Diphtheria outbreak in Jakarta and Tangerang, Indonesia: Epidemiological and clinical predictor factors for death

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Abstract

Background

In 2017, a diphtheria outbreak occurred in several provinces in Indonesia. The aim of this study was to identify predictors of mortality outcome of pediatric patients with clinical diphtheria.

Methods

A retrospective cohort study was conducted using patient medical records at five referral hospitals in the Province of Jakarta and one in Tangerang District, Banten Province during January 2017 to 31 August 2018. All children in the age group of 1–18 years old discharged with diagnosis of clinical diphtheria formed the study group. All anonymized patient data were evaluated for demographic issues, clinical features, immunization status, complication, laboratory profiles and outcome.

Results

A total of 283 patients with clinical diphtheria were included in the study group with case fatality rate of 3.5%. All mortal patients had the complication of myocarditis. Regression analyses revealed factors for predicting mortality. Incomplete primary diphtheria toxoid immunization, stridor, bull neck, leukocytosis ≥15 x10 ⁹ cells/L and thrombocytopenia ≤150 x10 ⁹ cells/L in each combination for 2 predictors modeling were correlated with death.

Conclusions

We report key predictors of mortality in pediatric patients with clinical diphtheria. The presence of these features when admitted to the hospital must be taken into account, because they can lead to fatal outcome.

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Most cited references 25

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The pathology of diphtheria.

T L Hadfield, Igor Yakovlev, Maureen P McEvoy … (2000)

Diphtheria is an acute, communicable disease caused by Corynebacterium diphtheriae. The disease is generally characterized by local growth of the bacterium in the pharynx with pseudomembrane formation or, less commonly, in the stomach or lungs; systemic dissemination of toxin then invokes lesions in distant organs. Acute disease of the upper respiratory tract usually involves one or more of the following: tonsillar zones, larynx, soft palate, uvula, and nasal cavities. A recent epidemic in Russia emphasized the role of vaccination in reducing disease in children and adults.

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The changing epidemiology of diphtheria in the vaccine era.

Martyna A. Galazka (2000)

The epidemic of diphtheria in the Newly Independent States (NIS) of the former Soviet Union has drawn attention to our incomplete understanding of the epidemiology of diphtheria. Many unanswered questions remain concerning the reasons for a resurgence of diphtheria and for the shift in the age of patients and concerning the mechanisms for acquisition of immunity in adults through natural infection under unfavorable living conditions. Other unanswered questions relate to the precise role of socioeconomic factors and hygiene conditions in the initiation, buildup, and spread of the epidemic. Important characteristics of the NIS epidemic can be used to help predict the spread of future diphtheria epidemics. These characteristics include a high proportion of infected adults, a progressive spread of disease from urban centers to rural areas, and transition from initial amplification of disease in groups with high rates of close contacts in focalized, well-distinguished outbreaks to a more generalized epidemic.

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Diphtheria in the Postepidemic Period, Europe, 2000–2009

Karen Wagner, Joanne White, Irina Lucenko … (2012)

In 1994, following success of widespread vaccination programs earlier in the century, diphtheria was proposed as a candidate for elimination in the World Health Organization (WHO) European Region; the goal was for elimination of indigenous diphtheria by 2000 ( 1 ). However, during the 1990s, when this goal seemed within sight, several factors caused a resurgence of diphtheria to epidemic proportions in the newly independent states of the former Soviet Union. There were a large number of unnecessary contraindications to vaccination in guidance for these countries at that time, which led to reductions in adequate vaccination coverage in children. This problem was exacerbated by mistrust in vaccinations among health professionals and the public and by use of low-dose formulation vaccine for primary vaccinations. Waning immunity in the adult population, large-scale population movements caused by breakup of the former Soviet Union, disruptions in health services, and lack of adequate supplies of vaccine and antitoxin for prevention and treatment in most affected countries provided conditions under which diphtheria could spread ( 2 , 3 ). At the peak of the epidemic in 1995, there were >50,000 cases reported in the WHO European Region ( 2 ). Intensive vaccination strategies brought the disease under control in most countries, but some endemic transmission still continues. Clinical diphtheria is caused by toxin-producing corynebacteria. Three species (Corynebacterium diphtheriae, C. ulcerans, and C. pseudotuberculosis) can potentially produce diphtheria toxin. C. diphtheriae is the most common of potentially toxigenic species and is associated with epidemic diphtheria and person-to-person spread. The organism has 4 biovars (gravis, mitis, intermedius, and belfanti). C. ulcerans is historically associated with cattle or raw dairy products, and, although it is rarely reported, its incidence has increased slightly in some countries in western Europe and in the United States in recent years ( 4 – 6 ). C. pseudotuberculosis rarely infects humans and is typically associated with farm animals ( 7 ). Currently, no direct evidence has been found of person-to-person spread of C. ulcerans or C. pseudotuberculosis. Classical respiratory diphtheria is characterized by formation of a gray-white pseudomembrane in the throat that is firmly adherent ( 8 ). A swollen, bull-neck appearance caused by inflammation and edema of soft tissues surrounding lymph nodes is associated with severe illness and higher death rates ( 8 ). In progressive disease, the toxin can bind to cardiac and nerve receptors and cause systemic complications. Milder respiratory disease may manifest as a sore throat, most commonly seen in patients who are fully or partially vaccinated. In some tropical areas, cutaneous symptoms, characterized by rolled-edge ulcers, are more common. Patients may have both cutaneous and respiratory disease. The purpose of this study was to analyze diphtheria data for Europe during 2000–2009. Methods Case-based diphtheria surveillance data from each of 25 Diphtheria Surveillance Network (DIPNET) member countries (Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Latvia, Lithuania, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Spain, Sweden, Turkey, and the United Kingdom) for 2000–2007 were submitted retrospectively to the coordinating center in the United Kingdom during 2008. Data for 2008 and 2009 were obtained in August 2009 and September 2010 from the DIPNET online database, which was launched in September 2007. We analyzed cases meeting the DIPNET case definition (isolation of a toxigenic strain or clinically compatible case with an epidemiologic link to a laboratory-confirmed case) (Technical Appendix 2). In addition, 48 cases without laboratory confirmation and pseudomembrane (mild diphtheria/severe pharyngitis) and 5 cases with unknown manifestations were included for Latvia because these cases had been recorded in the national dataset. For most cases, toxigenicity was confirmed by using the Elek phenotypic test ( 9 ). However, in some cases, toxigenicity was evaluated only by detection of the toxin gene with PCR. We assumed that all cases in this dataset were toxigenic (toxin producing) because the number of cases without Elek confirmation was small and referred to symptomatic cases. Data fields collected included year; organism; biovar; and patient age, sex, clinical manifestations, vaccination status, veterinary contact, risk group, and outcome. Further strain characterization (ribotyping) was available for a limited number of isolates as part of a screening study in 10 DIPNET countries ( 10 ). Cases were assigned to 5 clinical manifestation groups. These groups were classic respiratory diphtheria with pseudomembrane (the most serious form of the disease); mild diphtheria/severe pharyngitis (respiratory symptoms without the pseudomembrane); cutaneous (toxigenic organism isolated from skin lesions); other (e.g., toxigenic organism isolated from blood); and asymptomatic (carriers of toxigenic organisms, usually contacts of a confirmed case-patient). Additional information concerning countries in the WHO European Region that are not DIPNET member countries was provided by the WHO Regional Office for Europe. Twenty-five of 53 member states of the WHO European Region are members of DIPNET. WHO European Region countries (including DIPNET members) report total cases annually to the WHO Regional Office for Europe through the WHO/United Nations Children’s Fund Joint Reporting Form, which is the global annual data survey of WHO member states for vaccine-preventable diseases and immunization program indicators. In addition, 16 countries in 2003 (Figure 1) were asked to prospectively participate in monthly surveillance and provide more detailed information (e.g., pathogen biovar; patient age, sex, and outcome; and carriers among contacts). Twelve countries currently provide monthly reports to WHO Regional Office for Europe through this system. The only major source of cases that has not participated in the monthly reporting system (but does report annually) is the Russian Federation. Rates per 1 million person-years were calculated by using population estimates derived from the Population Division of Economic and Social Affairs of the United Nations Secretariat ( 11 ). Figure 1 Diphtheria Surveillance Network (DIPNET) and World Health Organization (WHO) European Region countries. 1, Albania; 2, Andorra; 3, Armenia; 4, Austria; 5, Azerbaijan; 6, Belarus; 7, Belgium; 8, Bosnia and Herzegovina; 9, Bulgaria; 10, Croatia; 11, Cyprus; 12, Czech Republic; 13, Denmark; 14, Estonia; 15, Finland; 16, France; 17, Georgia; 18, Germany; 19, Greece; 20, Hungary; 21, Iceland; 22, Ireland; 23, Israel (neighboring countries not shown); 24, Italy, 25; Kazakhstan; 26, Kyrgyzstan; 27, Latvia; 28, Lithuania; 29, Luxembourg; 30, Malta; 31, Monaco; 32, Montenegro; 33, the Netherlands; 34, Norway; 35, Poland; 36, Portugal; 37, Republic of Moldova; 38, Romania; 39, Russian Federation; 40, San Marino; 41, Serbia; 42, Slovakia; 43, Slovenia; 44, Spain; 45, Sweden; 46, Switzerland; 47, Tajikistan; 48, Former Yugoslav Republic of Macedonia; 49, Turkey; 50, Turkmenistan; 51, Ukraine; 52, United Kingdom (Great Britain and Northern Ireland); 53, Uzbekistan. Statistical Analyses Proportions were compared by using χ2 or Fisher exact tests, as appropriate, in Stata statistical software version 7.0 (StataCorp LP, College Station, TX, USA). For assessment of a trend for variables in ordered groups (vaccinated, partially vaccinated, unvaccinated) and severity of disease (classic respiratory, mild diphtheria/severe pharyngitis, asymptomatic), the Wilcoxon test for trend in Stata ( 12 ) was used. This test enabled nonparametric analysis across these groups. Results Overall, across the WHO European Region, the number of cases of diphtheria has substantially decreased since the epidemic in the 1990s (Figure 2). Data on clinically confirmed cases and toxigenic isolates of C. diphtheriae and C. ulcerans reported to DIPNET during 2000–2009 are shown in Table 1 and Table 2, respectively. Member countries that are not listed reported no isolates. Data are analyzed separately for Latvia, where diphtheria is endemic. Figure 2 Diphtheria cases per 1 million population in the World Health Organization (WHO) European Region and number of countries with a rate >1 cases/1 million population, 2000–2009. Table 1 Toxigenic Cornyebacterium diphtheriae isolates and epidemiologically linked cases and deaths reported by DIPNET member countries, Europe, 2000–2009* Characteristic Patient description† No. toxigenic isolates or clinical cases with epidemiologic link (no. deaths) 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Country Estonia Symptomatic 2 2 0 0 0 0 0 0 0 0 Asymptomatic 1 7 0 0 0 0 0 0 0 0 Total 3 9 0 0 0 0 0 0 0 0 Finland Total 0 2 (1) 0 0 0 0 0 0 0 0 France Total 0 0 1 0 1 0 1 1 (1) 1 0 Germany Total 1 2 4 0 0 1 0 0 0 2 Latvia Symptomatic 145 0 45 26 20 20 32 18 29 6 Asymptomatic 61 24 15 22 2 2 11 5 12 3 Not known 119 91 0 0 0 0 0 0 0 0 Total 325 (9) 115 (5) 60 (3) 48 (2) 22 (1) 22 (2) 43 (6) 23 (1) 41 (2) 9 (1) Lithuania Symptomatic 2 0 4 0 0 0 0 0 2 0 Asymptomatic 0 0 1 0 0 0 0 0 2 0 Total 2 0 5 (1) 0 0 0 0 0 4 (1) 0 Norway Symptomatic 0 0 0 0 0 0 0 0 3 0 Asymptomatic 0 0 0 0 0 0 0 0 1 0 Total 0 0 0 0 0 0 0 0 4 0 Sweden Total 0 0 0 0 0 0 0 0 0 1 Turkey Symptomatic 1 3 1 0 0 0 0 0 0 0 Asymptomatic 2 0 0 0 0 0 0 0 0 0 Not known 1 4 1 1 0 0 0 0 0 0 Total 4 (1) 7 (3) 2 (1) 1 0 0 0 0 0 0 United Kingdom Total 1 0 6 3 0 0 1 0 2 (1) 2 Total known symptomatic patients NA 152 9 61 29 21 21 34 19 37 11 Total (all countries) NA 336 (10) 135 (9) 78 (5) 52 (2) 23 (1) 23 (2) 45 (6) 24 (2) 52 (4) 14 (1) Total known symptomatic patients, excluding Latvia NA 7 9 16 3 1 1 2 1 8 5 Total, excluding Latvia NA 11 (1) 20 (4) 18 (2) 4 1 1 2 1 (1) 11 (2) 5 *DIPNET, Diphtheria Surveillance Network; NA, not applicable. A total of 89 cases were clinically diagnosed without microbiological confirmation (76 in Latvia, 11 in Turkey, and 2 in Lithuania). †If only total is displayed for a country, all patients were symptomatic. Table 2 Isolates of toxigenic Corynebacterium ulcerans and patient deaths reported by DIPNET member countries, Europe, 2000–2009* Characteristic Patient description† No. toxigenic isolates (no. deaths) 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Country France Total 0 1 0 1 3 0 2 1 0 1 Germany Total 1 1 (1) 0 0 1 2 1 2 0 2 Italy Total 0 0 1 0 0 0 0 0 0 0 The Netherlands Total 0 1 0 0 0 0 0 1 0 0 Romania Asymptomatic 0 0 1 0 0 0 0 0 0 0 Total 0 0 1 0 0 0 0 0 0 0 Sweden Symptomatic 0 0 0 0 0 0 0 0 1 0 Not known 0 0 0 0 1 0 1 0 0 0 Total 0 0 0 0 1 0 1 0 1 0 United Kingdom Total 7 (1) 3 2 2 1 2 2 (1) 3 3 2 No. symptomatic patients NA 8 6 3 3 5 4 5 7 4 5 No. isolates NA 8 (1) 6 (1) 4 3 6 4 6 (1) 7 4 5 *DIPNET, Diphtheria Surveillance Network; NA, not applicable †If only total is shown for a country, all patients were symptomatic. Diphtheria-Endemic Countries in WHO European Region During 2000–2009, Latvia reported the highest annual incidence rate of diphtheria in the European Region each year and a 10-year incidence rate of 23.8 cases/1 million person-years. This rate was ≈7× higher than in countries with the next highest 10-year incidence: i.e., Georgia (3.5), Ukraine (3.3), and the Russian Federation (3.0). However, during this time, 4,304 (>61%) of 7,032 cases in the WHO European Region were reported from the Russian Federation, and 2 countries, the Russian Federation and Ukraine, accounted for 83% of all cases. Over the past 10 years, diphtheria incidence decreased by >95% across the region (from 1.82/1 million population in 2000 to 0.07/million in 2009), including in Latvia (from 111.22/million in 2000 to 2.67/million in 2009). In 2009, Latvia was the only country in the region that had not yet achieved the elimination benchmark of an incidence 40 years of age (unvaccinated or with waning immunity). Although risk did not differ by sex in cases in children, during 2002–2009, ≈2× as many cases were reported in women >20 years of age than in men (510 [64%] vs. 292 [36%], respectively). Most (75%) case-patients reported in the European Region were at least partially vaccinated, but most (74%) case-patients and (93%) infants who died were unvaccinated). C. diphtheriae biovar gravis was the predominant strain (60%–80%). Of isolates from Latvia (Table 1), 355 (99%) of 358 with a known biovar were gravis and 3 (1%) were mitis. Clinical manifestations and vaccination status for cases from Latvia (all C. diphtheriae) reported to DIPNET are shown in Table 3. Most (340/341) case-patients with symptoms had respiratory manifestations, and 141 (41%) of 340 respiratory case-patients had classic diphtheria symptoms. Vaccination showed a significant protective effect with respect to severity of infection (p 45 years of age. Incidence rate was higher in female patients than in than male patients (0.014/1 million person-years vs. 0.004/1 million person-years). Eleven cutaneous cases, 38 respiratory (14 classic respiratory) cases, and 1 case with other manifestations were reported. Ninety-four percent of case-patients for which information was available had contact with domestic animals. Traditional risk factors such as consumption of raw milk products were not reported, and no patients had a recent history of travel. One of the 2 case-patients infected with C. ulcerans who died in the United Kingdom had an identical strain of C. ulcerans to that isolated from a dog with which the patient had been in contact ( 14 ). A similar finding was observed in France for a nontoxigenic case reported in 2003 ( 5 , 15 ). In 2007, identical strains were isolated from a patient infected with C. ulcerans and her pig in Germany ( 16 ). C. pseudotuberculosis Isolates Four case-patients with diphtheria caused by toxigenic C. pseudotuberculosis were reported: 1 in France in 2005 and 1 in 2008, 1 in Germany in 2004, and 1 in United Kingdom in 2008. Three of these patients had cutaneous manifestations (1 was unvaccinated, 2 had an unknown vaccination status) and 1 (partially vaccinated) had bacterial endocarditis. To our knowledge, none of these infected patients died. Animal contact (with a calf) was recorded for only 1 patient (1 had no history of animal contact and 2 had an unknown history of animal contact). Deaths Caused by Diphtheria During 2000–2009, a total of 32 deaths caused by diphtheria were reported in Latvia, and 13 deaths (10 caused by C. diphtheriae and 3 caused by C. ulcerans) (Table 1, Table 2) were reported by the remaining 24 DIPNET countries. Overall, patients with respiratory disease and a pseudomembrane had a significantly higher case-fatality rate (CFR) than patients with respiratory disease without a pseudomembrane (14.6% vs. 1.3%; p 40 years of age and 4 were 75 years of age) patients (unvaccinated or vaccination status unknown). Two of the patients infected with C. diphtheriae who died were unvaccinated infants (1 from Mayotte and 1 from Finland). The infant in Finland died at 3 months of age in 2001 after recent contact with visitors from Russia ( 17 ). Six other children died: an unvaccinated school age child in the United Kingdom ( 18 ) and 5 children 90% for most (85%) countries in the European Region, and 66% of countries (including Latvia, Lithuania, Turkmenistan, and the Russian Federation) reported coverage >95% ( 26 ). Coverage in Ukraine decreased from 98% in 2006 and 2007 to 90% in 2008 and 2009. Austria, Denmark, Georgia, and Moldova recorded diphtheria-tetanus-pertussis 3 vaccine coverage <90%. Azerbaijan and Malta had the lowest coverage (73% for both countries) in the European Region in 2009. Following high-profile vaccine-scare stories in some countries in eastern Europe, such as the Russian Federation and Ukraine, anti-vaccination groups have gained strength by using television, the Internet, and other media for publicity ( 27 ); this activity could seriously affect vaccination coverage. Adult diphtheria immunity can be increased through scheduled booster vaccinations every 10 years (e.g., as in Austria, Belgium, Bulgaria, Cyprus, Estonia, Finland, France, Germany, Greece, Latvia, Norway, Portugal, and Romania) or as part of a combined tetanus and low-dose diphtheria vaccine given for tetanus-prone injuries. In Latvia, annual adult vaccination coverage surveys are undertaken, but in most countries adult coverage is rarely assessed. Seroprevalence studies have indicated that many adults in some countries have immunity levels below the protective threshold ( 28 ). Gaps in immunity in the adult population contributed to the resurgence of diphtheria in eastern Europe during the 1990s. Trends in diphtheria cases in Europe are encouraging, but continued striving for improved vaccination coverage is essential. Diphtheria has a socioeconomic component; outbreaks are typically seen in marginalized groups. In the current economic climate, more socially deprived groups that are vulnerable to infection will emerge. The economic crisis may also threaten supplies of vaccine and antitoxin and delivery of immunization programs. Because reductions in finances can limit the capacity for surveillance, decreases in case reporting need to be interpreted with caution. Every effort must be made to maintain high diphtheria vaccination coverage. Supplementary Material Technical Appendix 1 Additional members of the Diphtheria Surveillance Network who contributed data. Technical Appendix 2 European Union Case Definition for National Diphtheria Surveillance, Community Decision of March 19, 2002 (under 2119/98/EC), Modified Version.

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Eggi Arguni:

ORCID: https://orcid.org/0000-0001-7462-7904

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Mulya Rahma Karyanti: Role: SupervisionRole: Writing – review & editing

Hindra Irawan Satari: Role: SupervisionRole: Writing – review & editing

Sri Rezeki Hadinegoro: Role: SupervisionRole: Writing – review & editing

Silvia Ricci: Role: Editor

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Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 4 February 2021

Publication date Collection: 2021

Volume: 16

Issue: 2

Electronic Location Identifier: e0246301

Affiliations

[1 ] Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia

[2 ] Department of Pediatric, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia

Meyer Children’s University Hospital - University of Florence, ITALY

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Competing Interests: The authors have declared that no competing interests exist.

* E-mail: eggiarguni@ 123456ugm.ac.id

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Eggi Arguni https://orcid.org/0000-0001-7462-7904

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Publisher ID: PONE-D-20-18955

DOI: 10.1371/journal.pone.0246301

PMC ID: 7861411

PubMed ID: 33539453

SO-VID: 5b9d1253-e246-4649-a1db-f49e42c138fb

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 19 June 2020

Date accepted : 16 January 2021

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Figures: 2, Tables: 4, Pages: 11

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The author(s) received no specific funding for this work.

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Data Availability All relevant data are within the manuscript and its Supporting Information files.

Diphtheria outbreak in Jakarta and Tangerang, Indonesia: Epidemiological and clinical predictor factors for death

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Most cited references 25

The pathology of diphtheria.

The changing epidemiology of diphtheria in the vaccine era.

Diphtheria in the Postepidemic Period, Europe, 2000–2009

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