Emerging Indication — Not Yet Formally Classified by ASFA
MIS-C is not currently listed as a standalone ASFA indication. TPE use for MIS-C is supported by case series and observational data, not RCTs. It is used as a rescue therapy in severe, refractory cases at specialized pediatric centers. Clinical decisions should involve pediatric intensivists and hematology/apheresis specialists.
Disease Overview
Multisystem Inflammatory Syndrome in Children (MIS-C) — also referred to as Pediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2 (PIMS-TS) — is a severe hyperinflammatory condition occurring 2–6 weeks after SARS-CoV-2 infection in children and adolescents. It is characterized by fever, multiorgan dysfunction, and markedly elevated inflammatory markers, and can progress to cardiogenic shock, coronary artery aneurysms, and death if untreated.
The pathophysiology involves a dysregulated immune response — a cytokine storm — driven by markedly elevated IL-6, IL-10, TNF-α, ferritin, and D-dimer. This cytokine profile is similar to that seen in macrophage activation syndrome (MAS) and HLH, which has led to the use of TPE as a cytokine removal strategy in severe cases.
WHO/CDC Diagnostic Criteria for MIS-C
🔴 Required Criteria (ALL must be present)
- Age <21 years
- Fever ≥38.0°C for ≥24 hours
- Evidence of multisystem organ involvement (≥2 organ systems)
- Elevated inflammatory markers (CRP, ESR, ferritin, IL-6, D-dimer)
- No alternative plausible diagnosis
- Recent or current SARS-CoV-2 infection (PCR, antigen, or serology)
🟢 Supportive Features (MIS-C vs. Kawasaki-like)
- Cardiac involvement (myocarditis, pericarditis, coronary dilation)
- Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea)
- Mucocutaneous features (rash, conjunctivitis, lip changes)
- Lymphadenopathy
- Neurological symptoms (headache, encephalopathy)
- Shock requiring vasopressor support
Role of Therapeutic Plasma Exchange in MIS-C
TPE is not a first-line treatment for MIS-C. Standard first-line therapy consists of IVIG (2 g/kg) and corticosteroids (methylprednisolone 1–2 mg/kg/day). TPE is considered in the following scenarios:
| Scenario | TPE Rationale | Evidence Level |
|---|---|---|
| IVIG + steroid refractory MIS-C | Cytokine removal (IL-6, TNF-α, ferritin); removes pathogenic antibodies and inflammatory mediators | Case series; observational data |
| Cardiogenic shock with cytokine storm | Rapid reduction of inflammatory burden; hemodynamic stabilization as bridge to recovery | Case reports; expert consensus |
| MAS/HLH overlap features | Ferritin >10,000 ng/mL, cytopenias, hepatosplenomegaly — TPE used as in primary HLH | Extrapolated from HLH evidence (ASFA Cat III) |
| Cytokine storm with multi-organ failure | Removes cytokines, complement factors, and coagulation mediators contributing to organ dysfunction | Case series; analogy to septic shock TPE |
A 2024 multicenter study of pediatric TPE (Dalkiran et al., Ther Apher Dial) reported an overall survival rate of 72.7% across all indications. MIS-C cases in this cohort showed improvement in inflammatory markers (CRP, ferritin, IL-6) after 2–3 TPE sessions, with hemodynamic stabilization in most survivors.
Proposed TPE Protocol for MIS-C
| Parameter | Recommendation | Notes |
|---|---|---|
| Indication Threshold | Failure of IVIG + 2 doses of steroids; or immediate threat to life (shock, MOF) | Involve pediatric intensivist and apheresis specialist jointly |
| Number of Sessions | 3–5 sessions; reassess after each session | Discontinue if no improvement after 3 sessions |
| Exchange Volume | 1.0–1.5 plasma volumes per session | Calculate TPV using age-appropriate TBV formula |
| Replacement Fluid | 5% Albumin (primary); FFP if coagulopathy present | Consider FFP if D-dimer markedly elevated or fibrinogen low |
| Frequency | Daily for acute/critical; every other day for stabilizing patients | Adjust based on clinical response and inflammatory markers |
| Monitoring | CRP, ferritin, IL-6, troponin, BNP, echocardiogram after each session | Cardiac monitoring continuous during procedure |
Pediatric Technical Considerations
All five pediatric safety pillars apply to MIS-C TPE. Particular attention to: (1) ECV priming — MIS-C patients are often hemodynamically compromised; pRBC prime is frequently required regardless of weight. (2) Fluid balance — patients in cardiogenic shock require precise fluid management; positive balance may worsen cardiac function. (3) Anticoagulation — MIS-C patients often have elevated D-dimer and coagulopathy; discuss anticoagulation strategy with the team. See the Pediatric Apheresis Hub for full technical guidance.
ASFA Classification Status
MIS-C is not currently listed as a standalone ASFA indication. Based on the available evidence and the analogy to other cytokine storm syndromes (HLH, macrophage activation syndrome), the anticipated classification would be:
| Proposed Category | Rationale | Comparator Indication |
|---|---|---|
| Category III, Grade 2C (most likely) | Optimum role of apheresis therapy not established; decision individualized. Evidence from case series only. | Similar to HLH (Cat III, 2C) and Septic Shock (Cat III, 2C) |
| Category II, Grade 2C (possible if RCT evidence emerges) | Second-line therapy for IVIG/steroid-refractory cases with reasonable evidence of benefit | Similar to refractory Kawasaki Disease |
References
All references verified February 2026. DOIs and PubMed IDs confirmed against publisher records. Links open in a new tab.
- World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. Scientific Brief. 15 May 2020. WHO.int Free — Official Source
- Centers for Disease Control and Prevention. Health Department–Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. Updated 2024. CDC.gov Free — Official Source
- Özkaya PY, Koç G, Ersayoğlu İ, Cebeci K, Özdemir HH, Karadas N, et al. Therapeutic plasma exchange in critically ill children: A single center experience. Ther Apher Dial. 2024;28(5):793–801. doi:10.1111/1744-9987.14141 Free PMC Article — PubMed 38747186 (Author corrected: first author is Özkaya PY, not Dalkiran T)
- Connelly-Smith L, Alquist CR, Aqui NA, Hofmann JC, Klingel R, Onwuemene OA, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice — Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue. J Clin Apher. 2023;38(2):77–278. doi:10.1002/jca.22043 Free Full Text — PubMed 37017433
- Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children: Version 3. Arthritis Rheumatol. 2022;74(4):e1–e20. doi:10.1002/art.42062 — PubMed 35118829 Free PMC Article