From association to inference: polyvalent antivenom and response-based algorithms in the Craspedocephalus malabaricus complex

Highlights

• •Registry associations should not be overinterpreted as antivenom efficacy in Malabar pit viper envenoming.
• •Response-based algorithms risk implying causality without controlled evidence.
• •Prospective multicentre studies are needed before algorithm adoption.

Dear Editor,

We read the article by Lath et al. describing Malabar pit viper (MPV) envenoming from the VENOMS registry with interest. The paper provides useful visibility to an under-recognised species and highlights practical challenges in regions where MPV is increasingly identified (Lath et al., 2025).

We would, however, like to comment on the interpretation of Indian polyvalent antivenom (ASV) effectiveness and how this is reflected in the proposed management algorithm. The authors report an “improving trend” in INR following ASV and suggest “possible cross-reactivity” (Lath et al., 2025). While this is a clinically relevant hypothesis, the retrospective, registry-based design without a comparator does not permit causal attribution. Moreover, as the authors themselves point out, available immunological data indicate weaker binding of Indian polyvalent antivenoms to Malabar pit viper venom components compared with Russell's viper venom (Vanuopadath et al., 2020), and ELISA cross-reactivity does not necessarily correlate with therapeutic effectiveness (Tan et al., 2017). Preclinical work also reports poor cross-recognition of Western Ghats pit viper venoms by marketed Indian polyvalent antivenoms (Khochare et al., 2023).

Temporal improvement in coagulation parameters may reflect the natural evolution of venom-induced coagulopathy rather than a direct antivenom effect. Plasma products are sometimes administered, but evidence for an independent, clinically meaningful benefit remains limited. Published studies evaluate FFP predominantly as an adjunct to effective antivenom, without a demonstrated mortality benefit, and with sparse, heterogeneous evidence from Asian snake species that constrains generalisability (Ganessane et al., 2025). Thus registry data are limited in their ability to disentangle natural history, adjunctive replacement therapy, and any true antivenom effect.

We are also concerned that the cited supporting literature may be interpreted as stronger external corroboration than it actually provides. Sajeeth Kumar et al. explicitly state that ASV was not administered for pit viper bites under their protocol and therefore cannot be cited as evidence supporting ASV responsiveness in MPV envenoming (Kumar et al., 2018). Menon et al. identify MPV among culprit species and document substantial adverse reactions to ASV, but do not establish clinical efficacy of ASV for MPV (Menon et al., 2016). Rajeev et al. (2024) is a preprint and should therefore be interpreted cautiously. The remaining reports cited in support (Sirur et al., 2022 Lath, 2021) largely arise from the same institution or closely linked authorship groups; while valuable as hypothesis-generating experience, independent replication across centres is needed before concluding consistent cross-reactivity.

The risk–benefit balance warrants emphasis. In the present series, 14 patients received ASV (up to 25 vials), with anaphylaxis reported in three (Lath et al., 2025). When benefit remains uncertain and harm is observed, language should clearly distinguish temporal association from therapeutic effect.

Inference is further limited by case attribution. The authors acknowledge that photographic identification “cannot be taken as confirmatory evidence,” and that registry attribution relies on “low grade evidence … along with circumstantial information” (Lath et al., 2025). This introduces potential misclassification and spectrum bias when treatment decisions and outcomes are interpreted as species-specific effects. Additionally, recent systematic work suggests that the entity commonly referred to as the Malabar pit viper represents a geographically structured species complex with multiple cryptic lineages separated by barriers and/or habitat association (Mallik et al., 2021). While genetic divergence does not in itself prove venom divergence, it is biologically plausible that venom composition and clinical phenotype may vary across clades, further cautioning against extrapolating apparent ASV–INR associations across the wider “Craspedocephalus malabaricus complex” from uncontrolled registry observations.

These limitations become more consequential when translated into an algorithm (Lath et al., 2025, Fig. 7). The bidirectional arrows reduce clarity, and more importantly, the branch suggesting that “no improvement in coagulopathy” should prompt consideration of an alternative species risks positioning “response to ASV” as a diagnostic discriminator. In a setting where coagulopathy can evolve with time and supportive care, and where species/lineage attribution may be imperfect, lack of improvement after ASV cannot reasonably be used to infer an alternative species. We suggest revising the figure to a unidirectional flow and explicitly framing ASV as an optional, selective intervention in severe systemic illness pending stronger evidence, rather than as an expected or diagnostic response.

Finally, the statement that dose-finding studies would be the next step may be premature, as it risks implying established efficacy that the current dataset cannot provide. At this stage, the more fundamental question is whether ASV confers reproducible, clinically meaningful benefit beyond supportive care in MPV envenoming—best addressed through prospective, multicentre clinical studies ideally paired with translational neutralisation data, before moving to dosing studies or algorithmic reliance on ASV response.

In summary, the paper contributes important descriptive data on MPV envenoming. However, conclusions regarding ASV cross-reactivity and clinical efficacy should be presented more conservatively, with a clearer distinction between observation, association, and causation—particularly given the potential for harm and the risk of the algorithm being interpreted as implying ASV efficacy is established.

Sincerely,

Siju V. Abraham, MD

Department of Emergency Medicine, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala, India

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: Scott Allen weinstein

Data availability

No data was used for the research described in the article.