Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with
Snake antivenoms are the only specific treatments for snakebite envenoming; they save lives but are associated with acute pyrogenic reactions, due to endotoxin contamination whilst in production, and acute anaphylaxis [
The mechanisms underlying antivenom-related anaphylaxis (ARA) are uncertain and are probably a combination of complement activation, a type I hypersensitivity reaction, non-allergen-specific activation of mast cells triggered by the antivenom impurities and immune priming due to the venom itself [
ARA has the same clinical features as other causes of anaphylaxis. Common (20-50%) features include urticaria, tachycardia, hypotension, tachypnoea, dyspnoea, wheeze, and angioedema. Restlessness, agitation, confusion, laryngeal obstruction, stridor, sinus bradycardia, and relative bradycardia with hypotension are seen less frequently [
Severe life-threatening ARA characterised by shock, hypoxia, and reduced consciousness/confusion were low (<2 – ~7%) in studies from Ecuador [
Intramuscular adrenaline (IMAd) is the treatment of choice for acute ARA, but ARA may respond poorly (protracted anaphylaxis) or recur later (biphasic anaphylaxis) [
Most venomous snake bites in Nepal are caused by spectacled and monocled cobras,
We reported previously the efficacy and tolerability of high vs. low dose antivenom in neurotoxic envenomed patients [
Study details are published elsewhere [
Ethical clearance was obtained from the B.P. Koirala Institute of Health Sciences Ethics Committee (approval n°ACA-575-/067/068), the Nepal Health Research Council (approval n°986), and the Geneva University Hospitals Ethics Committee (approval n°08-192). All study participants gave written informed consent to participate in this study.
Recruited patients were aged ≥ 5 years (y), with signs of neurotoxic envenoming, assessed using a neurotoxicity score (NS, Box
Inability to frown Inability to retract upper eyelids on looking up (bilateral ptosis) Inability to protrude the tongue beyond incisors Broken neck sign Inability to swallow Inability to open the mouth Skeletal muscle weakness Gag reflex loss Paradoxical breathing
We used the VINS manufactured polyvalent antivenom (VINS Bio-pharmaceuticals Corp. Ltd., Mumbai, India); all antivenom came from one batch: #01AS11004. This antivenom contains horse derived F(ab')2 antibody fragments against
Patients were randomised to either the Nepali recommended low dose (LD) regimen: 6 vials, 2 by IV push over 5-10 m, then 4 infused over 4 h (1h & 3h infusions), or high dose (HD) antivenom: 10 vials by IV push over 5-10 m, then 8 vials infused over 1 h and 3 h normal saline infusion to maintain the blind. Persisting neurotoxic signs were treated with 4h infusions of 4 vials (LD arm) or saline (HD arm). Acute neurological deterioration (i.e., increased NS) was treated with 2 vials (LD arm) or 5 vials (HD arm) by IV push.
All patients received neostigmine to enhance neuromuscular transmission [
Patients were monitored hourly until the NS became 0 (i.e., complete resolution of neurotoxic signs) then 6 hourly and included emergent symptoms and signs, vital signs, NS, and SpO2 measured by finger oximeter [MD300D (adults), MD 300C5 (children), Vandagraph, United Kingdom]. Patients were followed up on days 7 and 21 and at 6 months.
Severe acute anaphylaxis meets the definition of a serious adverse event (SAE), i.e., life-threatening, prolongs inpatient stay, or results in death [
For this report, the senior author reviewed again all SAE forms and associated communications to reconstruct the clinical picture from patient admission to discharge or death. Clinical events, defined as important symptoms or signs, were identified and the following details were recorded: (i) their timing, (ii) how often they occurred, (iii) what their causes were, (iv) how and at what times they were treated, and (v) outcomes. Data were entered into Microsoft Excel and analysed [descriptive analyses and Mann–Whitney U test (continuous data)] in Stata v14 (Stata Corporation, USA).
Premedication with SCAd was given in the second snakebite season in 2012 following the report by de Silva et al. [
We used the definition recommended by the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network, “anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death” [
All clinical teams received prestudy and refresher trainings in the recognition and treatment of anaphylaxis, including (i) a list of key symptoms and signs (itching, urticaria, swollen lips or tongue, angioedema, dry cough, wheezing, stridor, hoarse voice, ‘lump in throat’, nausea, vomiting, abdominal colic, diarrhoea, hypotension, and shock), (ii) ABC of resuscitation (airway: obstruction/compromise, breathing: tachypnoea, wheezing, and circulation: hypotension or shock +/- poor peripheral circulation), (iii) intubation and the use of an Ambu bag. We stressed the urgency of treating anaphylaxis when the first sign/s consistent with ARA appeared, irrespective of their severity [
For patients who had experienced ARA but needed more antivenom to treat envenoming, antivenom infusions were resumed when patients were either haemodynamically stable or when the treating physician thought the anaphylaxis was clinically resolved. A reappearance of ARA was treated as above, but we later replaced this practice with IVAIs to “cover” additional doses of antivenom infusion, following the regimen of Brown et al. [
155 patients with neurotoxic envenoming received at least one dose of antivenom and are included in this analysis, including one patient who later withdrew from the study (Figure
Trial profile.
In total, 13 [8.4%, 95% confidence interval (CI) 4.9-13.8%] patients had severe ARA, three were children aged 5, 6, and 11 y and 10 adults, aged 18–52 y (Table
Baseline characteristics of the 13 patients by dose of antivenom.
High dose antivenom | Standard dose antivenom | |
---|---|---|
n=9 | n=4 | |
Age | 23 (5–52) | 34.5 (6–52) |
Sex female:male | 2:7 | 1:3 |
Received subcutaneous adrenaline | 4 | 2 |
Snake species | ||
|
0 | 1 |
|
3 | 1 |
|
1 | 0 |
Unidentified | 5 | 2 |
Neurological score | 2 (1–4) | 3 (2–4) |
Over time, these 13 patients had 64 clinical events: two patients had 3 events, six had 4 events, two had 5 events, and three had 8 events (Table
Details of the clinical events in 13 neurotoxically envenomed patients with postantivenom serious adverse events.
Patient |
NS D0 | AVR | CR arrest | Shock | Hypotension | SB | Dyspnoea | Wheeze | Cyanosis | Cough |
|
Frothy secretions | P Resp | LO | VAP | Restless | Drowsy | Vomiting | Rash | Soft tissue oedema | Fever | Total | Outcome |
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13 | 2 | H | 1 | - | - | - | - | - | - | - | 2 | 1 | - | - | 1 | 1 | - | 1 | 1 | - | - | 8 | D |
12 | 2 | H | 2 | - | - | 2 | 1 | - | - | - | - | - | - | - | 1 | 1 | - | 1 | - | - | 8 | D | |
11 | 2 | L | - | - | - | - | 1 | - | - | - | - | - | - | 1 | - | - | - | - | 1 | 1 |
- | 4 | D |
10 | 2 | H | 1 | 1 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 |
1 | 5 | D |
9 | 2 | L | 1 | 1 | - | - | 1 | - | - | - | - | - | - | - | - | - | - | - | 1 | - | - | 4 | D |
8 | 2 | H | 1 | - | - | 1 | 1 | 1 | - | - | 1 | 1 | - | - | - | - | - | 1 | 1 | - | - | 8 | D |
7 | 3 | H | 2 | - | - | 1 | 1 | - | - | - | - | - | - | - | - | - | - | - | - | 4 | D | ||
6 | 3 | H | 1 | - | 1 | 1 | - | - | - | - | 1 | - | 1 | - | - | - | - | - | - | - | - | 5 | D |
5 | 2 | H | - | - | 1 | - | 1 | 1 | - | - | - | - | - | - | - | - | - | - | 1 | - | - | 4 | R |
4 | 4 | H | - | - | - | - | 1 | 1 | 1 | - | - | - | - | - | - | 1 | - | - | - | - | - | 4 | R |
3 | 4 | L | - | - | 1 | - | 1 | - | - | - | - | - | - | - | - | - | - | - | 1 | - | - | 3 | R |
2 | 1 | H | - | 1 | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | - | 1 | 4 | R |
1 | 4 | L | - | - | - | - | - | - | - | 1 | - | - | - | 1 | - | - | - | - | 1 | - | - | 3 | R |
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Total | |
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9 | 3 | 3 | 5 | 8 | 3 | 1 | 1 | 4 | 2 | 1 | 2 | 1 | 3 | 1 | 3 | 10 | 2 | 2 | 64 | |
NS D0: neurotoxicity score on Day 0 (baseline); AVR: antivenom regimen; H: high-dose antivenom regimen; L: low-dose antivenom regimen; CR: cardiorespiratory; SB: sinus bradycardia.
P Resp: paradoxical respiration; LO: laryngeal oedema; VAP: ventilator associated pneumonia; D: died; R: resolved.
Time course of antivenom administrations, clinical events, and adrenaline treatment. Time 0 is the start of antivenom administration.
Median (range) times to the first clinical symptom or sign consistent with ARA after the most recent dose of antivenom were (i) 19 (5-115) minutes (m) after the first IV push of antivenom, (ii) 52.5 (11-155) m (second dose), and (iii) 75 (30-770) m (third dose). SCAd was given to 6 patients in 2012 and four and nine patients received LD and HD antivenom, respectively, but the times to the first ARA event were not significantly different between (i) SCAd recipients 17 (5-40) m vs. nonrecipients 30
There were 8 deaths (#s 6–13, Table
Clinical notes on the eight patients with neurotoxic envenoming who died.
Patient |
SCAD | Antivenom dose | Clinical description | Time to death in h |
Commentary |
---|---|---|---|---|---|
Gender/ | |||||
Age | |||||
#13 |
N | H | 30m after IV push developed generalised erythematous rash. Treated with SC adrenaline x 2 & IV hydrocortisone. Antivenom infusion restarted when rash resolved. ~1.5h later became restless & NS increased from 2 to 4. Treated with IV AV push but his NS remained stable at 4 (1h post push). Another hour later (i.e. 2h after IV push), he had a sudden cardiorespiratory arrest. Intubated, resuscitated successfully, was stable but drowsy and continued on mechanical ventilation. Frothy secretions in ET tube treated with atropine. NS became 0 but he was unable to be extubated. Developed ventilator associated pneumonia and treated with antibiotics. Laryngeal spasm occurred during tracheostomy resulting in death. | 264 | Had an initially mild ARA. His later restlessness is consistent more with worsening envenoming (increase in NS) than delayed recurrent ARA but the sudden CR arrest is consistent with delayed ARA due to the earlier IV antivenom pushes. |
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#12 |
Y | H | Generalised itching & urticaria developed 5m after IV push started. Treated correctly. IV adrenaline infusion started to cover rest of IV push & antivenom infusion when ARA had resolved. Later at T0+3.8h (2h after antivenom infusion stopped), patient became drowsy & restless with neurotoxicity score=0. Not treated for ARA. Sent to intensive care unit for monitoring. 10h later found gasping. Intubated & improved on oxygen. 6h later fall in SpO2, sinus bradycardia, asystole, DC shocked and reverted to sinus tachycardia. Stable but 3.5h later another episode of sinus bradycardia and asystole. Resuscitation unsuccessful. | 23.8 | Initial itching and urticaria are typical features of mild ARA. |
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#11 |
N | L | Urticaria and unilateral eye oedema developed 5m after IV push started. Treated with x 2 SC adrenaline. ARA resolved. Antivenom restarted and stopped when neurotoxic signs disappeared. Patient later developed a hoarse voice (11h from T0, 8.5h since antivenom stopped) that worsened despite treatment with IM adrenaline and IV chlorphenamine. Dyspnoea and falling SpO2. Intubation attempt failed because laryngeal oedema was severe. Patient was transferred but died in the ambulance. | 13 | Late laryngeal oedema is consistent with delayed recurrent ARA. |
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#10 |
N | H | First indication of anaphylaxis was itching during antivenom infusion (30m after IV push). Antivenom stopped. Treated with chlorphenamine but IM adrenaline given 15m later when rash appeared. Antivenom restarted as rash was resolving. 1h 10m later while on antivenom infusion, patient became shocked with falling SpO2 and development of angioedema. Resuscitated, intubated & transferred but died in the ambulance. | 3.7 | Clinical picture of ARA. |
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#9 |
Y | L | Anaphylaxis manifested as mild urticaria 19m after IV push, treated with IM adrenaline & resolved. AV infusion restarted. Developed dyspnoea without wheezing & without an increase in NS (static at 2). Treated with oxygen but SpO2 fell to 70%. Then AV stopped and treated appropriately for ARA but progressed rapidly to cardiorespiratory arrest & died despite resuscitation. | 3.3 | Decline in respiratory function without wheezing was thought initially to be envenoming related. Poor response to ARA treatment after fall in SpO2 which was probably ARA related. |
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#8 |
Y | H | Developed vomiting 15m after IV push followed by urticaria and dyspnoea with wheezing 5m later. Treated with salbutamol and ipratropium inhalations. No IM adrenaline given. Antivenom continued (NS=2). 40m later developed increased NS of 4 (IV AV push given) that, 20m later, increased to 6 associated with frothy secretions and muscle weakness (IV AV push given again). Became restless with gasping respirations, BP 90/60 & SpO2 80%, pulse fell from 140 to 55/m (sinus bradycardia, given IV atropine). Intubated, manually ventilated, then cardiac arrest and died despite resuscitation. | 1.9 | Clinical picture dominated by rapidly progressive envenoming despite treatment with antivenom pushes. Patient did not receive IM adrenaline for initial episode of mild anaphylaxis nor adrenaline cover for the IV pushes, nor IMAd for possible ARA. |
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#7 |
Y | H | Presented with abdominal pain, vomiting, ptosis, tachypnoea (RR 40/m), tachycardia (120/m) and central cyanosis (SpO2 60%) treated with oxygen (SpO2 rose to 90%) before antivenom. 15m after AV push & while on AVI had a respiratory arrest associated with sinus bradycardia (50/m). Immediate intubation was followed by a cardiac arrest. Resuscitated with IV adrenaline & 300 mL IV fluid bolus; AVI continued. Pulse detected by oximeter but no recordable blood pressure. Decision made to transfer to hospital. Second cardiac arrest (exact time not noted) followed by death despite resuscitation in ambulance. | 1.3 | Clinical picture dominated by poor respiratory status before antivenom associated with NS score of 3. Respiratory arrest after antivenom followed by cardiac arrest. Given the rapidity of the events, ARA may have contributed to the clinical picture. |
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#6 |
Y | H | Rapid deterioration in cardiorespiratory function associated with sinus bradycardia and increasing NS. Culminated in a cardiorespiratory arrest and failed resuscitation. Treated for anaphylaxis and given IV antivenom push. | 1.3 | Treated for worsening envenoming and ARA. Clinical picture dominated by apparent worsening of envenoming that may have masked features of anaphylaxis. Died despite treatment for ARA |
h: hour, m: minute, y: years, NS: neurotoxicity score, AV: antivenom, AVI: antivenom infusion, ET: endotracheal tube, SpO2: oxygen saturation, ARA: antivenom related anaphylaxis.
The clinical features were similar between the LD and HD patients (Table
Clinical notes on the five patients with neurotoxic envenoming who survived.
Patient # | SCAD | Antivenom dose | Clinical description | Commentary |
---|---|---|---|---|
Gender/ | ||||
Age | ||||
#5 |
N | H | 1.55h after IV push & during AV infusion, developed acute wheezing & rash on forehead. AV stopped. Treated with nebulised salbutamol. 5m later, wheeze became worse, P-144/m, BP fell to 90/50, SaO2 90%. AV stopped immediately. Treated with IV hydrocortisone, chlorphenamine & N saline, followed by IMAd (6m delay). Transferred to ICU for observation. ARA resolved fully after 95m. AV restarted with no further ARAs. | Developed classic features of ARA. Additional doses of AV did not result in additional ARAs despite no prophylactic SCAd or IVAI. |
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#4 |
N | H | 1.5h after IV push & during AV infusion, developed acute restlessness, wheezing & cyanosis. Respiratory rate 32/m, SpO2 50%, P-76 BP160/100. AV stopped immediately. Treated with IMAd, IV hydrocortisone, oxygen, then intubated in ICU. Needed two boluses of AV in the ICU; both covered with SCAd. No additional ARAs & made a full recovery. | Developed classic features of life threatening ARA with rapid decline in respiratory function necessitating intubation. |
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#3 |
N | L | 10m after start of IV AV push, developed itchy red rash on upper arms, chest abdomen with respiratory distress. Tachycardia and fall in blood pressure (no measurements recorded). AV stopped immediately. Treated with 0.5 mg IVAd x 2, IV hydrocortisone & chlorphenamine & intubation. Rash resolved completely. IVAV restarted 15m after rash resolved under cover of IVAI started to cover. No additional ARAs. Extubated & made full recovery. | Developed classic features of life threatening ARA with rapid decline in respiratory function necessitating intubation. IV rather than IMAd given to treat ARA. |
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#2 |
N | H | 15m after start of IV AV push, developed urticaria. Treated with SCAd but AV not stopped. 5m after rash, patient became shocked with an unrecordable BP and cool peripheries. AV stopped. Treated with 1 mg IVAd, hydrocortisone, saline bolus, atropine, second dose of neostigmine & atropine. Stabilised & after 10m signs were P-99/m, BP 90/50, SpO2 90%. AV infusion restarted followed 10m later by a pyrogenic reaction (fever & chills). Treated symptomatically & with |
Initial ARA was a red rash that was treated with SCAd rather than IMAd. AV not stopped and may have resulted in life threatening ARA. |
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#1 |
Y | L | 40m after IV push & during AV infusion, developed red rash. AV stopped & treated with 0.5 mg IVAd, IV hydrocortisone & chlorphenamine. Rash resolved after 20m & AV infusion restarted under IVAI. 35m later developed cough, noisy breathing & fall in SpO2 to 63%. Acute laryngeal oedema suspected and transferred to ICU for intubation. | ARA started with a red rash and resolved with treatment. AV infusion restarted with IVAI but it did not prevent laryngeal oedema. |
SCAd: subcutaneous adrenaline, IMAd: intramuscular adrenaline, SC: subcutaneous, IV: intravenous, IM: intramuscular, h: hour, m: minute, y: years, NS: neurotoxicity score.
AV: antivenom, SpO2: oxygen saturation, ARA: antivenom related anaphylaxis.
In most ARA-diagnosed patients, antivenom was stopped and IMAd given almost immediately after the ARAs were recognised (Figure
Six patients (#s 6, 7, 8, 9, 12, 13) had events with clinical features consistent with severe ARA and severe neurotoxic envenoming, although they were all considered to be antivenom-related at the time by the treating physicians (Table
One patient died of LLO (#11) and the other of anaphylactic shock (#10). Both patients died in the ambulance during hospital transfer.
Our study has documented a relatively high rate (~8%) of VINS antivenom associated ARA that was clinically clear-cut in seven patients but clouded in six mostly by a mix of dyspnoea, restlessness, and increasing neurological scores, all consistent with envenoming.
Acute anaphylaxis is a predictable toxicity of antivenom. The Indian-manufactured antivenoms, used commonly in south Asian countries, are associated with rates of severe ARA as high as ~20 to 40% [
The most difficult patients were those who developed restlessness and/or acute dyspnoea/gasping respiration with (e.g., #s13, 8) or without (e.g., #12, 9) an increase in the NS score and patients who deteriorated rapidly, culminating in a cardiac/respiratory arrest, whether they were treated for ARA (#6) or not (#7). Sinus bradycardia was an ominous sign that preceded cardiac arrest and death. With an acute increase in NS, clinicians may believe the acute clinical deterioration is exclusively due to worsening envenoming. However, they should consider whether an earlier antivenom infusion or IV push is contributing either acutely or as biphasic ARA and should have a low threshold for treating with IMAd.
To increase clinical awareness, we suggest several “danger” signs that require urgent assessment such as sinus bradycardia, relative bradycardia and hypotension [
Five patients developed dyspnoea without wheezing; two (one as gasping respiration) did not have a concomitant decline in NS whilst one gasping patient did. Although wheeze is a classic sign of acute anaphylaxis, dyspnoea alone is well documented and was more common than wheeze in two large clinical series. In one ARA study, ~16% (32/198) patients developed hypoxia, 3% wheeze and hypoxia and 3.5% wheeze alone [
Two patients developed laryngeal oedema neither of whom had stridor. The LLO patient had recovered from his earlier mild ARA and envenoming and his hoarse voice developed 8.5 h postantivenom infusion. It is unclear whether LO developed late and progressed rapidly (i.e., biphasic anaphylaxis) or insidiously to become clinically manifest only when the oedema was severe. He was unresponsive to adrenaline and hydrocortisone and the extent of the LO precluded endotracheal intubation. Without surgical equipment and skilled staff to relieve his upper airway obstruction (UAO), he died. The risk of laryngeal obstruction/oedema/stridor/throat tightness was 2% (1/48) in snakebite victims in Australia [
UAO is classed as both moderately severe [
During the study, our guidelines on treating recurrent ARA changed from treating each episode with IMAd to IVI to cover subsequent antivenom infusions [
We had a crude fatality rate (CFR) of ~5%, higher than the 1.3% reported by de Silva et al. in their large (n=1007) trial that was conducted in hospitals with experience of snakebite management [
To conclude, we have highlighted the risks of severe ARA in neurotoxic envenomed patients and challenges in managing patients where resources are limited. Clinicians should have a low threshold for treating of ARA when the clinical picture is not clear-cut and ARA cannot be excluded. More research is needed to define optimal treatment strategies in different health settings, especially snakebite centres.
The data that are presented in this anaphylaxis paper are available in Microsoft XL. All data requests should be addressed to Professor F. Chappuis: Francois.Chappuis@hcuge.ch.
No author has conflicts of interest.
Walter Robert John Taylor extracted and analysed the key data and wrote the first draft of the paper. Professors Francois Chappuis and Sanjib Kumar Sharma were the study and site PIs, respectively. Sanjib Kumar Sharma, Francois Chappuis, Emilie Alirol, Anup Ghimire, David Warrell, and Ulrich Kuch critically reviewed the manuscript. Sanjib Kumar Sharma, Anup Ghimire, Suman Shrestha, Rupesh Jha, Surya B. Parajuli, Deekshya Shrestha, Surya Jyoti Shrestha, and Amir Bista provided clinical care and collected the data. Emilie Alirol and Walter Robert John Taylor monitored the trial. Francois Chappuis, Sanjib Kumar Sharma, Emilie Alirol, and Ulrich Kuch designed the study with input from David Warrell and Walter Robert John Taylor.
We thank the patients and their guardians for enrolling into this study and the members of the DSMB: Professors J. White (chair), M. Boelaert, J. Desmeules, N. Jha, and P. B. Kshetry. James Watson of the Mahidol Oxford Tropical Medicine Research Unit kindly constructed Figure