Highlight
– In the multi-center Amanita-PEX retrospective cohort (n=111), adjunctive therapeutic plasma exchange (PEX) was associated with increased 28‑day liver transplantation (LTX)-free survival in patients with amatoxin-associated acute liver failure (AT-ALF) who developed hepatic encephalopathy (HE) grade ≥2.
– In the HE ≥2 subgroup, 28‑day LTX-free survival was 36.4% with PEX versus 19.1% with standard of care (SOC); adjusted hazard ratio for death or LTX was 0.37 (95% CI 0.19–0.73).
– After propensity-score matching, LTX-free survival was 52% with PEX versus 28% with SOC in this subgroup.
Background: clinical context and unmet need
Amanita mushroom ingestion (principally amatoxins) is an uncommon but highly morbid cause of acute liver failure (ALF). Amatoxins inhibit RNA polymerase II, causing hepatocellular necrosis that may progress rapidly to multi-organ failure, cerebral edema, and death. Without liver transplantation (LTX), mortality for severe amatoxin-associated ALF (AT-ALF) is high. Supportive care, early transfer to transplant centers, and use of antidotes (e.g., silibinin where available) are mainstays, but therapeutic options are limited.
Therapeutic plasma exchange (PEX) has been proposed in ALF to remove circulating toxins, cytokines, and endogenous poisons and to replace deficient plasma constituents. Prior studies have suggested benefit of high-volume plasma exchange in mixed aetiology ALF populations, but the role of PEX specifically in AT-ALF has been uncertain. Because AT-ALF is rare and geographically clustered, high-quality randomized trials focusing on this subgroup are challenging to perform. The Amanita-PEX study sought to address this knowledge gap with a multinational, retrospective analysis of real-world outcomes.
Study design and methods
The Amanita-PEX study is an international, multi-center retrospective cohort study of adult patients with amatoxin-associated acute liver failure between 2013 and 2024. Twenty-five centers contributed data for 111 patients. Patients were managed with standard of care (SOC) alone or SOC plus at least one session of therapeutic plasma exchange (PEX); 82 patients received SOC only and 29 received PEX.
The primary outcome was 28‑day LTX-free survival, defined as survival without liver transplantation at 28 days after ALF diagnosis (a composite of death or LTX). Secondary analyses examined outcomes in clinically important subgroups, notably those who developed hepatic encephalopathy (HE) grade ≥2. Analyses included multivariable Cox proportional hazards models and propensity-score matching to account for baseline differences and treatment selection bias.
Key findings
Baseline characteristics: The SOC and PEX groups were broadly comparable at baseline in demographic and laboratory parameters, but a larger proportion of the PEX group developed HE grade ≥2 (76% vs 58%; p = 0.021), indicating that clinicians tended to offer PEX to sicker patients.
Overall cohort
In the entire cohort (n=111), there was no statistically significant difference in 28‑day LTX-free survival between PEX and SOC in unstratified analyses.
HE ≥2 subgroup (prespecified and clinically relevant)
Because HE grade reflects neurological compromise and often marks more severe ALF, a focused subgroup analysis was performed. Among patients who reached HE grade ≥2, 28‑day LTX-free survival was substantially higher in those receiving adjunctive PEX versus SOC:
- SOC: 19.1% (8/42)
- PEX: 36.4% (8/22)
Survival comparisons yielded a Gehan–Breslow–Wilcoxon p = 0.041 and a Log-Rank p = 0.060, consistent with early separation of event curves. In multivariable Cox regression restricted to the HE ≥2 subgroup, PEX was independently associated with a reduced risk of the composite endpoint (death or LTX) within 28 days (hazard ratio 0.37; 95% CI 0.19–0.73; p = 0.004).
To further address confounding by indication, propensity-score matching was performed. After matching, 28‑day LTX-free survival in the HE ≥2 matched sample was 52% in the PEX group versus 28% in the SOC group (Gehan–Breslow p = 0.036; Log‑Rank p = 0.035), reinforcing the association between adjunctive PEX and improved transplant-free survival in this subgroup.
Safety and procedural considerations
The paper reports routine procedural data but does not identify novel safety signals attributable to PEX beyond expected risks of the procedure (access-related complications, hemodynamic instability, transfusion reactions, coagulopathy from plasma removal). Detailed safety event rates, anticoagulation strategies, and PEX dose/volume parameters vary across centers and are described in the full manuscript.
Interpretation and biological plausibility
Several mechanistic rationales support the potential benefit of PEX in AT-ALF. Amatoxins are water-soluble and circulate bound to plasma proteins; PEX can directly remove circulating toxins and their protein complexes. Additionally, ALF is characterized by systemic inflammatory activation and accumulation of endogenous toxins that exacerbate organ dysfunction — PEX may help remove inflammatory mediators, replace deficient plasma components (coagulation factors, albumin), and mitigate secondary injury. By reducing systemic toxin and inflammatory burden, PEX could plausibly extend the therapeutic window, reduce progression to irreversible liver failure, and increase the chance of spontaneous recovery without transplantation.
Expert commentary and limitations
The Amanita-PEX study provides the largest multicenter, international dataset focusing specifically on PEX in amatoxin-associated ALF, and its strength lies in the real-world, pragmatic capture of clinical practice variation across many centers. The consistent signal in the clinically important HE ≥2 subgroup — observed in unadjusted, adjusted, and propensity-matched analyses — strengthens the credibility of a potential treatment effect.
However, important limitations merit emphasis:
- Observational, retrospective design: Even with multivariable adjustment and propensity matching, residual confounding and selection bias are possible. Clinicians may have selected PEX patients based on unmeasured factors (trajectory, comorbidity, transplant candidacy) that influenced outcomes.
- Heterogeneity in PEX protocols: The study captures diverse PEX practices (number of sessions, exchange volumes, replacement fluids, timing relative to symptom onset) that impede identification of an optimal regimen.
- Potential center effects: Outcomes may be influenced by differences in ICU care, access to transplantation, and availability of adjunctive therapies (e.g., silibinin); center-level clustering could affect results.
- Power and subgroup analysis: The beneficial association was concentrated in a subgroup (HE ≥2) and absolute numbers were modest, so findings should be interpreted as hypothesis-generating rather than definitive proof of efficacy.
Given the rarity of AT-ALF, a randomized controlled trial focused solely on amatoxin poisoning is unlikely to be feasible in many regions. Nevertheless, prospective registries and carefully designed multicenter pragmatic trials embedded within existing ALF networks could further clarify effectiveness and standardize PEX protocols.
Practical implications for clinicians
For patients with AT-ALF who progress to at least grade 2 hepatic encephalopathy, this study suggests that adjunctive PEX may be considered as part of a multimodal approach to increase the chance of transplant-free survival, particularly where prompt LTX is limited or as a bridge to recovery or transplantation. Clinicians should weigh potential benefits against logistic requirements and procedural risks, and decisions should be individualized within multidisciplinary teams including hepatology, toxicology, transplant surgery, and critical care.
When PEX is used, centers should document timing relative to symptom onset and number/volume of exchanges to contribute to prospective data collection and to inform best-practice protocols.
Conclusion and research agenda
The Amanita-PEX international retrospective cohort identifies a clinically meaningful association between adjunctive therapeutic plasma exchange and increased 28‑day transplant-free survival in patients with amatoxin-associated ALF who develop HE grade ≥2. While causality cannot be definitively established from observational data, the magnitude and consistency of the association in adjusted analyses and propensity-matched samples support consideration of PEX in severe AT-ALF as an adjunctive rescue therapy.
Priority research actions include: prospective registry-based data capture with standardized PEX protocols, pooled analyses across regional networks, and pragmatic trials that enroll patients with severe ALF of varied etiologies (including amatoxin poisoning) to assess whether PEX confers benefit and to determine optimal exchange dose and timing. Meanwhile, clinicians should consider PEX in the most severely affected AT-ALF patients after multidisciplinary discussion and with careful procedural monitoring.
Funding and clinicaltrials.gov
The published Amanita-PEX study lists author and group contributions; the primary manuscript should be consulted for declared funding sources and conflicts of interest. This retrospective cohort was not registered as a randomized trial on ClinicalTrials.gov; centers are encouraged to contribute to prospective registries that can inform future trial design.
References
1. Stahl K, Nalbant B, Pape T, Breteau I, Coirier V, Cardoso FS, de Haan J, Janik MK, Wasmuth JC, Madaleno J, Merle U, Frohme J, Tepasse PR, Müller M, Große K, Linke A, Mareljic N, Larsen FS, Dahlqvist G, Kolev M, Schulze M, Willuweit K, Janke-Maier P, Dondorf F, Fierro-Angulo ÓM, Geerts A, Toapanta D, Dejean C, Alharthi M, Reverter E, Schenk H, Raevens S, Macías-Rodríguez RU, Rauchfuß F, Berg CP, Schmidt H, Geier A, Semmo N, Lanthier N, Bjerring PN, Lange CM, Sterneck M, Bruns T, Schmid S, van de Loo D, Demir M, Boettler T, Borges C, Nattermann J, Wronka K, den Hoed CM, Marques HP, Artru F, Levesque E, Wedemeyer H, Campos-Murguia A, Taubert R; Amanita-PEX-study group. Therapeutic plasma exchange in amatoxin associated acute liver failure-results from the multi-center Amanita-PEX study. Crit Care. 2025 Oct 30;29(1):458. doi: 10.1186/s13054-025-05560-y. PMID: 41163058; PMCID: PMC12573913.
Author note
This summary interprets the Amanita-PEX study for clinicians and policy-makers. Readers are encouraged to consult the full manuscript for detailed methodology, center-level protocols, and complete safety data.
