We thank Dr. Sagui for his kind words about our research and his interesting observations. The title and the last sentence of his article are somewhat cryptic, but we presume he is alluding to the well-known phenomenon, whereby many individuals who develop exertional heat illness (EHI) do so through conscious maintenance of motor activity despite multiple adverse afferent inputs signaling failing physiological regulation. This may explain why many EHI cases occur during high-stakes military exercises. Although interesting and important, this phenomenon is tangential to the focus of the work presented in our article.1 In attempting to draw attention to the volitional element of EHI, Dr. Sagui seems to believe the need to dispute the premise that a subset of EHI cases occurs in individuals with an inherited defect in skeletal muscle handling of calcium. The limited space permitted here prevents us from detailing the many flaws in his arguments, but we would suggest he carefully rereads our article and previous publications on this subject.2,3 He might find it interesting to also read studies on transgenic murine models where disorders of skeletal muscle excitation–contraction coupling lead to heat intolerance.4,5
Perhaps Dr. Sagui is finding it difficult to reconcile findings in exertional heatstroke in French military personnel with other literature. He implies that our EHI cohort may simply be a sample of the general population. We use the term EHI rather than exertional heatstroke as the diagnosis of exertional heatstroke is often not established because of difficulty in measuring core body temperature in the field before cooling measures are implemented. It also recognizes that patients with heat illness who do not meet the definition of heatstroke may still have a life-threatening condition. So while EHI may encompass a wide range of clinical presentations, all the patients in our cohort required hospital admission and invariably sustained tissue damage from their heat illness. The great majority were isolated casualties from group participation events in whom predisposing factors (concurrent illness, drugs, alcohol ingestion, among others) had been excluded. Furthermore, they were all phenotypically characterized on at least two occasions as having impaired heat tolerance in a standardized heat tolerance test. We therefore reject the suggestion that our EHI cohort was a sample from the general population. In the study cited by Sagui et al.6 on French military personnel, details of the criteria for inclusion in investigations were not given. We also have to point out that the in vitro contracture tests conducted in Marseille are not done according to the guidelines of the European malignant hyperthermia (MH) group. We do not agree with the presumption that the severity of exertional heatstroke necessarily reflects the etiology: in our experience, severity of EHI reflects the delay in making the diagnosis and implementing effective treatment, just as is the case with MH. Similarly, the risk of recurrence of exertional heatstroke may not distinguish those genetically predisposed because a severe heat injury results in a prolonged period of heat intolerance that can take up to 2 yr to resolve. Furthermore, as we point out in our article,1 the in vitro contracture test may not be fully sensitive to all types of genetic predisposition to EHI.
Finally, we have to correct Dr. Sagui in his interpretation of our genetic findings. We did not conclude that polymorphisms were of “uncertain significance,” as by definition polymorphisms are unlikely to be major genetic contributors to uncommon heritable traits. Of greater difficulty is the interpretation of rare variants in RYR1 and CACNA1S, as such variants have been found in more than 6% of control populations.7 It is, therefore, inappropriate to make inferences based on the crude incidence of all variants in these genes in different subsets of our cohorts. Interpretation requires some assessment of likely functional significance. We have provided data on the prevalence of variants and their predicted pathogenicity but highlighted the limitations in this approach. We will seek to functionally characterize variants of interest and also extend our search for genetic variants implicated in MH and EHI. We wish Dr. Sagui well in pursuit of his research into the role of brain function in the development of heatstroke.
Dr. Hopkins is the Chairman of the European Malignant Hyperthermia Group and has not received any payment in connection with this role. The other authors declare no competing interests.