Epidemiology and pathophysiology of diphtheria

INTRODUCTION — Diphtheria is an infectious disease caused by the gram-positive bacillus Corynebacterium diphtheriae. Infection may lead to respiratory disease, cutaneous disease, or an asymptomatic carrier state. The word diphtheria comes from the Greek word for leather, which refers to the tough pharyngeal membrane that is the clinical hallmark of infection. Rarely, a similar disease can be caused by other Corynebacterium species: C. ulcerans, C. hemolyticum, and C. pseudotuberculosis [1].

The epidemiology and pathophysiology of diphtheria will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of diphtheria" and "Tetanus-diphtheria toxoid vaccination in adults" and "Diphtheria, tetanus, and pertussis immunization in children 7 through 18 years of age" and "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age".)

EPIDEMIOLOGY

Biotypes causing disease — There are at least four biotypes or biovars of C. diphtheriae: gravis, intermedius, mitis, and belfanti. All biotypes have been associated with both endemic and epidemic diphtheria. However, belfanti is rarely described as toxigenic, whereas the other biotypes are named for their association with disease severity: gravis (serious), intermedius (intermediate), and mitis (mild) [1].

C. ulcerans is a rare cause of respiratory illness that resembles diphtheria. It has been reported predominantly in industrialized countries, which may be due in part to detection bias [2-5]. Isolated cases of diphtheria-like illness due to C. ulcerans were reported in the United States in 2008 and 2010 [2,3]. Like C. diphtheriae, C. ulcerans can produce diphtheria toxin and lead to life-threatening disease that requires urgent treatment with diphtheria antitoxin and macrolide antibiotics. However, unlike C. diphtheriae, C. ulcerans is a zoonotic illness; evidence for human-to-human transmission is limited.

Transmission — The primary modes of spread consist of close contact with infectious material from respiratory secretions (direct or via airborne droplet) or from skin lesions. Humans are believed to be the only known reservoir for C. diphtheriae, although rare cases of disease in animals have been reported [6-9]. Infection may occur throughout the year with a peak incidence in the colder months.

Asymptomatic carriers are important for transmission of diphtheria. Immunity (either via natural infection or vaccine induced) does not prevent carriage [10,11]. In areas of endemicity, up to 5 percent of healthy individuals may have positive pharyngeal cultures [12].

Burden of disease — In the prevaccine era, diphtheria was a major cause of morbidity and mortality worldwide, primarily affecting children under the age of 15 [13]. Until the beginning of the 20th century, as many as 10 percent of American children developed clinical diphtheria, and a significant number died from its complications (case-fatality rate of 5 to 10 percent) [14]. By adolescence, 70 to 80 percent of the urban population was immune to diphtheria from natural infection [15].

During the 1930s and 1940s, diphtheria was virtually eliminated in many resource-rich countries following the introduction of routine childhood vaccination with diphtheria toxoid. As a result of vaccination, toxigenic strains of C. diphtheriae lose the selective advantage conferred by the tox+ gene and are less prevalent [16]; the worldwide incidence has fallen from about 100,000 per year to less than 8000 per year (although many cases may go unreported). Worldwide, the vaccination rate is >80 percent; outbreaks of diphtheria may occur when the density of unvaccinated individuals in one or more locations increases and herd immunity declines, as occurred in the former Soviet Union in the 1990s [17,18].

As the general population becomes immune, there are fewer cases of clinical diphtheria (from toxigenic strains) and less asymptomatic colonization with toxigenic strains and therefore decreased transmission to nonimmune people. However, there does not appear to be any reduction in the prevalence of carriers of nontoxigenic C. diphtheriae [19]. Immunized individuals can develop clinical diphtheria, although disease is less severe and occurs less frequently.

Diphtheria is reappearing in some regions. In countries experiencing a resurgence of diphtheria, epidemics have involved children as well as insufficiently immunized adults [20-22]. As an example, due to declining vaccine coverages, confirmed diphtheria outbreaks have occurred in Brazil (11 suspected cases in the first half of 2021, 59 probable cases between 2019 and 2020) and the Dominican Republic (35 probable cases in the first half of 2021) [23]. In Haiti, there were 1281 suspected cases between 2014 and 2021, and the Pan American Health Organization considers the disease endemic in that country.

Resource-rich countries — Since the availability of vaccination, diphtheria has remained rare in resource-rich countries. However, approximately 20 to 60 percent of adults are susceptible to diphtheria because of waning vaccine-induced immunity and failure to receive booster immunization [24-26]. Among 1000 British adults who underwent evaluation of serum diphtheria antitoxin titers, 38 percent were susceptible to diphtheria (serum diphtheria antitoxin concentration below 0.01 international units/mL); 31 percent had basic protection; and only 31 percent were fully protected [24]. Similarly, in a large United States serologic survey, immunity among adults over the age of 60 years was 30 percent; immunity among children between the ages of 6 and 11 years was 91 percent [26]. The United States Centers for Disease Control and Prevention (CDC) recommends that adults receive a diphtheria-toxoid–containing vaccine (Tdap or Td as indicated) every 10 years after completing a primary childhood vaccination series [27]. (See "Tetanus-diphtheria toxoid vaccination in adults".)

Despite incomplete immunity, the rate of clinical disease is low, in part because immunization has minimized the transmission of toxigenic strains [28]. As an example, the last major United States outbreak of diphtheria occurred in Seattle in the 1970s [29]. However, the disease continues to cause illness globally, and sporadic, imported cases can rarely occur in the United States. Between 2015 and 2018, four cases of cutaneous diphtheria due to toxigenic strains were reported by the CDC, all in travelers returning from countries where diphtheria is endemic [30]. If toxigenic strains became widely disseminated again, the incidence could increase.

Spain has a high immunization rate; it reported its first case of diphtheria since 1986 in May 2015 in an unvaccinated six-year-old boy; the patient died but eight close contacts with colonization were isolated and treated successfully [31]. Previous vaccination likely protected the contacts from clinical disease [32].

An epidemic of diphtheria spread throughout the newly independent states (NIS) of the former Soviet Union in the 1990s [17]. Between 1990 and 1998, more than 80 percent of all cases of diphtheria in the world were reported from the former Soviet Union; more than 157,000 cases were registered with the WHO from NIS, with 5000 deaths [33]. Factors contributing to the spread of the epidemic included shortages of antibiotics, antitoxin, and vaccine (resulting in the presence of a susceptible child and adult population), socioeconomic instability, population movement, and a deteriorating health infrastructure.

Several other European countries have experienced outbreaks, often characterized by high case fatality rates, a large proportion of patients with complications, and a high percentage of cases in adults [34].

Resource-limited countries — Diphtheria remains a serious disease throughout much of the world. Areas of endemicity include Africa (Algeria, Egypt, and countries in the sub-Saharan region), the Americas (Brazil, Colombia, the Dominican Republic, Ecuador, Haiti, and Paraguay), Asia (Afghanistan, Bangladesh, Bhutan, Cambodia, China, India, Indonesia, Laos, Mongolia, Burma [Myanmar], Nepal, Pakistan, Papua New Guinea, the Philippines, Thailand, and Vietnam), the Middle East (Iran, Iraq, Syria, and Yemen), and Europe (Turkey, Albania, and all countries of the former Soviet Union) [35,36].

Close contacts of unvaccinated or inadequately vaccinated travelers to endemic areas are also at risk for infection. For example, a case of respiratory diphtheria was reported in 2004 in a 60-year-old Haitian-born Massachusetts resident with unknown vaccination status against diphtheria with no recent travel [37]. The patient presented with fever and respiratory symptoms and was misdiagnosed with streptococcal pharyngitis based on a rapid antigen test. The throat culture yielded toxigenic C. diphtheriae. Her asymptomatic spouse also had a throat culture positive for toxigenic diphtheria and, two months earlier, had traveled to an area of Haiti where cases of diphtheria had been reported.

Re-emergence of diphtheria has occurred among populations in Burma (Myanmar) [38], Yemen [39], and Venezuela [40] impacted by the collapse of health care systems, limited access to vaccinations and medications, and an exodus of health care workers. They have exported diphtheria to neighboring countries (Rohingya to Bangladesh, Yemeni to countries in the Horn of Africa, and Venezuelans to other Latin American countries). Clinicians should maintain an appropriately high index of suspicion for diphtheria among migrant and displaced populations who may be suffering from lack of access to health care and vaccination, as well as exposure to conditions that facilitate spread of the disease.

PATHOPHYSIOLOGY — Symptomatic diphtherial infection results from localized inflammation of the respiratory tract or skin as well as local and systemic effects of a potent diphtheria exotoxin.

Exotoxin production depends on the presence of a lysogenic bacteriophage that carries the gene encoding for toxin (tox+) [41,42]. The toxin has a total of three domains. One domain is present in fragment A (the catalytic unit), and the remaining two domains are in fragment B (one for receptor binding and one that may participate in membrane insertion and translocation) [43].

Diphtheria toxin acts inside the cells, where it causes cell death by inactivating elongation factor 2 [44]. The toxin binds to a membrane receptor providing a mechanism of cell entry [44,45]. Diphtheria toxin exploits a growth factor precursor as a receptor: diphtheria toxin receptor appears to be identical to the precursor of a heparin-binding epidermal growth factor-like growth factor [45].

SUMMARY

●Overview – Diphtheria is an infectious disease caused by the gram-positive bacillus Corynebacterium diphtheriae. Infection may lead to respiratory disease, cutaneous disease, or an asymptomatic carrier state. (See 'Introduction' above.)

●Transmission – The primary modes of spread consist of close contact with infectious material from respiratory secretions (direct or via airborne droplet) or from skin lesions. Infection occurs throughout the year with a peak incidence in the colder months. (See 'Transmission' above.)

Humans are the only known reservoir for C. diphtheriae. Therefore, asymptomatic carriers are important in diphtheria transmission. Immunity (either via natural infection or vaccine induced) does not prevent carriage.

●Burden of disease – In areas of endemicity, up to 5 percent of healthy individuals may have positive pharyngeal cultures. Immunization has minimized the transmission of toxigenic strains; diphtheria is rare in resource-rich settings, although sporadic cases continue to occur. (See 'Burden of disease' above.)