Diphtheria in Children in Northern Haiti

Diphtheria in Children in Northern Haiti Abstract Infection with Corynebacterium diphtheriae persists in Haiti. Twenty-six children with clinically severe respiratory diphtheria presented to a hospital in northern Haiti during a 3-year period beginning in early 2015. The mortality rate was 50%. Partial or absent vaccinations as well as delayed and limited care contributed to mortality. This cohort offer insights into the multiple challenges involved in preventing and caring for children with diphtheria in resource-limited settings. Corynebacterium diphtheriae, diphtheria, vaccination, immunization INTRODUCTION Infection with Corynebacterium diphtheriae, nearly eradicated in most developed countries, continues to plague many resource-limited regions. In 2016, World Health Organization (WHO) statistics recorded 7097 cases of diphtheria globally, almost entirely in resource-limited countries [1]. As the disease remains endemic in war zones and remote parts of the world, there is concern that this number underestimates the true rate and that infection trends may worsen [2–5]. Haiti numbers among those countries where diphtheria persists. Although there were sporadic reports following the initiation of widespread immunization in 1977, the decade of the 1990s passed without a reported case until diphtheria reemerged in the 21st century. During a large outbreak in neighboring Dominican Republic in 2004, 37 cases of diphtheria were reported in Haiti, and dozens more occurred during the remainder of the decade [6]. In the months leading up to the catastrophic 2010 earthquake, 46 cases were reported. However, during the massive social disruption—and cholera epidemic—that followed, there were few reports until a recrudescence in 2014 [7]. In the next 3 years, at least 348 cases of probable diphtheria were reported and through 48 weeks of 2017 alone, 152 probable cases were reported, 53 of whom were ≥10 years old [8]. Included in these recent cases are most of the 26 children cared for at a referral hospital in the northern part of the country [7, 9]. The following cohort of children was treated at Hôpital Sacré Coeur (HSC) in Milot, Haiti from 1 February 2015 through 1 February 2018 with a clinical diagnosis of respiratory diphtheria. Their presentation, therapy, clinical course and outcomes were reviewed for this study, as were treatment options for the care of these children. PATIENTS AND METHODS A case series was prepared by reviewing the medical records of all 26 patients admitted to the pediatric service at HSC during a 25-month period between 1 February 2015 and 1 February 2018 with a clinical diagnosis of ‘probable’ diphtheria. This clinical diagnosis was based on the presence of sore throat, fever, upper respiratory tract illness and a grayish pseudomembrane adherent to tonsils, pharynx and/or nose [10–12]. Presence of neck swelling (‘bull neck’) was consistent with severe disease [13]. The dates chosen demarcate the first such admission during this recent outbreak until the most recent and include all patients with this diagnosis. HSC is a referral hospital of 125 beds (including 40 pediatric and neonatal beds) located in the North Department of Haiti. The data gathered included demographic information such as age (in months), gender, vaccination history, duration of symptoms before admission, pertinent physical exam findings on admission and therapy administered and interventions performed, including diphtheria antitoxin (DAT) and tracheostomy. DAT dosing was variable and depended on the amount made available by the Haitian Ministry of Health. Vaccination history was based on parental recollection. We also report outcomes, including mortality and, when available, results of bacterial cultures and polymerase chain reaction (PCR). Statistical significance was evaluated using Fischer exact and Mann–Whitney tests. Odds ratios were calculated for relevant associations. RESULTS Patients: Of the 26 patients admitted in this cohort, 15 were girls. The age range was 2–15 years, with a median age of 6 years (interquartile range 4–10). All patients presented in moderate to severe respiratory distress. False membranes were noted in all patients but one who, nonetheless, had other cardinal symptoms and a sibling who died from probable diphtheria. Duration of illness was recorded for 21 patients, with the mean duration of throat or respiratory symptoms before presentation of 4.8 days (SD ± 1.3). The medical record and parental recall reveal partial vaccination history in eight patients with no records or clear recollection of vaccines in the remaining patients. A diagnosis of probable diphtheria was made in all 26 cases with confirmation by culture and PCR in three patients; cultures were negative (after antibiotics) in two patients with no PCR performed (Table 1). Table 1 Summary of patient information Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Table 1 Summary of patient information Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Management: All the patients were placed in isolation at HSC. All but one child received penicillin, metronidazole and dexamethasone at HSC. Sixteen of the patients (61.5%) received DAT at doses ranging from 16 000 to 80 000 units with a mean dose of 56 000 units (SD ± 22 000). DAT was administered between 3 and 40 h after admission. All children were placed on oxygen via nasal cannula, none were intubated and six underwent tracheostomy. One child died during emergent cricothyrotomy after cardiorespiratory arrest. A program of antibiotic prophylaxis of immediate contacts was undertaken (Table 2). Table 2 Patient treatment and outcomes Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Table 2 Patient treatment and outcomes Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Outcomes: One-half of the patients died (13 of 26), one within an hour of presentation. The time from admission to death ranged from under an hour to 6 days. The proximal cause of death in all patients was respiratory collapse with 1 of the 13 dying from respiratory complications of tracheostomy 5 days after placement and a second, during emergent (post-arrest) cricothyrotomy. The median age was the same in survivors and those who died, and the age range of those who died was 2–11 years old. Four of those who died had a history of ‘partial’ vaccination, and the remainder had unknown or negative histories. Of those who survived, 10 of 13 (77%) received DAT, while 6 of 13 (45%) of non-survivors received this treatment (p = 0.23). The mean DAT doses administered to non-survivors (66 000 units) were higher than that given to survivors (54 000 units) (although one non-survivor initially received 30 000 units augmented a day later by 50 000 units). Odds ratios were calculated for death in those who did not receive DAT [3.39, confidence interval (CI) 0.72–21.06, p = 0.11]. The odds ratios for those with delayed presentation—i.e. symptoms for ≥4 days before presentation–were calculated (0.33, CI 0.209–3.84, p = 0.38). Average duration of symptoms in survivors receiving DAT was 5.0 days compared with 5.5 in non-survivors (p = 0.42). DISCUSSION Children succumbing to the ‘strangling angel’ present sad and dramatic evidence of a stressed and faltering health-care system [14]. In this series, we reviewed a cohort of children in northern Haiti with a clinical syndrome consistent with respiratory C. diphtheria infection. Though diphtheria is rare in wealthier countries, it continues to afflict children in resource-limited settings [7]. In fact, both in Haiti and globally, reported cases have risen in recent years. The mortality rate in this group was 50%. This is comparable with the historical, pre-vaccine levels. In contrast, the reported mortality rate in the larger, 2004 outbreak in the Dominican Republic was 32%, and reports from India describe rates of 24 and 9% in cohorts of 180 and 10 patients, respectively [6, 13, 15]. Factors known to influence outcomes in children infected with diphtheria are young age, immunization status, duration/severity of symptoms before presentation and treatment and use and timing of DAT [11, 13]. In our group, the median age of non-survivors was 6 years, older than the <5 year-old predominance in other reports, but consistent with recent national trends in Haiti [8, 9]. Historically, infection and mortality from diphtheria are associated with inadequate vaccination. The majority (69%) of deaths in this cohort occurred in children with an unknown immunization history, and no documentation was presented for those who reported a ‘partial’ history. Nationally, vaccination history was only known in a small percentage (17%) of recent cases and, for most of those, that history was negative [8]. There was minimal difference in reported duration of symptoms before presentation between survivors and non-survivors, and no significant evidence of increased odds of death for those with longer symptoms. This is not surprising, as the onset of symptoms is a subjective and often imprecise element of the history and, in any case, was not reported in nearly 25% of our pateints. For similar reasons, determining the crucial timing of DAT administration relative to onset of symptoms was problematic. Those who did not receive DAT did have an increased chance of death, which did not reach statistical significance. Nonetheless, 77% of survivors received DAT, which is clinically relevant. Finally, all deaths in our group were proximally attributable to upper airway obstruction and respiratory complications. It is still possible that varying degrees of myocardial dysfunction, commonly described in diphtheria, may have contributed to patient demise [6, 13]. Immunization remains unequivocally the most effective weapon against diphtheria, and global campaigns against infection have been highly successful. Following the adoption of the WHO’s Expanded Programmed on Immunizations (EPI) in the late 1970s (targeting three vaccines in early childhood), reported global fatalities from diphtheria dropped from nearly 100 000 in 1980 to 6654 in 2003 [16]. Yet this approach requires steadfast application, as evidenced by the epidemic in Eastern Europe in the 1990s following the collapse of the Soviet Bloc’s health network and recent global increases [1, 2, 17]. In Haiti, the WHO/UNICEF reported rates of full immunization (i.e. three vaccines) is 48%, with complete coverage in only slightly more than one-third of districts in the country. In fact, concerns had been raised regarding the reach of nationwide immunizations even before the catastrophic earthquake of 2010 [18]. The emergency immunization program (including diphtheria, pertussis, tetanus - DPT) that followed this disaster, however, was were felt to be suboptimally applied, even in areas not directly affected by the destruction [19, 20]. The age of those infected in Milot, and nationally, is consistent with gaps that have occurred since the earthquake. This vulnerability to diphtheria implies risk of contracting other similarly preventable illnesses; after 2 years without reported cases, 31 cases of tetanus were reported in Haiti between 2013–15 [21]. The primary therapy for diphtheria infection is neutralization of the toxin by DAT in doses of 80 000–100 000 units for children and adults with severe symptoms [11]. Yet this essential treatment must occur in a timely fashion, as DAT does not reverse the tissue damage already present. Unfortunately, DAT is currently only manufactured in four countries (Russia, Croatia, Brazil and India), leading to potential global shortages and logistical problems [22, 23]. These shortages notwithstanding, 97–100% of infected children in reports from India and the Dominican Republic received this essential therapy, compared with only 61% in our cohort, with more than a third receiving reduced dosing. This suggests problems with distribution rather than frank, global shortages and may represent, in part, problems of infrastructure and communication particular to Haiti. Penicillin is first-line antimicrobial treatment for C.diphtheria. All patients in this cohort except one (who died precipitously) received appropriately dosed therapy in addition to metronidazole and dexamethasone. The use of metronidazole is not recommended by the Redbook for C diphtheria [10]. Similarly, there are no data supporting steroid use for respiratory diphtheria, and available evidence suggests that steroids do not prevent cardiac or neurologic complications [24]. Also, of the six patients in this cohort who underwent tracheostomy, three died; two had been in extremis and died perioperatively and another, from complications of the tracheostomy while convalescing. Tracheostomy, commonly performed in cases of severe airway obstruction, is associated with both good and poor outcomes in RLS with outcomes related to levels of training and availability of appropriate supplies [6, 13, 15]. Finally, in response to this epidemic, in late 2016, the Haitian Ministry of Health put forward a number of initiatives to address this crisis, including revamped vaccination schedules, and measures to encourage the early diagnosis and treatment of diphtheria. More recently, caregiver workshops have been held in Port-au-Prince. While DAT has been available for most of the recent cases (in part because half-doses, or 40 000 units, were used in four cases), diagnostic efforts and, more importantly, focused vaccinations have not yet been undertaken. Intervening crises (e.g. hurricane Matthew, the cholera epidemic and the advent of chikungunya and Zika) have no doubt competed for limited resources, distracting from efforts to contain and eventually eradicate diphtheria. The principal limitation to this report is the small sample size and paucity of data, which do not allow for more in depth analysis and definitive conclusions. This deficiency, however, must be viewed in the context of a resource and personnel constrained setting with flawed medical record keeping and providers whose efforts were focused on caring for these severely ill children, rather than documentation. CONCLUSION Corynebacteriumdiphtheriae remains active in Haiti because of low rates of immunization. Delays in disease recognition, limited and delayed DAT administration and definitive care all contribute to the high mortality rate for those infected. Initiatives put forward by the Haitian Ministry of Health are promising, but addressing the near and long-term aspects of this problem will require comprehensive and coordinated action from an already severely stressed health-care system. REFERENCES 1 World Health Organization . Diphtheria: 2016 global figures. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. 2 Restrepo-Mendez MC , Barros AJ , Wong KL , et al. Missed opportunities in full immunization coverage: findings from low- and lower-middle-income countries . Glob Health Action 2016 ; 9 : 30963 . Google Scholar CrossRef Search ADS PubMed 3 Fatal Respiratory Dihtheria in a U.S. Traveler to Haiti–Pennsylvania 2004 . MMWR 2004 ; 52 : 1285 – 6 . PubMed 4 News release: Diphtheria is spreading fast in Cox's Basar, Bangladesh. World Health Organization, 2017 . http://www.who.int/mediacentre/news/releases/2017/diphtheria-spreading-bangladesh/en/. 5 News Release: WHO delivers medicines as Diphtheria spreads in Yemen. World Health Organization, 2017 . http://www.who.int/mediacentre/news/releases/2017/medicines-diphtheria-yemen/en/. 6 Garib Z , Danovaro-Holliday MC , Tavarez Y , et al. Diphtheria in the Dominican Republic: reduction of cases following a large outbreak . Rev Panam Salud Publica 2015 ; 38 : 292 – 9 . Google Scholar PubMed 7 World Health Organization . Diphtheria reported cases. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. (6 September 2017 , date last accessed). 8 Pan American Health Organization/World Health Organization Epidemiological Update : Diphtheria, 22 December 2017. Washingrton, DC: PAHO/WHO, 2017 . 9 Pan American Health Organization/World Health Organization Epidemiological Update: Diphtheria, 22 August 2017. Washingrton, DC: PAHO/WHO, 2017 . 10 American Academy of Pediatrics, Committee on Infectious Diseases, Committee on the Control of Infectious Diseases . Diphtheria ( 2015 ). Red book: report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics. https://redbook.solutions.aap.org/chapter.aspx? sectionId=88187137&bookId=1484&resultClick=1 (2 February 2018, date last accessed). 11 Tiwari T. Use of Diphtheria Antitoxin (DAT) for suspected Diphtheria Cases . Center for Disease Control and Prevention , 2014 . https://www.cdc.gov/diphtheria/downloads/protocol.pdf (1 September 2016, date last accessed). 12 Centers for Disease Control and Prevention . Epidemiology and Prevention of Vaccine-Preventable Diseases. Diphtheria . In: Hamborsky J , Kroger A , Wolfe S (eds), 13th edn . Washington DC : Public Health Foundation , 2015 . 13 Jain A , Samdani S , Meena V , et al. Diphtheria: it is still prevalent!!! . Int J Pediatr Otorhinolaryngol 2016 ; 86 : 68 – 71 . Google Scholar CrossRef Search ADS PubMed 14 Byard RW. Diphtheria—‘The strangling angel' of children . J Forensic Leg Med 2013 ; 20 : 65 – 8 . Google Scholar CrossRef Search ADS PubMed 15 Murhekar MV , Bitragunta S. Persistence of diphtheria in India . Indian J Community Med 2011 ; 36 : 164 – 5 . Google Scholar CrossRef Search ADS PubMed 16 Vitek CR. Diphtheria . Curr Top Microbiol Immunol 2006 ; 304 : 71 – 94 . Google Scholar PubMed 17 Vitek CR , Wharton M. Diphtheria in the former Soviet Union: reemergence of a pandemic disease . Emerg Infect Dis 1998 ; 4 : 539 – 50 . Google Scholar CrossRef Search ADS PubMed 18 Rainey JJ , Lacapere F , Danovaro-Holliday MC , et al. Vaccination coverage in Haiti: results from the 2009 national survey . Vaccine 2012 ; 30 : 1746 – 51 . Google Scholar CrossRef Search ADS PubMed 19 Rainey JJ , Sugerman D , Brennan M , et al. Rapid monitoring in vaccination campaigns during emergencies: the post-earthquake campaign in Haiti . Bull World Health Organ 2013 ; 91 : 957 – 62 . Google Scholar CrossRef Search ADS PubMed 20 World Health Organization . Haiti prepares to launch phase 2 of national post-disaster vaccination plan. Global Immunization Newsletter, 11 June 2010 . 21 World Health Organization . Tetanus: 2016 Global Figures. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. 22 Wagner KS , Stickings P , White JM , et al. A review of the international issues surrounding the availability and demand for diphtheria antitoxin for therapeutic use . Vaccine 2009 ; 28 : 14 – 20 . Google Scholar CrossRef Search ADS PubMed 23 Both L , White J , Mandal S , et al. Access to diphtheria antitoxin for therapy and diagnostics . Euro Surveill 2014 ; 19 . http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20830 (10 March 2017, date last accessed). 24 Thisyakorn U , Wongvanich J , Kumpeng V. Failure of corticosteroid therapy to prevent diphtheritic myocarditis or neuritis . Pediatr Infect Dis 1984 ; 3 : 126 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

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Abstract

Abstract Infection with Corynebacterium diphtheriae persists in Haiti. Twenty-six children with clinically severe respiratory diphtheria presented to a hospital in northern Haiti during a 3-year period beginning in early 2015. The mortality rate was 50%. Partial or absent vaccinations as well as delayed and limited care contributed to mortality. This cohort offer insights into the multiple challenges involved in preventing and caring for children with diphtheria in resource-limited settings. Corynebacterium diphtheriae, diphtheria, vaccination, immunization INTRODUCTION Infection with Corynebacterium diphtheriae, nearly eradicated in most developed countries, continues to plague many resource-limited regions. In 2016, World Health Organization (WHO) statistics recorded 7097 cases of diphtheria globally, almost entirely in resource-limited countries [1]. As the disease remains endemic in war zones and remote parts of the world, there is concern that this number underestimates the true rate and that infection trends may worsen [2–5]. Haiti numbers among those countries where diphtheria persists. Although there were sporadic reports following the initiation of widespread immunization in 1977, the decade of the 1990s passed without a reported case until diphtheria reemerged in the 21st century. During a large outbreak in neighboring Dominican Republic in 2004, 37 cases of diphtheria were reported in Haiti, and dozens more occurred during the remainder of the decade [6]. In the months leading up to the catastrophic 2010 earthquake, 46 cases were reported. However, during the massive social disruption—and cholera epidemic—that followed, there were few reports until a recrudescence in 2014 [7]. In the next 3 years, at least 348 cases of probable diphtheria were reported and through 48 weeks of 2017 alone, 152 probable cases were reported, 53 of whom were ≥10 years old [8]. Included in these recent cases are most of the 26 children cared for at a referral hospital in the northern part of the country [7, 9]. The following cohort of children was treated at Hôpital Sacré Coeur (HSC) in Milot, Haiti from 1 February 2015 through 1 February 2018 with a clinical diagnosis of respiratory diphtheria. Their presentation, therapy, clinical course and outcomes were reviewed for this study, as were treatment options for the care of these children. PATIENTS AND METHODS A case series was prepared by reviewing the medical records of all 26 patients admitted to the pediatric service at HSC during a 25-month period between 1 February 2015 and 1 February 2018 with a clinical diagnosis of ‘probable’ diphtheria. This clinical diagnosis was based on the presence of sore throat, fever, upper respiratory tract illness and a grayish pseudomembrane adherent to tonsils, pharynx and/or nose [10–12]. Presence of neck swelling (‘bull neck’) was consistent with severe disease [13]. The dates chosen demarcate the first such admission during this recent outbreak until the most recent and include all patients with this diagnosis. HSC is a referral hospital of 125 beds (including 40 pediatric and neonatal beds) located in the North Department of Haiti. The data gathered included demographic information such as age (in months), gender, vaccination history, duration of symptoms before admission, pertinent physical exam findings on admission and therapy administered and interventions performed, including diphtheria antitoxin (DAT) and tracheostomy. DAT dosing was variable and depended on the amount made available by the Haitian Ministry of Health. Vaccination history was based on parental recollection. We also report outcomes, including mortality and, when available, results of bacterial cultures and polymerase chain reaction (PCR). Statistical significance was evaluated using Fischer exact and Mann–Whitney tests. Odds ratios were calculated for relevant associations. RESULTS Patients: Of the 26 patients admitted in this cohort, 15 were girls. The age range was 2–15 years, with a median age of 6 years (interquartile range 4–10). All patients presented in moderate to severe respiratory distress. False membranes were noted in all patients but one who, nonetheless, had other cardinal symptoms and a sibling who died from probable diphtheria. Duration of illness was recorded for 21 patients, with the mean duration of throat or respiratory symptoms before presentation of 4.8 days (SD ± 1.3). The medical record and parental recall reveal partial vaccination history in eight patients with no records or clear recollection of vaccines in the remaining patients. A diagnosis of probable diphtheria was made in all 26 cases with confirmation by culture and PCR in three patients; cultures were negative (after antibiotics) in two patients with no PCR performed (Table 1). Table 1 Summary of patient information Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Table 1 Summary of patient information Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Patient information N (%) Number of patients 26 Female 15 (58) Immunizations (none/partial) 18/8 Duration of symptoms (days) 4.8 (±1.3) Presence of pseudomembrane 25 (96) Presence of ‘bull neck’ 17 (65) Management: All the patients were placed in isolation at HSC. All but one child received penicillin, metronidazole and dexamethasone at HSC. Sixteen of the patients (61.5%) received DAT at doses ranging from 16 000 to 80 000 units with a mean dose of 56 000 units (SD ± 22 000). DAT was administered between 3 and 40 h after admission. All children were placed on oxygen via nasal cannula, none were intubated and six underwent tracheostomy. One child died during emergent cricothyrotomy after cardiorespiratory arrest. A program of antibiotic prophylaxis of immediate contacts was undertaken (Table 2). Table 2 Patient treatment and outcomes Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Table 2 Patient treatment and outcomes Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Treatment/outcome N (%) Appropriate antibiotics 25 (96) DAT 16 (61) Dose of DAT (mean) 56 000 (±23 000) Tracheostomy 6 (23) Survival 13 (50) Outcomes: One-half of the patients died (13 of 26), one within an hour of presentation. The time from admission to death ranged from under an hour to 6 days. The proximal cause of death in all patients was respiratory collapse with 1 of the 13 dying from respiratory complications of tracheostomy 5 days after placement and a second, during emergent (post-arrest) cricothyrotomy. The median age was the same in survivors and those who died, and the age range of those who died was 2–11 years old. Four of those who died had a history of ‘partial’ vaccination, and the remainder had unknown or negative histories. Of those who survived, 10 of 13 (77%) received DAT, while 6 of 13 (45%) of non-survivors received this treatment (p = 0.23). The mean DAT doses administered to non-survivors (66 000 units) were higher than that given to survivors (54 000 units) (although one non-survivor initially received 30 000 units augmented a day later by 50 000 units). Odds ratios were calculated for death in those who did not receive DAT [3.39, confidence interval (CI) 0.72–21.06, p = 0.11]. The odds ratios for those with delayed presentation—i.e. symptoms for ≥4 days before presentation–were calculated (0.33, CI 0.209–3.84, p = 0.38). Average duration of symptoms in survivors receiving DAT was 5.0 days compared with 5.5 in non-survivors (p = 0.42). DISCUSSION Children succumbing to the ‘strangling angel’ present sad and dramatic evidence of a stressed and faltering health-care system [14]. In this series, we reviewed a cohort of children in northern Haiti with a clinical syndrome consistent with respiratory C. diphtheria infection. Though diphtheria is rare in wealthier countries, it continues to afflict children in resource-limited settings [7]. In fact, both in Haiti and globally, reported cases have risen in recent years. The mortality rate in this group was 50%. This is comparable with the historical, pre-vaccine levels. In contrast, the reported mortality rate in the larger, 2004 outbreak in the Dominican Republic was 32%, and reports from India describe rates of 24 and 9% in cohorts of 180 and 10 patients, respectively [6, 13, 15]. Factors known to influence outcomes in children infected with diphtheria are young age, immunization status, duration/severity of symptoms before presentation and treatment and use and timing of DAT [11, 13]. In our group, the median age of non-survivors was 6 years, older than the <5 year-old predominance in other reports, but consistent with recent national trends in Haiti [8, 9]. Historically, infection and mortality from diphtheria are associated with inadequate vaccination. The majority (69%) of deaths in this cohort occurred in children with an unknown immunization history, and no documentation was presented for those who reported a ‘partial’ history. Nationally, vaccination history was only known in a small percentage (17%) of recent cases and, for most of those, that history was negative [8]. There was minimal difference in reported duration of symptoms before presentation between survivors and non-survivors, and no significant evidence of increased odds of death for those with longer symptoms. This is not surprising, as the onset of symptoms is a subjective and often imprecise element of the history and, in any case, was not reported in nearly 25% of our pateints. For similar reasons, determining the crucial timing of DAT administration relative to onset of symptoms was problematic. Those who did not receive DAT did have an increased chance of death, which did not reach statistical significance. Nonetheless, 77% of survivors received DAT, which is clinically relevant. Finally, all deaths in our group were proximally attributable to upper airway obstruction and respiratory complications. It is still possible that varying degrees of myocardial dysfunction, commonly described in diphtheria, may have contributed to patient demise [6, 13]. Immunization remains unequivocally the most effective weapon against diphtheria, and global campaigns against infection have been highly successful. Following the adoption of the WHO’s Expanded Programmed on Immunizations (EPI) in the late 1970s (targeting three vaccines in early childhood), reported global fatalities from diphtheria dropped from nearly 100 000 in 1980 to 6654 in 2003 [16]. Yet this approach requires steadfast application, as evidenced by the epidemic in Eastern Europe in the 1990s following the collapse of the Soviet Bloc’s health network and recent global increases [1, 2, 17]. In Haiti, the WHO/UNICEF reported rates of full immunization (i.e. three vaccines) is 48%, with complete coverage in only slightly more than one-third of districts in the country. In fact, concerns had been raised regarding the reach of nationwide immunizations even before the catastrophic earthquake of 2010 [18]. The emergency immunization program (including diphtheria, pertussis, tetanus - DPT) that followed this disaster, however, was were felt to be suboptimally applied, even in areas not directly affected by the destruction [19, 20]. The age of those infected in Milot, and nationally, is consistent with gaps that have occurred since the earthquake. This vulnerability to diphtheria implies risk of contracting other similarly preventable illnesses; after 2 years without reported cases, 31 cases of tetanus were reported in Haiti between 2013–15 [21]. The primary therapy for diphtheria infection is neutralization of the toxin by DAT in doses of 80 000–100 000 units for children and adults with severe symptoms [11]. Yet this essential treatment must occur in a timely fashion, as DAT does not reverse the tissue damage already present. Unfortunately, DAT is currently only manufactured in four countries (Russia, Croatia, Brazil and India), leading to potential global shortages and logistical problems [22, 23]. These shortages notwithstanding, 97–100% of infected children in reports from India and the Dominican Republic received this essential therapy, compared with only 61% in our cohort, with more than a third receiving reduced dosing. This suggests problems with distribution rather than frank, global shortages and may represent, in part, problems of infrastructure and communication particular to Haiti. Penicillin is first-line antimicrobial treatment for C.diphtheria. All patients in this cohort except one (who died precipitously) received appropriately dosed therapy in addition to metronidazole and dexamethasone. The use of metronidazole is not recommended by the Redbook for C diphtheria [10]. Similarly, there are no data supporting steroid use for respiratory diphtheria, and available evidence suggests that steroids do not prevent cardiac or neurologic complications [24]. Also, of the six patients in this cohort who underwent tracheostomy, three died; two had been in extremis and died perioperatively and another, from complications of the tracheostomy while convalescing. Tracheostomy, commonly performed in cases of severe airway obstruction, is associated with both good and poor outcomes in RLS with outcomes related to levels of training and availability of appropriate supplies [6, 13, 15]. Finally, in response to this epidemic, in late 2016, the Haitian Ministry of Health put forward a number of initiatives to address this crisis, including revamped vaccination schedules, and measures to encourage the early diagnosis and treatment of diphtheria. More recently, caregiver workshops have been held in Port-au-Prince. While DAT has been available for most of the recent cases (in part because half-doses, or 40 000 units, were used in four cases), diagnostic efforts and, more importantly, focused vaccinations have not yet been undertaken. Intervening crises (e.g. hurricane Matthew, the cholera epidemic and the advent of chikungunya and Zika) have no doubt competed for limited resources, distracting from efforts to contain and eventually eradicate diphtheria. The principal limitation to this report is the small sample size and paucity of data, which do not allow for more in depth analysis and definitive conclusions. This deficiency, however, must be viewed in the context of a resource and personnel constrained setting with flawed medical record keeping and providers whose efforts were focused on caring for these severely ill children, rather than documentation. CONCLUSION Corynebacteriumdiphtheriae remains active in Haiti because of low rates of immunization. Delays in disease recognition, limited and delayed DAT administration and definitive care all contribute to the high mortality rate for those infected. Initiatives put forward by the Haitian Ministry of Health are promising, but addressing the near and long-term aspects of this problem will require comprehensive and coordinated action from an already severely stressed health-care system. REFERENCES 1 World Health Organization . Diphtheria: 2016 global figures. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. 2 Restrepo-Mendez MC , Barros AJ , Wong KL , et al. Missed opportunities in full immunization coverage: findings from low- and lower-middle-income countries . Glob Health Action 2016 ; 9 : 30963 . Google Scholar CrossRef Search ADS PubMed 3 Fatal Respiratory Dihtheria in a U.S. Traveler to Haiti–Pennsylvania 2004 . MMWR 2004 ; 52 : 1285 – 6 . PubMed 4 News release: Diphtheria is spreading fast in Cox's Basar, Bangladesh. World Health Organization, 2017 . http://www.who.int/mediacentre/news/releases/2017/diphtheria-spreading-bangladesh/en/. 5 News Release: WHO delivers medicines as Diphtheria spreads in Yemen. World Health Organization, 2017 . http://www.who.int/mediacentre/news/releases/2017/medicines-diphtheria-yemen/en/. 6 Garib Z , Danovaro-Holliday MC , Tavarez Y , et al. Diphtheria in the Dominican Republic: reduction of cases following a large outbreak . Rev Panam Salud Publica 2015 ; 38 : 292 – 9 . Google Scholar PubMed 7 World Health Organization . Diphtheria reported cases. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. (6 September 2017 , date last accessed). 8 Pan American Health Organization/World Health Organization Epidemiological Update : Diphtheria, 22 December 2017. Washingrton, DC: PAHO/WHO, 2017 . 9 Pan American Health Organization/World Health Organization Epidemiological Update: Diphtheria, 22 August 2017. Washingrton, DC: PAHO/WHO, 2017 . 10 American Academy of Pediatrics, Committee on Infectious Diseases, Committee on the Control of Infectious Diseases . Diphtheria ( 2015 ). Red book: report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics. https://redbook.solutions.aap.org/chapter.aspx? sectionId=88187137&bookId=1484&resultClick=1 (2 February 2018, date last accessed). 11 Tiwari T. Use of Diphtheria Antitoxin (DAT) for suspected Diphtheria Cases . Center for Disease Control and Prevention , 2014 . https://www.cdc.gov/diphtheria/downloads/protocol.pdf (1 September 2016, date last accessed). 12 Centers for Disease Control and Prevention . Epidemiology and Prevention of Vaccine-Preventable Diseases. Diphtheria . In: Hamborsky J , Kroger A , Wolfe S (eds), 13th edn . Washington DC : Public Health Foundation , 2015 . 13 Jain A , Samdani S , Meena V , et al. Diphtheria: it is still prevalent!!! . 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Rapid monitoring in vaccination campaigns during emergencies: the post-earthquake campaign in Haiti . Bull World Health Organ 2013 ; 91 : 957 – 62 . Google Scholar CrossRef Search ADS PubMed 20 World Health Organization . Haiti prepares to launch phase 2 of national post-disaster vaccination plan. Global Immunization Newsletter, 11 June 2010 . 21 World Health Organization . Tetanus: 2016 Global Figures. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html. 22 Wagner KS , Stickings P , White JM , et al. A review of the international issues surrounding the availability and demand for diphtheria antitoxin for therapeutic use . Vaccine 2009 ; 28 : 14 – 20 . Google Scholar CrossRef Search ADS PubMed 23 Both L , White J , Mandal S , et al. Access to diphtheria antitoxin for therapy and diagnostics . Euro Surveill 2014 ; 19 . http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20830 (10 March 2017, date last accessed). 24 Thisyakorn U , Wongvanich J , Kumpeng V. Failure of corticosteroid therapy to prevent diphtheritic myocarditis or neuritis . Pediatr Infect Dis 1984 ; 3 : 126 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Tropical PediatricsOxford University Press

Published: Apr 23, 2018

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