Clinical manifestations, diagnosis and treatment of diphtheria
- Luis F Barroso, MD
Luis F Barroso, MD
- Wake Forest University, Baptist Medical Center
- P Samuel Pegram, MD, FACP
P Samuel Pegram, MD, FACP
- Professor Emeritus of Medicine
- Bowman Gray School of Medicine
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.
The clinical manifestations, diagnosis, and treatment of diphtheria will be reviewed here. The epidemiology, pathophysiology, and prevention of this infection are discussed separately. (See "Epidemiology and pathophysiology of diphtheria" and "Standard immunizations for children and adolescents", section on 'Diphtheria, tetanus, and/or pertussis vaccines' and "Tetanus-diphtheria toxoid vaccination in adults".)
Respiratory diphtheria — Respiratory diphtheria is typically caused by toxin-producing strains of C. diphtheriae; rarely, it is caused by toxigenic strains of other Corynebacterium species (C. ulcerans, C. hemolyticum, or C. pseudotuberculosis) . Symptoms typically begin two to five days after infection. In addition to respiratory symptoms, absorption and dissemination of diphtheria toxin can lead to toxin damage of the heart (myocarditis), nervous system, and kidneys.
The onset of symptoms is typically gradual; the most common presenting symptoms are sore throat, malaise, cervical lymphadenopathy, and low-grade fever. The earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. In at least one-third of cases, local elaboration of toxin induces the formation of a coalescing pseudomembrane (composed of necrotic fibrin, leukocytes, erythrocytes, epithelial cells, and organisms) (picture 1 and picture 2). This membrane adheres tightly to the underlying tissue and bleeds with scraping.
This membrane can extend to any portion of the respiratory tract from the nasal passages to the tracheobronchial tree. Up to two-thirds of cases are tonsillopharyngeal; involvement of the laryngeal, nasal, and tracheobronchial areas is less common . Systemic toxicity increases as the pseudomembrane spreads from the tonsillopharyngeal area. A form of malignant diphtheria is associated with extensive "membranous pharyngitis" plus massive swelling of the tonsils, uvula, cervical lymph nodes, submandibular region, and anterior neck (the so-called "bull neck" of toxic diphtheria). In such cases, respiratory stridor may ensue, leading to respiratory insufficiency and death. In addition, aspiration of the membrane can lead to suffocation.
- Wong TP, Groman N. Production of diphtheria toxin by selected isolates of Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. Infect Immun 1984; 43:1114.
- NAIDITCH MJ, BOWER AG. Diphtheria; a study of 1,433 cases observed during a ten-year period at the Los Angeles County Hospital. Am J Med 1954; 17:229.
- Kadirova R, Kartoglu HU, Strebel PM. Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995. J Infect Dis 2000; 181 Suppl 1:S110.
- Lumio JT, Groundstroem KW, Melnick OB, et al. Electrocardiographic abnormalities in patients with diphtheria: a prospective study. Am J Med 2004; 116:78.
- BOYER NH, WEINSTEIN L. Diphtheritic myocarditis. N Engl J Med 1948; 239:913.
- MORGAN BC. CARDIAC COMPLICATIONS OF DIPHTHERIA. Pediatrics 1963; 32:549.
- Kneen R, Nguyen MD, Solomon T, et al. Clinical features and predictors of diphtheritic cardiomyopathy in Vietnamese children. Clin Infect Dis 2004; 39:1591.
- Jayashree M, Shruthi N, Singhi S. Predictors of outcome in patients with diphtheria receiving intensive care. Indian Pediatr 2006; 43:155.
- Dobie RA, Tobey DN. Clinical features of diphtheria in the respiratory tract. JAMA 1979; 242:2197.
- Wilson AP, Efstratiou A, Weaver E, et al. Unusual non-toxigenic Corynebacterium diphtheriae in homosexual men. Lancet 1992; 339:998.
- Tiley SM, Kociuba KR, Heron LG, Munro R. Infective endocarditis due to nontoxigenic Corynebacterium diphtheriae: report of seven cases and review. Clin Infect Dis 1993; 16:271.
- Gruner E, Opravil M, Altwegg M, von Graevenitz A. Nontoxigenic Corynebacterium diphtheriae isolated from intravenous drug users. Clin Infect Dis 1994; 18:94.
- Höfler W. Cutaneous diphtheria. Int J Dermatol 1991; 30:845.
- Lowe CF, Bernard KA, Romney MG. Cutaneous diphtheria in the urban poor population of Vancouver, British Columbia, Canada: a 10-year review. J Clin Microbiol 2011; 49:2664.
- Bray JP, Burt EG, Potter EV, et al. Epidemic diphtheria and skin infections in Trinidad. J Infect Dis 1972; 126:34.
- Sing A, Heesemann J. Imported cutaneous diphtheria, Germany, 1997-2003. Emerg Infect Dis 2005; 11:343.
- Zeegelaar JE, Faber WR. Imported tropical infectious ulcers in travelers. Am J Clin Dermatol 2008; 9:219.
- de Benoist AC, White JM, Efstratiou A, et al. Imported cutaneous diphtheria, United Kingdom. Emerg Infect Dis 2004; 10:511.
- Harnisch JP, Tronca E, Nolan CM, et al. Diphtheria among alcoholic urban adults. A decade of experience in Seattle. Ann Intern Med 1989; 111:71.
- Belsey MA, Sinclair M, Roder MR, LeBlanc DR. Corynebacterium diphtheriae skin infections in Alabama and Louisiana. A factor in the epidemiology of diphtheria. N Engl J Med 1969; 280:135.
- Farizo KM, Strebel PM, Chen RT, et al. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis 1993; 16:59.
- Clarridge JE, Popovic T, Inzana TJ. Diphtheria and other corynebacterial and coryneform infections. In: Topley and Wilson's Microbiology and Microbial Infections, Hausler WJ, Sussman M (Eds), Oxford University Press, New York City 1998. Vol 3, p.347.
- MacGregor RR. Corynebacterium diphtheriae. In: Principles and Practice of Infectious Diseases, 6th ed, Mandell GL, Bennett JE, Dolin R (Eds), Churchill Livingstone, Philadelphia 2005. p.2457.
- Efstratiou A, Engler KH, Mazurova IK, et al. Current approaches to the laboratory diagnosis of diphtheria. J Infect Dis 2000; 181 Suppl 1:S138.
- Colman G, Weaver E, Efstratiou A. Screening tests for pathogenic corynebacteria. J Clin Pathol 1992; 45:46.
- Efstratiou A, Engler KH, Dawes CS, Sesardic D. Comparison of phenotypic and genotypic methods for detection of diphtheria toxin among isolates of pathogenic corynebacteria. J Clin Microbiol 1998; 36:3173.
- Komiya T, Shibata N, Ito M, et al. Retrospective diagnosis of diphtheria by detection of the Corynebacterium diphtheriae tox gene in a formaldehyde-fixed throat swab using PCR and sequencing analysis. J Clin Microbiol 2000; 38:2400.
- Engler KH, Efstratiou A. Rapid enzyme immunoassay for determination of toxigenicity among clinical isolates of corynebacteria. J Clin Microbiol 2000; 38:1385.
- Tiwari TS, Golaz A, Yu DT, et al. Investigations of 2 cases of diphtheria-like illness due to toxigenic Corynebacterium ulcerans. Clin Infect Dis 2008; 46:395.
- Kovatch AL, Schuit KE, Michaels RH. Corynebacterium hemolyticum peritonsillar abscess mimicking diphtheria. JAMA 1983; 249:1757.
- American Academy of Pediatrics. Diphtheria. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th, Kimberlin DW, Brady MT, Jackson MA, Long SS. (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.325.
- Park WH, Atkinson JP. The relation of the toxicity of diphtheria toxin to its neutralizing value upon antitoxin at different stages in the growth of culture. J Exp Med 1898; 3:513.
- Kneen R, Pham NG, Solomon T, et al. Penicillin vs. erythromycin in the treatment of diphtheria. Clin Infect Dis 1998; 27:845.
- Zalma VM, Older JJ, Brooks GF. The Austin, Texas, diphtheria outbreak. Clinical and epidemiological aspects. JAMA 1970; 211:2125.
- McCloskey RV, Eller JJ, Green M, et al. The 1970 epidemic of diphtheria in San Antonio. Ann Intern Med 1971; 75:495.
- Miller LW, Bickham S, Jones WL, et al. Diphtheria carriers and the effect of erythromycin therapy. Antimicrob Agents Chemother 1974; 6:166.
- Zasada AA, Baczewska-Rej M, Wardak S. An increase in non-toxigenic Corynebacterium diphtheriae infections in Poland--molecular epidemiology and antimicrobial susceptibility of strains isolated from past outbreaks and those currently circulating in Poland. Int J Infect Dis 2010; 14:e907.
- Engler KH, Warner M, George RC. In vitro activity of ketolides HMR 3004 and HMR 3647 and seven other antimicrobial agents against Corynebacterium diphtheriae. J Antimicrob Chemother 2001; 47:27.