The forty-paged May 1967 issue of Indian
Pediatrics published four observational studies (growth in the first
year of life, clinical and bacteriological study of diphtheria, cephalic
index changes during the first ten months of life and therapeutic
efficacy of Tin in hymenolepiasis), besides case reports and other
regular features. We selected a study on Diphtheria for this section as
it exemplified the scientific curiosity that existed in those days, and
meticulousness of protocol planning in order to solve a diagnostic
dilemma. This is followed by a brief discussion of the change in
epidemiology, clinical profile, diagnostic tests and treatment protocols
over the last five decades.
The Past
The study by Pohowalla, et al. [1] aimed
to evaluate the clinical and bacteriological profile of children
presenting with white patches in their mouths. At that time, on one
hand, many cases of diphtheria were being missed in the early stages
resulting in fatalities, while on the other, oropharyngeal moniliasis
and follicular tonsillitis were being misdiagnosed and treated as
diphtheria. The study population comprised of 116 children diagnosed
clinically as diphtheria at MGM Medical College, Indore over nine
months. Two throat swabs were collected from each patient before
treatment was started. One was used to prepare smears with Albert-,
methylene blue- and Gram-stain, while the other was directly plated on
Loeffler’s medium and cornmeal agar followed by sub-culture on potassium
tellurite medium and blood agar. This was followed by a detailed
bacteriological routine that included colony morphology and various
biochemical tests that enabled differentiation of diphtheria from
moniliasis and pyogenic follicular tonsillitis. Thirty nine (33.6%)
cases were culture positive for diphtheria (37 gravis, 1
intermedius and 1 mitis). The remaining 63 (55.8%) isolated
pyogenic organisms (Streptococcus hemolyticus, Staphylococcus,
E. Coli, Pseudomonas, Aerobacter and others); 8 combinations of
diphtheria and pyogenic organisms (also including pneumococcus), and 9
combinations of monilia (various types of candida) and pyogenic
organisms. Clinically all cases of proven diphtheria were above 6 months
of age. Fever was the most common presentation, and ten children
developed obstructive breathing necessitating tracheostomy. The case
fatality was 8.6% (10/116), out of which four had required tracheostomy
and two developed myocarditis. As bacteriological evidence was found in
only one-third of the cases of suspected diphtheria, the authors
concluded that majority of children with oropharyngeal white patches
were due to either bacteria other than C. diphtheria or mycotic
organisms. Authors recommended that when a bacteriological diagnosis
could not be established in suspected diphtheria, a combination of
either penicillin or erythromycin with nystatin be used.
Historical background and past knowledge:
Since the Biblical ages, Diphtheria has historically been identified as
a childhood disease marked by sore throat, membrane in the oral cavity
or pharynx, and death through suffocation. In the mid-sixties, it was
recognized that making a correct and early diagnosis was the cornerstone
of effective management. Though the number of cases of diphtheria had
started to decline, this trend was mainly observed in developed
countries.
In 1980, nearly 97000 cases of Diphtheria were
reported globally, which decreased to 21000 by 1992 [2]. Most of these
(80–90%) were from the developing countries. By the 1990’s, it appeared
that diphtheria was under control. However resurgence occurred with the
collapse of the Soviet Union that evolved into an epidemic extending
into Europe. By 1996, 140,000 cases (mostly adults) were reported
(29–95% culture positive), with a case fatality rate of 3–23% [3]. This
was attributed to a reduction in vaccination coverage during childhood,
use of vaccines with low dose formulation, waning adult immunity,
large-scale population movements, disruptions in health services, and
inadequate supplies of vaccine and antitoxin.
Diagnosis of diphtheria remains primarily clinical,
supported by careful visualization of the pseudomembrane. Confirmatory
laboratory diagnosis is by isolation of the diphtheria bacillus in
Tellurite-containing culture media. Toxigenicity tests detect the potent
exotoxin, which is a phage-encoded protein. In vivo virulence
testing in guinea pigs was replaced by the Elek test, first described in
1949 and later modified in the early 1990s.
The mainstay of treatment of diphtheria is
antitoxins, which work by neutralizing the free toxins. A single
dose of 20,000-100,000 units should be administered as soon as a
clinical diagnosis is made. Antibiotics abort toxin production, treat
localized infection and prevent transmission to susceptible contacts.
The antibiotics of choice are penicillin or erythromycin for 14 days
after which two negative cultures from nose and throat should be
obtained. Subsequently, the immunization protocol should be completed as
per individual status. All close contacts must be identified,
immunization status ascertained, given diphtheria booster appropriate
for age, monitored for 7 days and treated if disease develops.
Asymptomatic unimmunized contacts should receive erythromycin for 7 days
or a single intramuscular dose of Benzathine penicillin if surveillance
is not feasible. Immunization should be completed according to schedule.
The Present
Though diphtheria is on the verge of being eliminated
in a few developed countries, 4530 cases were reported worldwide in
2015. Unfortunately 2365 (52.2%) of these were from India [2]. The World
Health Organization Vaccine Preventable Diseases Monitoring System has
also reported periodic resurgence in India. A waxing and waning pattern
has been evident over the last three decades. The number of cases have
been 39231 in 1980, 1326 in 1997, 8465 in 2004, 2525 in 2012 and 6094 in
2014 [2]. Though there are multiple causes, dismal vaccination coverage
stands out. According to successive National Family Health Survey
reports, the coverage of 3 primary doses of DPT vaccine has been
significantly lower than the desired goal of >90%; 51.7% in 1993, 55% in
1999, 55.3% in 2006 and 78.4% in 2016 [4]. After the advent of
widespread vaccination against diphtheria, circulation of toxigenic
strains have reduced, resulting in decline in immunity in older age
groups and increased susceptibility. This age shift has been
demonstrated in studies from West Bengal, Southern India, and Delhi
[5-7]. Reasons for high case fatality include inconsistent and
restricted availability of antitoxin and delay in diagnosis [8].
Improvements in respiratory care and support have resulted in the main
cause of death shifting from obstructive respiration to myocarditis
[9,10].
The diagnosis of diphtheria still remains mainly
clinical, supported by microbiological demonstration of corynebacterium
by Albert stain, and confirmation by positive culture. Recently,
polymerase chain reaction has made establishment of toxigenicity
possible within a few hours. In situations where children have already
received antibiotics, a low (<0.1 IU) level of diphtheria antibody titer
in serum (signifying non protection) and isolation of C. diphtheria
from close contacts can facilitate diagnosis.
At an individual level, each one of us can play an
important role in the journey towards elimination of diphtheria in
India. The immunization status of each child we encounter in our daily
practice should be actively enquired about, and primary and catch-up
immunization should be promoted. A high level of clinical suspicion
towards diphtheria should be maintained and early treatment should be
initiated. We should not overlook treatment of carriers and close
contacts.
References
1. Pohowalla JN, Upadhyaya LN, Chhaparwal BC, Gupta
JC, Bhoraskar SN. Clinical and bacteriological study of diphtheria in
children. Indian Pediatr. 1967;4:208-20.
2. World Health Organization. Reported cases of
selected vaccine preventable diseases. Available from:
http://www.who.int/immunization/monitoring_surveillance/data/en.
Accessed March 28, 2017.
3. Vitek CR, Wharton M. Diphtheria in the former
Soviet Union: Reemergence of a pandemic disease. Emerg Infect Dis.
1998;4:539-50.
4. International Institute for Population Sciences.
National Family Health Survey, India. Available from:
http://rchiips.org/NFHS/index.shtml. Accessed March 28, 2017.
5. Ray SR, Gupta SD, Saha I. A report of diphtheria
surveillance from a rural medical college hospital. J Indian Med Assoc.
1998;96;236-8.
6. Havaldar PV. Diphtheria in eighties: experience in
a south Indian district hospital. J Indian Med Assoc. 1992;90:155-6.
7. Singhal T, Lodha R, Kapil A, Jain Y, Kabra SK.
Diphtheria – down but not out. Indian Pediatr. 2000;37:728-38.
8. Dandinarasaiah M, Vikram BK, Krishnamurthy N,
Chetan AC, Jain A. Diphtheria re-emergence: Problems faced by developing
countries. Indian J Otolaryngol Head Neck Surg. 2013;65:314-8.
9. Jayashree M, Shruthi N, Singhi S. Predictors of
outcome in patients with diphtheria receiving intensive care. Indian
Pediatr. 2006;43:155-60.
10. Jain A, Samdani S, Meena V, Sharma MP. Diphtheria: It is still
prevalent!!!. Int J Pediatr Otorhinolaryngol. 2016;86:68-71.