Brugada syndrome unmasked by Plasmodium falciparum malaria and dihydroartemisinin-piperaquine treatment: a case report

Brugada syndrome unmasked by Plasmodium falciparum malaria and dihydroartemisinin-piperaquine treatment: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Brugada syndrome unmasked by Plasmodium falciparum malaria and dihydroartemisinin-piperaquine treatment: a case report Jaouad Nguadi, Hanae elghiati, Youssef lahmouz, Jihane Fagouri, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8789144/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Brugada syndrome is a rare channelopathy that can remain asymptomatic until unmasked by fever or certain drugs. Malaria, through intense fever and antimalarial treatments, represents a potential trigger; this association is rarely reported and highlights a novel diagnostic challenge in endemic areas. Case presentation A 28-year-old Moroccan man (Arab-Berber ethnicity) with no family history of sudden death presented with a 3-day febrile syndrome after a trip to Cameroon. Blood smear confirmed Plasmodium falciparum malaria (3% parasitemia). On day 1 of dihydroartemisinin-piperaquine treatment, fever (38°C) and palpitations prompted an ECG showing type 1 Brugada pattern. The pattern resolved after defervescence (day 2). A flecainide provocation test induced ventricular fibrillation, treated by external shock. An implantable cardioverter-defibrillator (ICD) was placed. The patient was discharged after favorable evolution. Conclusions This rare case emphasizes the critical need for ECG monitoring in malaria patients presenting with fever or cardiac symptoms. Fever and QT-prolonging antimalarials can unmask latent Brugada syndrome, warranting cautious drug selection and prompt electrophysiological evaluation. ICD implantation remains the cornerstone of secondary prevention in high-risk patients. Brugada syndrome malaria fever dihydroartemisinin-piperaquine arrhythmia sudden death Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Brugada syndrome is a hereditary channelopathy characterized by ST-segment elevation in the right precordial leads (V1-V3) on the electrocardiogram (ECG), associated with an increased risk of sudden death from ventricular arrhythmia. This condition may remain asymptomatic until a triggering factor, such as fever or certain medications, reveals its clinical expression. Malaria, a parasitic infection endemic in many regions, is known to induce intense fever and requires antimalarial treatments, such as dihydroartemisinin-piperaquine, which can have cardiotoxic effects. These features make malaria a potential trigger for Brugada syndrome, an association rarely described in the literature. This report describes the case of a patient whose Brugada syndrome was unmasked by a malaria episode, highlighting the interactions between the infection, fever, and antimalarial treatments. A review of the literature accompanies this case to discuss the pathophysiological mechanisms, diagnostic challenges, and implications for managing febrile patients in an infectious context, incorporating recent American and international recommendations. 2 Case Report We report the case of a 28-year-old Moroccan man (Arab-Berber ethnicity), with no family history of sudden death, admitted to the emergency department for a febrile syndrome evolving for three days. The history revealed a recent three-week trip to Cameroon, two months prior, in an area endemic for malaria. On admission, the patient was afebrile, without signs of heart failure or cardiac murmur. A blood smear confirmed Plasmodium falciparum infection with 3% parasitemia. Blood cultures were negative, and transthoracic echocardiography revealed no significant abnormalities. The patient was treated with dihydroartemisinin-piperaquine in accordance with local recommendations for malaria. On day 1 of treatment, the patient presented a fever peak of 38°C with palpitations; a subsequent ECG showed ST-segment elevation in V1-V2, consistent with a type 1 Brugada pattern (Fig. 2 ). After resolution of the fever (day 2), the ECG showed regression of the Brugada pattern (Fig. 3 ). To confirm the diagnosis of Brugada syndrome, a flecainide provocation test (in the absence of ajmaline) was performed after defervescence. This test reproduced the characteristic ECG pattern and triggered ventricular fibrillation, promptly treated with external electrical shock (Fig. 4 ). The patient was transferred to the intensive care unit, where close monitoring, aggressive antipyretic treatment, and in-depth cardiological evaluation were implemented. Placement of an implantable cardioverter-defibrillator (ICD) was performed to prevent fatal arrhythmias, in line with the recommendations of the AHA/ACC/HRS and ESC for patients with documented ventricular fibrillation (Fig. 5 ). Family screening by ECG and history revealed no characteristic abnormalities. The patient was discharged after favorable clinical evolution with complete resolution of symptoms and stable cardiac status. The timeline of the case is summarized in Fig. 1 . Patient’s Perspective One month after discharge, ICD interrogation showed no episodes of ventricular tachycardia or fibrillation. The patient reported no loss of consciousness, palpitations, fever, or infectious symptomsand no shok. He strictly adheres to medical advice, avoiding self-medication and fever triggers. He expressed relief at resuming normal activities with restored confidence and well-being. 3 Discussion This case illustrates the complex interplay between infectious triggers and genetic channelopathies, with malaria serving as a rare but clinically significant unmasking factor for Brugada syndrome. The pathophysiological cascade likely begins with fever-induced thermal stress on cardiac sodium channels. Elevated body temperature reduces the availability of functional NaV1.5 channels by accelerating inactivation kinetics and shifting the voltage dependence of steady-state inactivation toward more negative potentials [ 1 , 4 ]. In patients harboring loss-of-function mutations in SCN5A or related genes, this temperature-sensitive dysfunction unmasks the characteristic coved ST-segment elevation in right precordial leads, transforming a concealed phenotype into a high-risk electrocardiographic pattern. The role of Plasmodium falciparum extends beyond fever. Parasite-derived glycoproteins, such as GPI anchors, may induce proinflammatory cytokine surges (TNF-α, IL-6, IL-1β), which further depress sodium current density via protein kinase modulation and oxidative stress [ 11 ]. Although direct evidence in Brugada patients is limited, experimental models demonstrate that inflammatory mediators can exacerbate repolarization heterogeneity in the right ventricular outflow tract—the epicenter of Brugada-related arrhythmogenesis [ 12 ]. Antimalarial therapy introduces an additional layer of risk. Dihydroartemisinin-piperaquine combines a short-acting artemisinin derivative with piperaquine, a bisquinoline with a prolonged elimination half-life (> 20 days). Piperaquine blocks the hERG potassium channel in a concentration-dependent manner, prolonging the QT interval and potentially amplifying phase 2 reentry in Brugada substrate [ 2 , 3 ]. A Bayesian meta-analysis of over 30,000 patients confirmed a 3–5-fold increased odds of QTc > 500 ms with piperaquine-containing regimens compared to artemether-lumefantrine [ 2 ]. In Brugada patients, this repolarization delay may synergize with sodium channel impairment to precipitate polymorphic ventricular tachycardia or fibrillation, as observed during the flecainide challenge in our case. Current guidelines reflect evolving awareness of these interactions. The 2022 ESC guidelines on ventricular arrhythmias and sudden cardiac death assign a class IIa recommendation for fever surveillance and prompt antipyretic therapy in known Brugada patients (level of evidence B) [ 13 ]. While CDC and WHO malaria treatment protocols do not explicitly address Brugada syndrome, both caution against QT-prolonging antimalarials in patients with “known cardiac disease” [ 6 – 8 ]. BrugadaDrugs.org categorizes piperaquine as “conditionally risky” (yellow list), recommending ECG monitoring and alternative regimens (e.g., artesunate or artemether-lumefantrine) when feasible [ 9 ]. In resource-limited settings, however, dihydroartemisinin-piperaquine remains a first-line option due to high efficacy and post-treatment prophylaxis. Diagnostic strategy in febrile patients merits refinement. Transient Brugada pattern during infection does not invariably indicate underlying channelopathy; however, persistence after normothermia or inducibility with class I antiarrhythmics confirms diagnosis. Our patient’s spontaneous type 1 ECG during fever, followed by flecainide-induced ventricular fibrillation, fulfills Shanghai criteria for definitive Brugada syndrome [ 14 ]. Genetic testing, although not performed here, could identify SCN5A variants to enable cascade screening—particularly relevant given the autosomal dominant inheritance and 30–50% penetrance. Risk stratification post-diagnosis integrates multiple variables. The 2015 PRIORITY score assigns 4 points for spontaneous type 1 ECG and 3 points for inducible ventricular fibrillation, yielding a predicted 5-year risk of arrhythmic events exceeding 10% [ 15 ]. ICD implantation, performed in our patient, aligns with class I recommendations for secondary prevention after documented ventricular fibrillation (AHA/ACC/HRS 2017; ESC 2022) [ 13 , 16 ]. One-month ICD interrogation showing no sustained arrhythmias, coupled with absence of syncope or palpitations, supports effective risk mitigation—particularly with strict fever avoidance and drug vigilance. Comparative literature remains sparse. A 2021 case series from India reported three malaria-related Brugada unmaskings, all with P. vivax ; none required ICD due to negative provocation testing [ 3 ]. In contrast, a Singaporean report described piperaquine-triggered torsades in a Brugada patient, resolved after drug discontinuation and magnesium [ 2 ]. Our case is distinguished by documented ventricular fibrillation during pharmacological challenge, necessitating device therapy. Long-term management must address lifestyle and pharmacotherapy. Patients should receive fever action plans: immediate antipyretics (paracetamol 1 g q6h), physical cooling, and urgent ECG if temperature exceeds 38.5°C. A personalized “drugs to avoid” list—incorporating sodium channel blockers, QT-prolonging agents, and alpha-agonists—should be provided, with annual cardiology follow-up including ICD interrogation and Holter monitoring. In endemic regions, pre-travel counseling for Brugada carriers could include alternative antimalarials (atovaquone-proguanil) and prophylactic antipyretics. This case underscores the need for interdisciplinary collaboration between infectious disease specialists and electrophysiologists in malaria-endemic areas. Routine ECG screening during febrile illnesses, particularly in young males with syncope or palpitations, may enable early detection of latent channelopathies. Future research should focus on genotype–phenotype correlations in tropical populations and randomized comparisons of antimalarial safety in Brugada cohorts. 4 Conclusion This rare case emphasizes the critical need for ECG monitoring in malaria patients presenting with fever or cardiac symptoms. Fever and QT-prolonging antimalarials can unmask latent Brugada syndrome, warranting cautious drug selection and prompt electrophysiological evaluation. ICD implantation remains the cornerstone of secondary prevention. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author Contribution JN: conception, data collection, drafting. JF, HEG: data interpretation, critical revision. MC: clinical follow-up, internal medicine input. HB, AC: supervision, final approval. All authors read and approved the final manuscript. Acknowledgements Not applicable. Authors' information (optional) Not applicable. Data Availability Not applicable. References Fadilah I, et al. J Cardiol Cases. 2022;18(3):97–100. Chan XHS, et al. Lancet Infect Dis. 2018;18(11):1198–206. Gupta S, et al. Malar J. 2021;23:339. Alings M, Wilde A. Circulation. 1999;99(5):666–73. CDC. Treatment of Uncomplicated Malaria. https://www.cdc.gov/malaria/hcp/clinical-guidance/treatment-uncomplicated.html CDC. General Approach to Treatment | Malaria. https://www.cdc.gov/malaria/hcp/clinical-guidance/general-treatment.html WHO. Guidelines for malaria, 13. August 2025. https://www.ncbi.nlm.nih.gov/books/NBK588130/pdf/Bookshelf_NBK588130.pdf BrugadaDrugs.org. https://www.brugadadrugs.org/avoid/ SADS UK. https://www.sads.org.uk/drugs-to-avoid/ Francis SE, et al. Mol Biochem Parasitol. 1997;88(1–2):1–12. Junge S, et al. Circ Arrhythm Electrophysiol. 2020;13(6):e008337. Zeppenfeld K, et al. Eur Heart J. 2022;43(32):e1–112. Antzelevitch C, et al. J Arrhythm. 2016;32(5):315–26. Probst V, et al. Eur Heart J. 2015;36(25):1600–7. Al-Khatib SM, et al. Circulation. 2018;137(12):e190–252. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 09 Mar, 2026 Reviewers invited by journal 02 Mar, 2026 Editor assigned by journal 13 Feb, 2026 Submission checks completed at journal 12 Feb, 2026 First submitted to journal 04 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8789144","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":585871249,"identity":"a2832c93-3ff4-4109-8e98-b9c9ea32fbf4","order_by":0,"name":"Jaouad 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pattern\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8789144/v1/bf09dd3484314f34b9a1a01a.jpg"},{"id":101941334,"identity":"21429be0-1794-409e-823e-e758f82cf7a6","added_by":"auto","created_at":"2026-02-05 09:20:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":28434,"visible":true,"origin":"","legend":"\u003cp\u003eECG showed a regression of Brugada pattern\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8789144/v1/265c42a0ff42d17d26f8272e.jpg"},{"id":101941333,"identity":"a2f51d3e-7e11-4b20-87b8-13835db55de6","added_by":"auto","created_at":"2026-02-05 09:20:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":406308,"visible":true,"origin":"","legend":"\u003cp\u003eFlecainide provocation test triggering ventricular fibrillation treated with external electrical shock\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8789144/v1/9b25df52424e86e0c1b90ae5.jpg"},{"id":101941332,"identity":"66a40636-eda0-4c05-ba59-5ee3b3fad29b","added_by":"auto","created_at":"2026-02-05 09:20:43","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":36210,"visible":true,"origin":"","legend":"\u003cp\u003eChest X-ray after subcutaneous defibrillator implantation\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8789144/v1/19b12e2f63feb207aa5d1419.jpg"},{"id":101944651,"identity":"dff07e34-1a0a-4d90-93f4-9c5f7b74ec6e","added_by":"auto","created_at":"2026-02-05 09:53:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1312288,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8789144/v1/d39b1fd5-59b1-4f51-a7e5-93dfac03a925.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Brugada syndrome unmasked by Plasmodium falciparum malaria and dihydroartemisinin-piperaquine treatment: a case report","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eBrugada syndrome is a hereditary channelopathy characterized by ST-segment elevation in the right precordial leads (V1-V3) on the electrocardiogram (ECG), associated with an increased risk of sudden death from ventricular arrhythmia. This condition may remain asymptomatic until a triggering factor, such as fever or certain medications, reveals its clinical expression. Malaria, a parasitic infection endemic in many regions, is known to induce intense fever and requires antimalarial treatments, such as dihydroartemisinin-piperaquine, which can have cardiotoxic effects. These features make malaria a potential trigger for Brugada syndrome, an association rarely described in the literature.\u003c/p\u003e \u003cp\u003eThis report describes the case of a patient whose Brugada syndrome was unmasked by a malaria episode, highlighting the interactions between the infection, fever, and antimalarial treatments. A review of the literature accompanies this case to discuss the pathophysiological mechanisms, diagnostic challenges, and implications for managing febrile patients in an infectious context, incorporating recent American and international recommendations.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2 Case Report","content":"\u003cp\u003eWe report the case of a 28-year-old Moroccan man (Arab-Berber ethnicity), with no family history of sudden death, admitted to the emergency department for a febrile syndrome evolving for three days. The history revealed a recent three-week trip to Cameroon, two months prior, in an area endemic for malaria. On admission, the patient was afebrile, without signs of heart failure or cardiac murmur.\u003c/p\u003e \u003cp\u003eA blood smear confirmed \u003cem\u003ePlasmodium falciparum\u003c/em\u003e infection with 3% parasitemia. Blood cultures were negative, and transthoracic echocardiography revealed no significant abnormalities. The patient was treated with dihydroartemisinin-piperaquine in accordance with local recommendations for malaria. On day 1 of treatment, the patient presented a fever peak of 38\u0026deg;C with palpitations; a subsequent ECG showed ST-segment elevation in V1-V2, consistent with a type 1 Brugada pattern (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After resolution of the fever (day 2), the ECG showed regression of the Brugada pattern (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo confirm the diagnosis of Brugada syndrome, a flecainide provocation test (in the absence of ajmaline) was performed after defervescence. This test reproduced the characteristic ECG pattern and triggered ventricular fibrillation, promptly treated with external electrical shock (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The patient was transferred to the intensive care unit, where close monitoring, aggressive antipyretic treatment, and in-depth cardiological evaluation were implemented. Placement of an implantable cardioverter-defibrillator (ICD) was performed to prevent fatal arrhythmias, in line with the recommendations of the AHA/ACC/HRS and ESC for patients with documented ventricular fibrillation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Family screening by ECG and history revealed no characteristic abnormalities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient was discharged after favorable clinical evolution with complete resolution of symptoms and stable cardiac status. The timeline of the case is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePatient\u0026rsquo;s Perspective\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOne month after discharge, ICD interrogation showed no episodes of ventricular tachycardia or fibrillation. The patient reported no loss of consciousness, palpitations, fever, or infectious symptomsand no shok. He strictly adheres to medical advice, avoiding self-medication and fever triggers. He expressed relief at resuming normal activities with restored confidence and well-being.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"3 Discussion","content":"\u003cp\u003eThis case illustrates the complex interplay between infectious triggers and genetic channelopathies, with malaria serving as a rare but clinically significant unmasking factor for Brugada syndrome. The pathophysiological cascade likely begins with fever-induced thermal stress on cardiac sodium channels. Elevated body temperature reduces the availability of functional NaV1.5 channels by accelerating inactivation kinetics and shifting the voltage dependence of steady-state inactivation toward more negative potentials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In patients harboring loss-of-function mutations in \u003cem\u003eSCN5A\u003c/em\u003e or related genes, this temperature-sensitive dysfunction unmasks the characteristic coved ST-segment elevation in right precordial leads, transforming a concealed phenotype into a high-risk electrocardiographic pattern.\u003c/p\u003e \u003cp\u003eThe role of \u003cem\u003ePlasmodium falciparum\u003c/em\u003e extends beyond fever. Parasite-derived glycoproteins, such as GPI anchors, may induce proinflammatory cytokine surges (TNF-α, IL-6, IL-1β), which further depress sodium current density via protein kinase modulation and oxidative stress [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although direct evidence in Brugada patients is limited, experimental models demonstrate that inflammatory mediators can exacerbate repolarization heterogeneity in the right ventricular outflow tract\u0026mdash;the epicenter of Brugada-related arrhythmogenesis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAntimalarial therapy introduces an additional layer of risk. Dihydroartemisinin-piperaquine combines a short-acting artemisinin derivative with piperaquine, a bisquinoline with a prolonged elimination half-life (\u0026gt;\u0026thinsp;20 days). Piperaquine blocks the hERG potassium channel in a concentration-dependent manner, prolonging the QT interval and potentially amplifying phase 2 reentry in Brugada substrate [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A Bayesian meta-analysis of over 30,000 patients confirmed a 3\u0026ndash;5-fold increased odds of QTc\u0026thinsp;\u0026gt;\u0026thinsp;500 ms with piperaquine-containing regimens compared to artemether-lumefantrine [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Brugada patients, this repolarization delay may synergize with sodium channel impairment to precipitate polymorphic ventricular tachycardia or fibrillation, as observed during the flecainide challenge in our case.\u003c/p\u003e \u003cp\u003eCurrent guidelines reflect evolving awareness of these interactions. The 2022 ESC guidelines on ventricular arrhythmias and sudden cardiac death assign a class IIa recommendation for fever surveillance and prompt antipyretic therapy in known Brugada patients (level of evidence B) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. While CDC and WHO malaria treatment protocols do not explicitly address Brugada syndrome, both caution against QT-prolonging antimalarials in patients with \u0026ldquo;known cardiac disease\u0026rdquo; [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. BrugadaDrugs.org categorizes piperaquine as \u0026ldquo;conditionally risky\u0026rdquo; (yellow list), recommending ECG monitoring and alternative regimens (e.g., artesunate or artemether-lumefantrine) when feasible [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In resource-limited settings, however, dihydroartemisinin-piperaquine remains a first-line option due to high efficacy and post-treatment prophylaxis.\u003c/p\u003e \u003cp\u003eDiagnostic strategy in febrile patients merits refinement. Transient Brugada pattern during infection does not invariably indicate underlying channelopathy; however, persistence after normothermia or inducibility with class I antiarrhythmics confirms diagnosis. Our patient\u0026rsquo;s spontaneous type 1 ECG during fever, followed by flecainide-induced ventricular fibrillation, fulfills Shanghai criteria for definitive Brugada syndrome [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Genetic testing, although not performed here, could identify \u003cem\u003eSCN5A\u003c/em\u003e variants to enable cascade screening\u0026mdash;particularly relevant given the autosomal dominant inheritance and 30\u0026ndash;50% penetrance.\u003c/p\u003e \u003cp\u003eRisk stratification post-diagnosis integrates multiple variables. The 2015 PRIORITY score assigns 4 points for spontaneous type 1 ECG and 3 points for inducible ventricular fibrillation, yielding a predicted 5-year risk of arrhythmic events exceeding 10% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. ICD implantation, performed in our patient, aligns with class I recommendations for secondary prevention after documented ventricular fibrillation (AHA/ACC/HRS 2017; ESC 2022) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One-month ICD interrogation showing no sustained arrhythmias, coupled with absence of syncope or palpitations, supports effective risk mitigation\u0026mdash;particularly with strict fever avoidance and drug vigilance.\u003c/p\u003e \u003cp\u003eComparative literature remains sparse. A 2021 case series from India reported three malaria-related Brugada unmaskings, all with \u003cem\u003eP. vivax\u003c/em\u003e; none required ICD due to negative provocation testing [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, a Singaporean report described piperaquine-triggered torsades in a Brugada patient, resolved after drug discontinuation and magnesium [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Our case is distinguished by documented ventricular fibrillation during pharmacological challenge, necessitating device therapy.\u003c/p\u003e \u003cp\u003eLong-term management must address lifestyle and pharmacotherapy. Patients should receive fever action plans: immediate antipyretics (paracetamol 1 g q6h), physical cooling, and urgent ECG if temperature exceeds 38.5\u0026deg;C. A personalized \u0026ldquo;drugs to avoid\u0026rdquo; list\u0026mdash;incorporating sodium channel blockers, QT-prolonging agents, and alpha-agonists\u0026mdash;should be provided, with annual cardiology follow-up including ICD interrogation and Holter monitoring. In endemic regions, pre-travel counseling for Brugada carriers could include alternative antimalarials (atovaquone-proguanil) and prophylactic antipyretics.\u003c/p\u003e \u003cp\u003eThis case underscores the need for interdisciplinary collaboration between infectious disease specialists and electrophysiologists in malaria-endemic areas. Routine ECG screening during febrile illnesses, particularly in young males with syncope or palpitations, may enable early detection of latent channelopathies. Future research should focus on genotype\u0026ndash;phenotype correlations in tropical populations and randomized comparisons of antimalarial safety in Brugada cohorts.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4 Conclusion","content":"\u003cp\u003eThis rare case emphasizes the critical need for ECG monitoring in malaria patients presenting with fever or cardiac symptoms. Fever and QT-prolonging antimalarials can unmask latent Brugada syndrome, warranting cautious drug selection and prompt electrophysiological evaluation. ICD implantation remains the cornerstone of secondary prevention.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJN: conception, data collection, drafting. JF, HEG: data interpretation, critical revision. MC: clinical follow-up, internal medicine input. HB, AC: supervision, final approval. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAuthors' information (optional)\u003c/b\u003e Not applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFadilah I, et al. J Cardiol Cases. 2022;18(3):97\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan XHS, et al. Lancet Infect Dis. 2018;18(11):1198\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta S, et al. Malar J. 2021;23:339.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlings M, Wilde A. Circulation. 1999;99(5):666\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCDC. Treatment of Uncomplicated Malaria. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/malaria/hcp/clinical-guidance/treatment-uncomplicated.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/malaria/hcp/clinical-guidance/treatment-uncomplicated.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCDC. General Approach to Treatment | Malaria. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/malaria/hcp/clinical-guidance/general-treatment.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/malaria/hcp/clinical-guidance/general-treatment.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO. Guidelines for malaria, 13. August 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK588130/pdf/Bookshelf_NBK588130.pdf\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK588130/pdf/Bookshelf_NBK588130.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrugadaDrugs.org. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.brugadadrugs.org/avoid/\u003c/span\u003e\u003cspan address=\"https://www.brugadadrugs.org/avoid/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSADS UK. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.sads.org.uk/drugs-to-avoid/\u003c/span\u003e\u003cspan address=\"https://www.sads.org.uk/drugs-to-avoid/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancis SE, et al. Mol Biochem Parasitol. 1997;88(1\u0026ndash;2):1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJunge S, et al. Circ Arrhythm Electrophysiol. 2020;13(6):e008337.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeppenfeld K, et al. Eur Heart J. 2022;43(32):e1\u0026ndash;112.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntzelevitch C, et al. J Arrhythm. 2016;32(5):315\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProbst V, et al. Eur Heart J. 2015;36(25):1600\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Khatib SM, et al. Circulation. 2018;137(12):e190\u0026ndash;252.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Brugada syndrome, malaria, fever, dihydroartemisinin-piperaquine, arrhythmia, sudden death","lastPublishedDoi":"10.21203/rs.3.rs-8789144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8789144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBrugada syndrome is a rare channelopathy that can remain asymptomatic until unmasked by fever or certain drugs. Malaria, through intense fever and antimalarial treatments, represents a potential trigger; this association is rarely reported and highlights a novel diagnostic challenge in endemic areas.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eA 28-year-old Moroccan man (Arab-Berber ethnicity) with no family history of sudden death presented with a 3-day febrile syndrome after a trip to Cameroon. Blood smear confirmed \u003cem\u003ePlasmodium falciparum\u003c/em\u003e malaria (3% parasitemia). On day 1 of dihydroartemisinin-piperaquine treatment, fever (38\u0026deg;C) and palpitations prompted an ECG showing type 1 Brugada pattern. The pattern resolved after defervescence (day 2). A flecainide provocation test induced ventricular fibrillation, treated by external shock. An implantable cardioverter-defibrillator (ICD) was placed. The patient was discharged after favorable evolution.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis rare case emphasizes the critical need for ECG monitoring in malaria patients presenting with fever or cardiac symptoms. Fever and QT-prolonging antimalarials can unmask latent Brugada syndrome, warranting cautious drug selection and prompt electrophysiological evaluation. ICD implantation remains the cornerstone of secondary prevention in high-risk patients.\u003c/p\u003e","manuscriptTitle":"Brugada syndrome unmasked by Plasmodium falciparum malaria and dihydroartemisinin-piperaquine treatment: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 09:20:34","doi":"10.21203/rs.3.rs-8789144/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"329768992718057402037960098323910217852","date":"2026-03-09T06:32:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-02T14:22:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-13T16:26:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-12T07:32:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Malaria Journal","date":"2026-02-04T17:09:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d588fc4-b7ee-4eef-8adf-27501cda81f0","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T14:38:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 09:20:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8789144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8789144","identity":"rs-8789144","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}