent NK cell activity, ferritin ≥500 μg/L (though >10,000 μg/L is highly specific), soluble CD25 ≥2,400 U/mL, fever, splenomegaly, and hemophagocytosis on bone marrow examination. 2 However, clinical judgment may warrant treatment initiation even when fewer criteria are met, particularly in life-threatening presentations. 1

Critical pitfall: MAS is frequently underdiagnosed because features overlap with severe sepsis, disease flares, or cytokine release syndrome. 2 Serial bone marrow assessment may be necessary, as absence of hemophagocytosis does not exclude MAS. 2

First-Line Treatment Protocol

High-Dose Glucocorticoids

• Administer intravenous methylprednisolone pulses at 15-30 mg/kg/day (maximum 1g/infusion) for 3-5 consecutive days. 1, 3
• For central nervous system involvement, use dexamethasone instead, as it crosses the blood-brain barrier more effectively. 1
• Methylprednisolone pulse therapy is effective in approximately two-thirds of patients. 4

Early Addition of Cyclosporine A

• Add cyclosporine A within 24-48 hours for severe cases or inadequate response to steroids alone. 1
• Cyclosporine can be administered orally or intravenously, particularly in critical care settings. 1
• This combination is particularly effective in systemic juvenile idiopathic arthritis (sJIA)-associated MAS. 4, 5, 6

Anakinra (IL-1 Receptor Antagonist)

• Administer at 2-10 mg/kg/day subcutaneously in divided doses as an effective alternative or addition to cyclosporine, particularly in Still's disease-related MAS. 1
• High-dose anakinra may be required in refractory cases. 7

Second-Line Therapies for Refractory Disease

Intravenous Immunoglobulin (IVIG)

• Consider IVIG at 2 gm/kg for patients not responding adequately to first-line therapy. 2
• IVIG was effective in two out of six patients in one pediatric series. 4

Tocilizumab (IL-6 Blockade)

• Increasing evidence supports efficacy in MAS-HLH, particularly when associated with systemic rheumatic conditions. 1

Emapalumab (Anti-IFN-γ Antibody)

• For refractory MAS failing standard therapy, emapalumab has demonstrated efficacy in achieving remission in the majority of patients. 1
• Successfully used in combination with etoposide, anakinra, tacrolimus, and corticosteroids in infection-induced MAS. 7

JAK Inhibitors

• Ruxolitinib or baricitinib have shown efficacy in case reports of refractory MAS. 1

Etoposide

• Consider in severe, refractory cases, though this represents escalation to chemotherapy-level immunosuppression. 2, 7

Critical Care Management

Reassess clinical status at least every 12 hours to determine need for escalation of therapy. 1 Consider ICU admission for patients with shock, severe organ dysfunction, or grade 3 or higher neurotoxicity. 1

Monitoring Parameters

• Serial laboratory testing including ferritin levels, complete blood count, coagulation parameters, and liver function tests. 2
• Sequential monitoring of inflammation markers, BNP/NT-proBNP, and troponin T levels. 8
• EKG at minimum every 48 hours in hospitalized patients to detect conduction abnormalities. 8

Disease-Specific Considerations

Still's Disease (sJIA/AOSD)-Related MAS

• First-line: high-dose glucocorticoids, cyclosporine A, anakinra, or tocilizumab. 1
• Patients with sJIA respond particularly well to corticosteroids and cyclosporine combination. 4
• Etanercept has been successfully used in steroid and cyclosporine-resistant cases. 6

Infection-Triggered MAS

• Initiate appropriate antimicrobial therapy alongside immunosuppressive treatment. 1
• Epstein-Barr virus and adenovirus are common triggers in sJIA patients. 4, 7
• Monitor for opportunistic infections including Pneumocystis jiroveci during immunosuppression. 4

MAS Complicating MIS-C

• Treatment must deviate from standard MIS-C protocols when overt MAS develops. 8
• Follow MAS-specific recommendations rather than standard IVIG/glucocorticoid protocols for MIS-C. 8

Common Pitfalls and Complications

• Avoid delaying treatment while awaiting complete diagnostic workup in life-threatening presentations. 1 Pursue ongoing diagnostic evaluation in parallel with treatment by a multidisciplinary team. 8
• Monitor for hepatotoxicity, particularly in young children (<3 years), where 2-fold to 25-fold elevations in AST/ALT can occur as early as 7 days after starting interferon-based therapies. 9
• Watch for opportunistic infections, multiple organ failure, and ICU myopathy as potential complications. 4
• Combination therapies with multiple agents on a background of high-dose glucocorticoids are often necessary and should be considered as initial therapy in severe cases. 1

Prognosis

With prompt recognition and aggressive treatment, mortality has decreased significantly. 4 The mortality rate in treated pediatric autoimmune disease-associated MAS is approximately 12.5%, compared to historical rates exceeding 50% without treatment. 4 Early initiation of combination immunosuppressive therapy strongly influences prognosis. 3