During 2007–2011, a total of 55 countries worldwide, including 10 high-income countries, reported >20,000 cases of diphtheria to WHO (4). India reported the most cases of diphtheria of any country (n = 17,926) and more than all of the other highest reporting countries combined (Table 2). During 1998–2008, India had 19%–84% of the global incidence of diphtheria. Since the Expanded Program on Immunization was introduced in the late 1970s, the number of diphtheria cases in India has decreased but diphtheria remains a major cause of illness and death. There were 39,231 reported cases in 1980, 8,425 in 1990, 5,125 in 2000, and 3,485 in 2011 (12).

Most persons with diphtheria in India are either not vaccinated or have only partial immunization from DTP or DTP combination vaccines (13). In this case series, vaccination status for DTP was not unreported during routine AFP surveillance because the programmatic focus was on poliomyelitis. In India in 2011, >4 million children did not receive a first dose of DTP vaccination and >2.5 million did not receive a third dose (12,14). Although this number represents the minority of all children in India, this country had the highest number of children worldwide who had not received DTP vaccine (12,14).

Diphtheritic polyneuropathy is a toxic complication of initial infection with C. diphtheriae resulting from hematogenous dissemination of intracellular toxin subunit A. Transport down the axon of newly synthesized protein with eventual destruction of the myelin sheath accounts for the delay in neuropathic symptoms (mean 8 weeks) after initial infection (15). Diphtheritic polyneuropathy is potentially reversible, and surviving patients often report few to no neurologic symptoms (16). Our report attempts to underscore the key clinical features of diphtheritic polyneuropathy, including initial sore throat; nasal, laryngeal, and pharyngeal involvement; neck swelling with the classic bull neck appearance; and the potentially long time course between initial infection and neuropathic symptoms.

Diphtheritic polyneuropathy is generally considered a demyelinating neuropathy with proximal to distal spread of weakness and prominent sensory features. However, in children and in resource-limited settings, simply examining for pharyngeal exudate in the setting of AFP may help lead to a clinical diagnosis, throat swab, and appropriate management with antidiphtheroid serum and antimicrobial drugs when available (17,18). Isolation of the bacterium from a throat swab specimen is unlikely in most cases. Other reports of diphtheritic neuropathy in India have been bacteriologically confirmed for 15%–39% of patients (19–21). Indiscriminate use of antimicrobial drugs before the diagnosis of diphtheria may make culture positivity even more difficult (17,19) and is also possible in this case series because many parents in India first seek the advice of local healers and health care workers before seeking formal medical evaluation.

In the United States, diphtheria antitoxin is available only through the Centers for Disease Control and Prevention and should be given as soon as possible after diagnosis of diphtheria or suspected diphtheria (2,18). Although rapid administration of diphtheria antitoxin reduces the case-fatality rate for respiratory diphtheria, antitoxin administration after day 1 of diphtheritic polyneuropathy shows no benefit (22). Many countries no longer store diphtheria antitoxin for therapeutic use. A recent survey including 47 countries in which the diphtheria antitoxin stock was known during 2007–2008 found that only 57% stocked antitoxin, including countries in which diphtheria antitoxin is still produced (23). India produces and exports diphtheria antitoxin, but local patients are often unable to pay for this therapy (20,23).

Our study demonstrates that diphtheritic neuropathy can be detected through existing AFP surveillance systems designed to detect poliomyelitis and may be pragmatically expanded to include diphtheritic neuropathy in children <15 years of age. Several additional features make diphtheritic polyneuropathy more difficult to detect than poliomyelitis. Awareness of diphtheritic polyneuropathy may be lower than that of poliomyelitis among health care workers and surveillance officers. Laboratory testing for diphtheria requires special growth media and is less sensitive and less specific for diagnosis of diphtheria than fecal testing for poliomyelitis, especially for patients who have received antimicrobial drugs. In the case of diphtheritic polyneuropathy, nasopharyngeal involvement precedes development of neuropathy and may be resolved by the time AFP develops. Isolated cranial nerve involvement is notable in patients with diphtheritic polyneuropathy and is not currently a major focus of AFP surveillance. Case definitions were developed in higher-income settings and may not be developed for or by low-income practitioners for general use in resource-constrained settings.

Nonetheless, simple additions to the current screening for AFP in diphtheria-endemic areas, including dedicated questions about DTP or DTP combination vaccination status, contacts with known diphtheria case-patients, cutaneous lesions, and nasopharyngeal symptoms might inexpensively improve the detection of diphtheritic neuropathy. Notably, diphtheritic neuropathy, which accounts for a minority of all diphtheritic illness, can signal the need for improved routine DTP or DTP combination vaccination coverage, lead to booster vaccinations for persons in various age groups, and herald the need for release of antitoxin from storage for administration to patients. Because antitoxin is not fully available and must be administered promptly, routine and bolstered immunization strategies remain crucial for reducing the incidence of diphtheria, and early detection through existing surveillance systems is especially needed for nonimmunized community populations.

Although this study represents a convenience sample because of chart availability and may represent reporting bias, the case-patients reported had high case-fatality and disability rates at last known follow-up evaluation at 60 days. The cases have fairly complete information regarding onset and course of the neuropathy but lack details surrounding the first phase of the diphtheritic illness, infectious contacts, and community-level and person-level vaccination status. None of the case-patients reported, with the possible exception of 1 case-patient, represent definite diphtheria diagnosed without bacteriological identification. This finding is also common in outbreaks in middle-income countries because the organism may be difficult to identify (19,21–24). All cases in this report should be best considered as suggestive of diphtheria.

It is possible but unlikely that these case-patients had Guillain-Barré syndrome, poliomyelitis, or other causes of AFP (25,26). In addition to diphtheria, there are other differential diagnoses for AFP with respiratory involvement for patients in this age group. However, these case-patients displayed several classic features of diphtheria and meet the definition of having probable cases. Finally, AFP surveillance in India is targeted to persons <15 years of age. Diphtheria is not limited to persons in this age group and may be seen in adults, including older adults. In higher-income countries, eradication of diphtheria was first achieved among children in the youngest age groups and later older children and adults became more vulnerable because of waning immunity or incomplete immunization (27). A study specific to healthy adults in India found that adults in the oldest age group were least likely to have protective levels of antibodies against C. diphtheria (28).

Given resource constraints, the high reported mortality rate in this case series approximates the mortality rate for reports of diphtheria outbreaks in India in general but represents selection bias for more severe cases. The mortality rate was 73% in a case series from Assam and was maximal in persons 3–5 years of age (27). Another report for Assam found that 31% of patients with diphtheria died (20). These case series identified polyneuropathy in a minority of cases, suggesting that diphtheritic polyneuropathy in low-income settings might represent more severe presentations of the disease and, by the time of presentation, might be less responsive to standard interventions.

The present study reports a sample of diphtheritic polyneuropathy that occurred in India over a 7-year time frame. Diphtheria represents a small proportion of AFP cases in India. AFP is the most severe presentation of polyneuropathy. If polyneuropathy also occurs in 20% of patients with diphtheria in this region, then surveillance of diphtheritic polyneuropathy by existing networks identifies a small but major fraction of severe diphtheria cases in India.

Diphtheria can be eliminated for several reasons: the reservoir is only humans; there is a safe, effective, and affordable vaccine; and seasonal outbreaks make transmission interruption possible (27). However, a low level of transmission of diphtheria, a fully vaccine-preventable disease, leaves the possibility for long-term reemergence of diphtheria in many countries in which vaccination has been inadequate. Asymptomatic carriers persist. Partial immunization; increased numbers of diphtheria cases in certain groups, such as women and certain religious groups; and changing demographic patterns, such as cases in older children, are all concerning features that lead to continued disease transmission (13). Poor awareness for additional protection of DTP and DTP combination vaccines compared with other vaccinations and societal and individual-level fatigue with vaccinations in general can reduce free and available vaccination against diphtheria (19). Late and missed diagnoses and limited expertise in sample collection may contribute to the high case-fatality rate. Case-based surveillance and mandatory booster vaccination at the time of primary school entry have been suggested for children in India (13).