Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis

Abstract

Background: Diphtheria, once a major cause of childhood morbidity and mortality, all but disappeared following introduction of diphtheria vaccine. Recent outbreaks highlight the risk diphtheria poses when civil unrest interrupts vaccination and healthcare access. Lack of interest over the last century resulted in knowledge gaps about diphtheria's epidemiology, transmission, and control.

Methods: We conducted 9 distinct systematic reviews on PubMed and Scopus (March-May 2018). We pooled and analyzed extracted data to fill in these key knowledge gaps.

Results: We identified 6934 articles, reviewed 781 full texts, and included 266. From this, we estimate that the median incubation period is 1.4 days. On average, untreated cases are colonized for 18.5 days (95% credible interval [CrI], 17.7-19.4 days), and 95% clear Corynebacterium diphtheriae within 48 days (95% CrI, 46-51 days). Asymptomatic carriers cause 76% (95% confidence interval, 59%-87%) fewer cases over the course of infection than symptomatic cases. The basic reproductive number is 1.7-4.3. Receipt of 3 doses of diphtheria toxoid vaccine is 87% (95% CrI, 68%-97%) effective against symptomatic disease and reduces transmission by 60% (95% CrI, 51%-68%). Vaccinated individuals can become colonized and transmit; consequently, vaccination alone can only interrupt transmission in 28% of outbreak settings, making isolation and antibiotics essential. While antibiotics reduce the duration of infection, they must be paired with diphtheria antitoxin to limit morbidity.

Conclusions: Appropriate tools to confront diphtheria exist; however, accurate understanding of the unique characteristics is crucial and lifesaving treatments must be made widely available. This comprehensive update provides clinical and public health guidance for diphtheria-specific preparedness and response.

Keywords: critical vaccination threshold; diphtheria; outbreak; reproductive number; systematic review.

Figure 1.

Natural history of diphtheria with prevention and treatment interventions. Of the unvaccinated individuals who become infected with toxigenic Corynebacterium diphtheriae (a), 70% develop prodromal symptoms (b), whereas 30% become asymptomatic carriers (e). Eighty percent of individuals with nonspecific symptoms develop membranous diphtheria (c) whereas 20% recover. Of those with membranous diphtheria, 5%–50% of individuals die of complications, and 50%–95% recover. Vaccinated individuals can be colonized; however, the toxoid vaccine provides protection against symptoms. Thus, 90% of fully vaccinated individuals become asymptomatic carriers (e), whereas only 10% develop prodromal symptoms (b). Vaccinated individuals who develop nonspecific symptoms have lower risk of severe disease and death compared with unvaccinated individuals and are more likely to recover directly from prodromal symptoms, although they can develop severe complications (c) and die.

Figure 2.

Epidemiological characteristics of diphtheria. A, Incubation period for diphtheria (data from 4 studies). B, Time to clearance of Corynebacterium diphtheriae in cases treated with antibiotics and untreated cases. Clearance time among treated cases is from initiation of antibiotic treatment (data from 11 studies). C, Serial interval (proxy for generation time; data from 8 studies).

Figure 3.

Case fatality ratio. A, Case fatality ratio by year, with World Health Organization (WHO) region (color), outbreak size (point size), and the weighted mean over time (black line). B, Case fatality ratio by age. C, Case fatality ratio by diphtheria antitoxin treatment. D, Case fatality ratio by diphtheria antitoxin treatment delay. E, Case fatality ratio by vaccination status. The former Soviet Union (FSU) is not a WHO region but is specific to the 1990–1998 outbreak. Abbreviations: AFR, African Region; AMR, Region of the Americas; DTP, diphtheria-tetanus-pertussis vaccine; EMR, Eastern Mediterranean Region; EUR, European Region; SEAR, South-East Asia Region.

Figure 4.

Diphtheria control and outbreak response. The critical vaccination threshold, V_c, or vaccination coverage needed to achieve herd immunity, for diphtheria is dependent on the basic reproductive number, R₀. Based on data from 23 outbreaks, without additional intervention or antibiotic treatment, achievable critical vaccination thresholds are only possible in 28% of simulated outbreak settings (Supplementary Table 4). The relationship between the critical vaccination threshold and basic reproductive number is shown in the top portion of each panel. The blue-shaded region indicates estimates where the critical vaccination threshold is below 100% and herd immunity is achievable through vaccination, and the red points correspond to simulated outbreaks for which herd immunity is not achievable through vaccination alone. The lower portion of each panel demonstrates the corresponding density plot of basic reproductive numbers and is shaded according to the proportion of simulated outbreaks where herd immunity is achievable (blue) compared to where herd immunity is not achievable (red). The light gray–shaded region indicates the interquartile range of our R₀ estimates. A, Scenario for no treatment (replicated in B–D in light blue for reference). With each increase in the proportion of cases treated (25%, 50%, 90%), and each decrease in average delay to treatment (5-, 2-, and 1-day delays), the vaccination coverage required at each value of the basic reproductive number decreases (comparing the dark blue to the light blue wedge). The proportion of observed R₀ values for which the critical vaccination threshold is achievable increases (increased blue) as treatment coverage increases and delay decreases. These scenarios demonstrate the critical importance of rapid antibiotic treatment for diphtheria outbreak prevention or response.