Resurgence of diphtheria outbreaks in the African Region 2023-2024

¹World Health Organization Regional Office for Africa, Brazzaville, Congo, ²United Nations Children's Fund West and Central Africa Regional Office, Dakar, Senegal, ³World Health Organization, HQ/IVB, Geneva, Switzerland

^&Corresponding author
André Arsène Bita Fouda, World Health Organization Regional Office for Africa, Cité du Djoué, Brazzaville, Congo

Introduction    

Diphtheria is an acute communicable upper-respiratory illness caused by Corynebacterium species, mostly by toxin-producing Corynebacterium diphtheriae. The disease affects the mucous membranes of the respiratory tract, the skin and rarely mucous membranes at other non-respiratory sites, such as genital and conjunctiva. For unvaccinated individuals, without proper treatment, diphtheria can be fatal in around 30% of cases, with young children at higher risk of dying [1-3]. The risk factors for diphtheria transmission/outbreaks include overcrowding, poor hygiene and absent or incomplete immunization, including booster doses. The use of antitoxin, improvements in treatment, and widespread immunization using the toxoid have dramatically reduced mortality and morbidity due to diphtheria [1,4,5]. For many years, diphtheria caused devastating epidemics in Europe, Africa, India, the United States, the Russian Federation with millions of cases and thousands of deaths since the 19^th century [1,4,5]. According to WHO, diphtheria is uncommon in the African Region. Of the 97,438 cases reported globally between 2013 and 2022, a total of 29 163 (29.9%) were reported in the African Region [4,5]. After the establishment of the Expanded Program on Immunization (EPI) in 1974, with diphtheria vaccine mainly diphtheria, tetanus, and pertussis vaccine (DTP) and tetanus-diphtheria (Td) as one of the original six EPI vaccines, the incidence and deaths of diphtheria decreased dramatically worldwide. However, diphtheria remains endemic in several areas of the world [6-9]. Continuing high diphtheria immunization coverage is crucial to keeping this disease under control. The priority goal for diphtheria control for every country is to reach at least 95% coverage with three primary doses of pentavalent vaccine among under one year-old children in each district [1,10].

The contacts of a diphtheria case should also be vaccinated according to their age and immunization status. Routine use of Td vaccine, rather than monovalent tetanus toxoid, also helps maintain diphtheria immunity in adults. Catch-up schedule in children aged =1 year should be considered to reduce the burden of diphtheria [1,10-12]. Despite the tremendous efforts made in the past decades, diphtheria remains a significant health threat in countries with low routine immunization coverage and a high number of un and unvaccinated children [7,11,13]. Diphtheria appears to persist in some countries, particularly those with numerous cases of susceptible individuals accumulated over the past twenty years and the age distribution shifted, and adolescents and adults are affected [5,14,15]. This study will present the epidemiological profile of diphtheria between 2021 and 2024, and the effects of the response strategies implemented, the challenges and the lessons learned in the response to epidemics recorded in African countries.

Methods     

We conducted a cross-sectional study of diphtheria outbreak from 2021 to 2025 in the 47 countries of the WHO African region. The study population was people living in the 47 countries of the WHO African region. The sampling was not randomized and was exhaustive.

Surveillance of diphtheria

Diphtheria surveillance is effective at the national, subnational and facility levels. All facilities identifying cases are required to report those cases. All outbreaks should be investigated immediately, and case-based data should be collected. Laboratory testing of all suspected cases should ideally be conducted for case confirmation. Few countries of the WHO African countries introduced diphtheria into their surveillance system. This can be explained because it is not included among the priority diseases, conditions and events for the Integrated Disease Surveillance and Response (IDSR) implemented by the WHO African region [5,16]. Case definitions are used as recommended by WHO were used. Suspected cases of diphtheria are characterized by upper respiratory tract illnesses such as pharyngitis, nasopharyngitis, tonsillitis or laryngitis and an adherent pseudo membrane. Some countries may expand the suspected case definition to include mild cases without a pseudo membrane, non-healing ulcers in people with a travel history to endemic or diphtheria-affected countries, and a bull-neck appearance caused by swollen anterior cervical lymph nodes, inflammation and surrounding tissue oedema. Final diphtheria case classification includes laboratory-confirmed cases; epidemiologically linked confirmed cases; clinically compatible confirmed cases; and discarded cases (not a diphtheria case, final diagnosis to be specified) [4].

Laboratory-confirmed cases are individuals with C. diphtheriae isolated by culture and positive for toxin production, regardless of symptoms. Toxigenicity must be confirmed by the phenotypic Elek test, and polymerase chain reaction (PCR) can complement surveillance. Laboratory-confirmed cases may be further classified into three subcategories based on the type of surveillance occurring in the country. Epidemiologically linked confirmed cases meet the definition of a suspected case and are linked epidemiologically to a laboratory-confirmed case. Clinically compatible confirmed cases meet the definition of a suspected case but lack both confirmatory laboratory test results and epidemiologic linkage to a laboratory-confirmed case. A discarded case is a suspected case that meets either criterion: a non-toxigenic Corynebacterium spp. but a negative Elek test or a negative PCR for the diphtheria toxin gene [4,5]. A single laboratory-confirmed case of diphtheria and or two cases epidemiologically linked to at least one laboratory-confirmed case is/are considered an outbreak. During an outbreak, surveillance should be improved [4,5,17].

The AFR conducted a rapid risk assessment and diphtheria vulnerability mapping in October 2023. Then, a grade 2 emergency was decided for Diphtheria following a global grading call on 13 October 2023. Since July 2023, three countries in the AFR have reported an unusual increase in diphtheria cases: Nigeria, Niger, and Guinea. Then after, an incident management system team was established to support outbreak response in the African region.

Laboratory diagnosis of diphtheria

To detect C. diphtheriae, two swabs (throat, nasal, pharynx, or skin) from suspected cases at first contact are collected ideally, before starting antibiotics. Samples collected are stored and transported (within 24 hours) to the laboratory at room temperature for culture. They are labelled with unique identifiers and sources, placed in appropriate media or placed in dry swabs in silica gel sachets. If there are delays in transport, place the samples at 2-8°C, and pseudo membrane samples should be collected and sent to the laboratory. Diphtheria laboratory analyses to be performed include isolation of C. diphtheriae by culture, toxicity testing and bio typing for diagnosis and confirmation of toxin production, and antimicrobial sensitivity testing. A diagnosis is confirmed through culture and toxin production using immunoprecipitation reactions. Primary culture on blood tellurite medium and selective culture on cystinase medium are used to examine clinical specimens. Toxigenicity testing and bio typing are also necessary [4,5].

Response to diphtheria outbreaks

An outbreak triggers a public health response with preventing and minimizing the spread of cases, preventing complications and deaths through early diagnosis and proper management, assisting public health workers in risk assessment, identifying high-risk areas, implementing appropriate public health control measures, and raising community awareness about diphtheria and its prevention. The choice of antibiotics should be guided by the results of the antimicrobial sensitivity tests. Administering Diphtheria Antitoxin (DAT) neutralizes the toxin and reduces complications and mortality. Adverse reactions to DAT include hypersensitivity reactions, febrile reactions, and serum sickness. Immunization with DTP, Pentavalent, and Td is crucial for preventing cases and stopping outbreaks. Preparedness for diphtheria outbreaks includes understanding the main areas of risk, ensuring good preparatory outbreak response coordination, rapidly detecting and assessing diphtheria-related events, and understanding existing DAT supplies [4,5,17].

Data collection

Diphtheria data from January 2000 to December 2024 were extracted in countries from health facility registers, line lists, and in WHO from WHO diphtheria database, WHO/UNICEF estimates of national immunization coverage (WUENIC) and WHO/UNICEF electronic Joint Reporting Form on Immunization (eJRF). The population is from the 47 countries of the WHO African region (WHO AFR). The 47 countries of African region are Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cabo Verde, Cameroon, Central African Republic, Chad, Comoros, Congo, Cote d'Ivoire, Democratic Republic of Congo, Equatorial Guinea, Eritrea, Eswatini, Ethiopia, Gabon, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, South Sudan, The Gambia, Togo, Uganda, United Republic of Tanzania, Zambia, Zimbabwe. Variables used were suspected diphtheria cases from eJRF and pentavalent coverage from 2018-2023 from WUENIC. Concerning outbreaks, the variables used were laboratory-confirmed cases, epidemiologically linked confirmed cases, clinically compatible confirmed cases, discarded cases, and deaths gathered in WHO AFR database.

Ethical considerations

The anonymity and confidentiality of patients were respected. Since we used publicly available secondary data, formal ethical clearance was not required.

Results     

Epidemiology of diphtheria in the African region from 2000-2024 in the WHO African region

Figure 1 shows that between 2000 and 2024, a total of 75,789 suspected cases of diphtheria were reported in the AFR with an average of 3,500 cases per year. About 45% cases were reported between 2023 and 2024. Since 2014 cases are increasing and the peak was reported in 2023 with 18, 684 suspected cases reported. Most of cases reported are children under fifteen years and male are the most affected. Trends in DTP 1 vs. DTP 3 and un and under-vaccinated children in the African region, 2000-2024 Figure 2 shows DTP1 and DTP3 coverage trends from 2000 to 2024, and the number of un and under-vaccinated children. From 2000 to 2024, DTP1 coverage increased from 66% in 2019 (year before COVID-19) to 83% in 2024. The DTP1 remained of 83% with slight decrease from 2020 to 2022. The DTP3 coverage increase from 51% in 2000 to 76% in 2024 and remained of 76% between 2019 to 2024. Moreover, the number of children unvaccinated (zero-dose children) and under-vaccinated decreased from 12.4 million in 2000 to 9.5 million in 2024 and the average of un- and under-vaccinated children from 2000 to 2024 was 10.2 million.

outbreaks 2023-2024 in the WHO African region

From 2023 to 2024, Algeria, Chad, Gabon, Guinea, Mali, Mauritania, Nigeria, Niger, and South Africa, and reported diphtheria outbreaks, and countries most affected were Nigeria, Guinea and Niger (Figure 3). Table 1 shows that 58,910 suspected cases and 1,991 deaths with CFR of 3.4% were reported in the countries which experienced outbreaks. The number of confirmed cases was 33,789 out of 58,910 (56.4%) and 25,185 (43.6%) were discarded. Concerning cases final classification, a total of 1,012 (3.0%) cases were laboratory confirmed, 795 (2.4%) epidemiologically linked, and 33,789 (94.6%) clinically compatible. Female (around 60%) were most affected than man. Children aged less than 15 years were the most affected. The immunization status of non-vaccinated or unknown patients varied between 58% in Niger to 100% in Mauritania.

Discussion     

Epidemiology of diphtheria from 2000-2024 in the WHO African region

The introduction of DTP vaccine in national EPI programmes contributed dramatically to reduce diphtheria since 1974 [1-9]. This study showed that diphtheria is recorded every year in AFR. This result is similar as findings in literature. This is explained mostly by the poor performance of DTP immunization coverage from 2000 to 2024, countries recorded every year diphtheria cases and deaths [1-3]. The majority of cases are not confirmed. This lack of confirmation can be explained by the fact that the disease is not well-known. It was classified as eliminated. However, it seems to reemerge in the countries with high number of people un or non-vaccinated [18-23].

Trends in DTP 1 vs. DTP 3 and un- and under-vaccinated children in the African region, 2000-2023

The study found that children under 15 years were the most affected. This result is like studies conducted by Agrawal et al., Clarke et al., [22,23]. WHO, Vitek and Wenger found that CFR is less than 30% different from CFR found study which varied from 1.3 to 10.4 [1-3]. Most of cases were unvaccinated or with unknown immunization status. This result is like findings in literature [18-23]. However, recent diphtheria epidemiology has not been well described. In countries with higher case counts, 66% of case-patients were unvaccinated and 63.6% were <15 years of age [22]. The study showed that Nigeria, Niger and Guinea were the most affected, Agrawal et al., also found that in Nigeria diphtheria has been a long-standing concern for public health, much like in many other countries around the world [23].

Classification of diphtheria cases during outbreaks 2023-2024

The classification of cases is very important because confirmation depends on the laboratory, epidemiological link and the Clinic [1-3]. Some countries report only suspected cases, deaths and confirmed cases without clarifying the reason for confirmation and in most cases are from laboratory confirmation. Only 3.0% of cases are laboratory confirmed, which can be explained by the inability of some countries to test for diphtheria or there has been a significant lack of laboratory reagents or difficulties in transporting samples collected in hospitals to reference laboratories. Only 2.4% of cases have an epidemiological link, which could be explained by a low epidemiological investigation activity of suspected cases. However, the Clinical definition seems well mastered; 83.0% of cases were found to be clinically compatible.

Limitations: epidemiology of diphtheriae is not well-described in a few countries that cannot classify cases and provide immunization status or the gender most affected. That was also found by Clarke et al., that might create biases of information and selection [22]. There are discrepancies in suspected cases reported in eJRF by few countries.

Conclusion     

iphtheria remains a major public health problem in the AFR. Numerous cases are reported each year. From 2023 to 2024, epidemics were confirmed in the AFR, affecting many children under 15 years of age with low DTP vaccination protection. Countries are experiencing difficulties confirming cases through laboratory and case and epidemic investigations. However, the clinical situation appears to be under control in health facilities in the AFR. It is suggested that diphtheria be considered a priority disease and prevent it from becoming endemic again. This requires considerable efforts to increase the performance of immunization programs with the strengthening of large-scale catch-up vaccination beyond 5 years of age.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

André Arsène Bita Fouda: conceptualization, writing - original draft methodology, data curation, validation, software, visualization, formal analysis, writing- reviewing and editing. Charles Shey Wiysonge: conceptualization, methodology, data curation, validation writing- reviewing, editing, funding acquisition, and supervision. Balcha Girma Masresha: conceptualization, methodology, data curation, validation writing- reviewing and editing. Ahmadou Diallo: conceptualization, methodology, data curation, validation writing- reviewing and editing. Alain Blaise Tatsinkou: conceptualization, methodology, data curation, validation writing- reviewing and editing. Patrick Cossy Otim Ramadan: conceptualization, methodology, data curation, validation writing- reviewing and editing. Junholv Obo and John Otshudiema: conceptualization, methodology, data curation, visualization, validation, software, writing- reviewing and editing. Aschalew Teka Bekele: conceptualization, methodology, data curation, validation writing- reviewing and editing. Joseph Nsiari-muzeyi Biey: conceptualization, methodology, data curation, validation writing- reviewing and editing. Gautier Bikindou: conceptualization, methodology, data curation, visualization, validation, software, writing- reviewing and editing. Charles Lukoya Okot: conceptualization, methodology, data curation, validation writing- reviewing and editing. Marcellin Nimpa Mengouo: conceptualization, methodology, data curation, validation writing- reviewing and editing. Abdu Abdullahi Adamu: conceptualization, methodology, data curation, validation writing- reviewing and editing. Castilla Echenique Jorge: conceptualization, validation writing, editing. Franck Fortune Roland Mboussou: conceptualization, methodology, data curation, validation writing- reviewing and editing. Ado Mpia Bwaka: conceptualization, methodology, data curation, validation writing- reviewing and editing. Benido Impouma: conceptualization, methodology, data curation, validation writing- reviewing, editing, and supervision. All the authors read and approved the final version of this manuscript.

Acknowledgments     

The WHO AFRO Member States especially the countries that reported diphtheria outbreaks from 2023 to 2024 (Chad, Gabon, Guinea, Mali, Mauritania, Nigeria, Niger, and South Africa), and UNICEF.

Table and figures     

Table 1: diphtheria outbreaks-cases and deaths from 2023-2024 in the WHO African region

Figure 1: number of diphtheria suspected cases from 2000-2024 of WHO African region (eJRF)

Figure 2: estimated coverage and number of un- and under-vaccinated children for DTP 1,3, AFR 2000-2024 (WUENIC)

Figure 3: distribution of diphtheria confirmed cases from 2023 to 2024

References