Emeritus Professor David A Warrell FMedSci FRCP
|Research Area:||Global Health|
|Technology Exchange:||Drug discovery and Vaccine production and evaluation|
|Scientific Themes:||Tropical Medicine & Global Health|
|Keywords:||tropical medicine, snake bite, neglected tropical diseases, clinical toxinology and venomous bites and stings|
Figure 3: Estimated deaths and standardized death rates in states with high prevalence of snakebite ...
Faiz MA, Ghose A, Ahsan MF, Rahman MR, Amin MR, Hassan MM, Chowdhury MA, Kuch U, Rocha T, Harris JB, ...
Scott A. Weinstein, David A. Warrell, Julian White, Daniel E. Keyler. “Venomous” Bites from Non-Veno ...
WHO SEARO Guidelines for the management of snake-bites. WHO Regional Office for South-East Asia, 2nd ...
WHO AFRO Guidelines: Prevention and Clinical Management of Snakebite in Africa. WHO Regional Office ...
WHO Recommendations on Rabies Post-Exposure Treatment and the Correct technique of Intradermal Immun ...
Rabies and Envenomings A Neglected Public Health Issue Report of a Consultative Meeting WHO Geneva 1 ...
Research on the incidence, morbidity and mortality of snake bites in Africa, Asia, Oceania and Latin America; and on the clinical presentation, pathophysiology, treatment and prevention of envenoming by snakes and other venomous animals. Current sites of active research are Nepal, Bangladesh and Papua New Guinea. The key component of snake bite treatment is provision of specific antivenom. New antivenoms for treatment of saw-scaled viper bites in Nigeria and of taipan bites in Papua New Guinea have been developed and have or are being clinically tested. Recent findings in India give support to the belief that snake bite is the most neglected of all neglected tropical diseases and deserves reprioritisation. This programme is aimed at producing evidence relevant to establishing the true status of snake bite as a public health problem.
|Dr Sanjib K Sharma||Medicine||B.P. Koirala Institute of Health Sciences, Dharan||Nepal|
|Professor M Abul Faiz FRCP||Medicine||Sir Salimullah Medical College||Bangladesh|
|Professor Sir Isi Kevau KBE||Medical School||University of Papua New Guinea, Port Moresby||Papua New Guinea|
|Mr David J Williams||Pharmacology||University of Melbourne||Australia|
|Dr Abdulrazaq G Habib FRCP||Medicine||Bayero University, Kano||Nigeria|
BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India. Hide abstract
Prospective studies of snake bite patients in Chittagong, Bangladesh, included five cases of bites by greater black kraits (Bungarus niger), proven by examination of the snakes that had been responsible. This species was previously known only from India, Nepal, Bhutan and Burma. The index case presented with descending flaccid paralysis typical of neurotoxic envenoming by all Bungarus species, but later developed generalized rhabdomyolysis (peak serum creatine kinase concentration 29,960 units/l) with myoglobinuria and acute renal failure from which he succumbed. Among the other four patients, one died of respiratory paralysis in a peripheral hospital and three recovered after developing paralysis, requiring mechanical ventilation in one patient. One patient suffered severe generalized myalgia and odynophagia associated with a modest increase in serum creatine kinase concentration. These are the first cases of Bungarus niger envenoming to be reported from any country. Generalized rhabdomyolysis has not been previously recognized as a feature of envenoming by any terrestrial Asian elapid snake, but a review of the literature suggests that venoms of some populations of Bungarus candidus and Bungarus multicinctus in Thailand and Vietnam may also have this effect in human victims. To investigate this unexpected property of Bungarus niger venom, venom from the snake responsible for one of the human cases of neuro-myotoxic envenoming was injected into one hind limb of rats and saline into the other under buprenorphine analgesia. All animals developed paralysis of the venom-injected limb within two hours. Twenty-four hours later, the soleus muscles were compared histopathologically and cytochemically. Results indicated a predominantly pre-synaptic action (β-bungarotoxins) of Bungarus niger venom at neuromuscular junctions, causing loss of synaptophysin and the degeneration of the terminal components of the motor innervation of rat skeletal muscle. There was oedema and necrosis of extrafusal muscle fibres in envenomed rat soleus muscles confirming the myotoxic effect of Bungarus niger venom, attributable to phospholipases A₂. This study has demonstrated that Bungarus niger is widely distributed in Bangladesh and confirms the risk of fatal neuro-myotoxic envenoming, especially as no specific antivenom is currently manufactured. The unexpected finding of rhabdomyolysis should prompt further investigation of the venom components responsible. The practical implications of having to treat patients with rhabdomyolysis and consequent acute renal failure, in addition to the more familiar respiratory failure associated with krait bite envenoming, should not be underestimated in a country that is poorly equipped to deal with such emergencies. Hide abstract
LANCET, 375 (9715), pp. 640-640.2010. Snake bite (vol 375, pg 77, 2010)
BACKGROUND: In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358). METHODS: In a randomised, double-blind, controlled, non-inferiority trial, "EchiTAb Plus-ICP" (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to "EchiTAb G" (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions. FINDINGS: Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively. CONCLUSION: At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01257358. Hide abstract
CLINICAL TOXICOLOGY, 46 (5), pp. 380-380.2008. A randomised controlled trial of multiple dose activated charcoal in acute self-poisoning
BACKGROUND: The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. METHODS: Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. FINDINGS: All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. CONCLUSIONS: This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN 30087513. Hide abstract
The full scale of the global burden of human rabies is unknown, owing to inadequate surveillance of this fatal disease. However, the terror of hydrophobia, a cardinal symptom of rabies encephalitis, is suffered by tens of thousands of people each year. The recent discovery of enzootic European bat lyssavirus infection in the UK is indicative of our expanding awareness of the Lyssavirus genus. The main mammalian vector species vary geographically, so the health problems created by the lyssaviruses and their management differ throughout the world. The methods by which these neurotropic viruses hijack neurophysiological mechanisms while evading immune surveillance is beginning to be unravelled by, for example, studies of molecular motor transport systems. Meanwhile, enormous challenges remain in the control of animal rabies and the provision of accessible, appropriate human prophylaxis worldwide. Hide abstract
Lancet, 358 (9297), pp. 1983-1988. | Read more2001. "To search and Studdy out the secrett of Tropical Diseases by way of Experiment".
BACKGROUND: Severe cardiac glycoside cardiotoxicity after ingestion of yellow oleander seeds is an important problem in rural areas of Sri Lanka. Currently, patients must be transferred to the capital for temporary cardiac pacing. We did a randomised controlled trial to investigate whether anti-digoxin Fab could reverse serious oleander-induced arrhythmias. METHODS: After a preliminary dose-finding study, 66 patients who presented to hospital with a serious cardiac arrhythmia were randomised to receive either 1200 mg of anti-digoxin Fab or a saline placebo. A 12-lead electrocardiogram, 3 min rhythm strip, and blood sample for measurement of electrolytes and cardiac glycosides were taken before treatment and at 12 timepoints thereafter. FINDINGS: 34 patients received anti-digoxin Fab and 32 received placebo. The presenting arrhythmia had resolved completely after 2 h in 15 antibody-treated patients and two controls (p<0.001); 24 and five patients, respectively, were in sinus rhythm at 8 h (p<0.001). Kaplan-Meier analysis of time to first reversal showed a significant response to anti-digoxin Fab. The heart rate increased in cases, from 49.1 per min at baseline to 66.8 at 2 h, but not in controls (50.6 per min at baseline to 51.5; p<0.001). Mean serum potassium concentrations decreased from 4.9 mmol/L to 4.1 mmol/L at 2 h in cases; no such decrease occurred in controls. INTERPRETATION: Anti-digoxin Fab fragments are a safe and effective treatment for serious cardiac arrhythmias induced by yellow oleander. Their use in small rural hospitals in Sri Lanka should minimise costly transfer of patients and reduce the numbers of deaths; however, further study will be required to confirm this reduction. Hide abstract
Massive release of tumor necrosis factor is responsible for the potentially fatal larisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis. We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii. We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis. Hide abstract
Plasmodium falciparum remains one of the most common causes of central nervous system infection worldwide. Recently, differences between the pathophysiology of cerebral malaria in African children and nonimmune adults have been discovered, new syndromes occurring after malaria infection described, and mechanisms for the pathogenesis proposed. In addition, new antimalarial agents have been examined worldwide and initial studies on supportive studies conducted. This paper reviews these new advances, putting them into the perspective of the more established knowledge. Hide abstract
BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever. Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006). The controls had significantly greater mean maximal increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons). Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis. Hide abstract
Pituitary function was investigated in 9 patients in shock after Russell's viper bites and in 24 individuals who had been severely envenomed 2 weeks to 24 years previously. 3 out of 9 patients had hypoglycaemia and inappropriately low serum cortisol, plasma growth hormone, and plasma prolactin concentrations. 4 who died had pituitary haemorrhage and 1 had adrenal haemorrhage as well. Of the 24 who had apparently recovered from bites, 7 had clinical features of hypopituitarism and no response in plasma growth hormone or prolactin concentrations to symptom-producing insulin-induced hypoglycaemia. 4 of these 7 had a sluggish serum cortisol response to 'Synacthen Depot' and 5 had an abnormal cortisol response to hypoglycaemia. 4 men with symptoms who were tested had low serum testosterone concentrations; serum thyroxine was also low in these men but not in 2 women with menstrual disturbances and impaired insulin responses. Of the 17 individuals without clinical evidence of endocrine disease, 4 had pituitary hormonal abnormalities. Russell's viper envenoming may thus produce a disorder resembling Sheehan's syndrome. Hide abstract
To study the ability of anticholinesterase drugs to reverse the potentially fatal paralytic effects of cobra venom, we conducted a placebo-controlled, double-blind crossover trial of intravenous edrophonium (Tensilon) in 10 adults with neurotoxic envenoming caused by bites of the Philippine cobra (Naja naja philippinensis). There was significantly more improvement in ptosis and endurance of upward gaze after edrophonium than after placebo. Five minutes after injection, the mean difference (+/- SD) in the percentage of the iris that was uncovered was 39 +/- 5.47 (70 vs. 31 percent; P less than 0.01), and the mean difference in the number of seconds of upward gaze was 33.1 +/- 9.29 (39.7 vs. 6.6 seconds; P less than 0.01). The expiratory and inspiratory pressures, forced vital capacity, and ability to cough, speak, and swallow also improved after edrophonium. In both the patients who were studied electromyographically, pretreatment and postplacebo responses were typical of myasthenia gravis and became normal after edrophonium. We conclude that anticholinesterases are beneficial in the management of neurotoxic envenoming by Asian cobras (Naja naja), and we recommended a test of edrophonium in any patient with signs of neurotoxic envenoming after snakebite. Hide abstract
High-dose dexamethasone was compared with placebo in a double-blind trial involving 100 comatose patients with strictly defined cerebral malaria. The two treatment groups, whose members were six to 70 years old, proved comparable on admission. There were eight deaths in the dexamethasone group and nine in the placebo group (no significant difference; P = 0.8); at post-mortem examination the brain showed features diagnostic of cerebral malaria in all but one patient who died. Dexamethasone prolonged coma among the survivors: the interval between the start of treatment and the full recovery of consciousness was 63.2 +/- 5.9 hours (mean +/- S.E.M.) in the dexamethasone group, as compared with 47.4 +/- 3.2 hours in the placebo group (P = 0.02). Complications, including pneumonia and gastrointestinal bleeding, occurred in 26 patients given dexamethasone and 11 given placebo (P = 0.004). Only five patients had neurologic sequelae. Results were similar in a subgroup of 28 children six to 14 years old. Dexamethasone is deleterious in cerebral malaria and should no longer be used. Hide abstract