History
C diphtheriae
Respiratory: After an incubation period of 2 days to 4 days, patients typically report upper respiratory tract symptoms (eg, nasal discharge, sore throat). The posterior pharynx and tonsillar pillars are most often involved. Onset is often sudden, with low-grade fevers, malaise, and membrane development on one or both tonsils, with extension to other parts of the respiratory system.
Cardiac: The toxic effect in the myocardium characteristically occurs within 1 week to 2 weeks following onset of infection, often when the upper respiratory tract symptoms are improving. Manifestations are due to arrhythmias and congestive heart failure (CHF).
Neurologic: Neurological symptoms can occur immediately or after several weeks. Bulbar symptoms generally occur within the first 2 weeks after disease onset and can range from mild symptoms (eg, difficulty swallowing) to bilateral symmetric paresis of the palatal and ocular muscles. The bulbar symptoms may remit or progress to paralysis of the proximal and then distal skeletal muscles over the next 30 days to 90 days. Although recovery can be very slow, patients generally regain complete neurologic function. Secondary complications include aspiration from bulbar paralysis and bronchopneumonia from respiratory muscle dysfunction.
Skin: Cutaneous infections can occur, often in more tropical climates, presenting as nonhealing ulcers. A recent surveillance study of Native Americans presenting to the Indian Health Service clinics in South Dakota recovered C diphtheriae from six (5%) of the 133 patients, one of whom had skin ulcers.
Diphtheroids
Because these corynebacteria are also pathogenic in animals (eg, C ulcerans, C pseudotuberculosis, C ovis), a history of exposure to sick animals or to animal products (eg, milk, offal, hides) is common. C ulcerans generally causes respiratory symptoms, while C ovis produces a suppurative lymphadenitis.
In hosts colonized with diphtheroids (eg, groups D2, JK), bacteria can be recovered from both skin and mucosal surfaces. Corynebacterium striatum and C pseudodiphtheriticum (or C hofmannii) are normal inhabitants of the anterior nares and skin. Symptoms relate to the organ system affected. Immunocompromised patients appear to have higher colonization rates than healthy persons and may be at a greater risk of developing an infection after being colonized. Bittar et al demonstrated that children with cystic fibrosis in France were often colonized by C pseudodiphtheriticum, while healthy children were not. [17] Antimicrobial resistance is also more common in isolates from immunosuppressed patients. Bnaya et al [10] reported that 30% of peritoneal dialysis patients (9/30) with nontubulous peritonitis demonstrated diphtheroid or corynebacteria spp. Catheter removal was required in most patients.
The methods of transmission for nondiphtherial corynebacteria are incompletely understood. Transmission from patient to patient, from colonized hospital staff to patients, and from environmental contamination to patients have all been suggested. In antibiotic-resistant corynebacteria, transmission of the plasmid responsible for the resistance may be important.
Physical
C diphtheriae - Respiratory signs
Nasal infection may present as serosanguineous or seropurulent drainage.
With tonsillar and pharyngeal infection, exudates coalesce to form the characteristic pseudomembrane of diphtheria.
The membrane usually is grayish-white, although it can become blackish or greenish with necrosis (see the photograph below).
The characteristic thick membrane of diphtheria infection in the posterior pharynx.
The extent of disease correlates with the severity of symptoms. Extension of the membrane to the posterior pharyngeal wall, soft palate, or nasopharynx is associated with profound malaise, weakness, cervical adenopathy, and swelling (see the photograph below), which can distort the airway and cause stridor.
Cervical edema and cervical lymphadenopathy from diphtheria infection produce a bullneck appearance in this child. Courtesy of Immunize.org, formerly Immunization Action Coalition (IAC) [https://www.immunize.org/].
Symptoms of hoarseness, dyspnea, stridor, and a loud brassy cough are associated with extension into the larynx and bronchial tree.
Edema and membrane formation can cause further respiratory distress and respiratory muscle fatigue, requiring intubation.
In fatal diphtheria, the airways are edematous, with necrosis of the epithelium covered by the pseudomembrane, and the lungs are hemorrhagic.
C diphtheriae - Cardiac signs
Subtle evidence of myocarditis may occur in many patients, but 10% to 25% of patients develop clinical cardiac dysfunction.
Signs of CHF (eg, cardiomegaly, volume overload) are not uncommon.
C diphtheriae - Nervous system signs
Signs of cranial nerve dysfunction can occur within a few days of disease onset, with paralysis of the soft palate and posterior pharyngeal wall causing dysphagia and regurgitation.
Although the motor component is usually affected most severely, both sensory and motor nerves are affected by the peripheral neuritis that occurs later.
The symptoms start in the proximal muscle groups of the extremities and spread distally.
In mild cases, only the hip girdle muscles may be affected; these patients have trouble getting out of a chair unassisted. In these patients, the motor reflexes of the lower extremities may be normal.
In the most extreme cases, respiratory muscle dysfunction occurs and patients may require respiratory support.
Interestingly, reports show that the paralysis disappears at the same rate that it appears.
Even in extremely serious cases, the neuropathy is reversible with few or no sequelae.
In severe cases, the paralysis can spread to the trunk and cause temporary bowel and bladder dysfunction.
Paresthesias, which mainly occur distally, are the most commonly reported sensory abnormalities.
C diphtheriae - Skin signs
C diphtheriae can cause skin infections with nonhealing ulcers.
A vesicle or pustule develops initially and progresses to one or more punched-out lesions that measure from a few millimeters to several centimeters, with curved elevated margins.
The lesions are initially painful and may be covered with eschar.
After a few weeks, the lesions become painless and often have a serosanguineous exudate.
Diphtheroids
Signs of diphtheroid-associated infection relate to the affected organ systems. Species of corynebacteria recovered from skin ulcers include C ulcerans, C bovis, and A haemolyticum. Those associated with bacteremia and sepsis include C pyogenes; C bovis; Corynebacterium xerosis; and groups D2, E, and JK. Case reports depict that these organisms are associated with endocarditis, prosthetic device infection, pneumonia, septic arthritis, and osteomyelitis.
Type D2 was originally identified as a pathogen causing chronic or recurrent cystitis, bladder stones, and pyelonephritis. People with prior urinary tract abnormalities or who have recently undergone urologic procedures are at highest risk for this disease. C urealyticum has been associated with chronic nephrolithiasis and renal failure. [36]
A haemolyticum is reported to cause as many as 10% of all pharyngitis cases in patients aged 10-30 years. These bacteria are capable of producing an extracellular toxin that can cause an erythrogenic rash associated with the pharyngitis.
C ulcerans usually causes skin infections but is occasionally associated with pharyngitis and respiratory disease. In 1996, a 54-year-old, otherwise healthy woman in Indiana who had never received diphtheria immunization developed a membranous pharyngitis with a toxin-producing strain of these bacteria. [37] More recently, a review of clinical samples from the National Microbiology Laboratory in Canada has demonstrated C ulcerans isolates from blood cultures. [38]
C striatum is an emerging nosocomial pathogen. [12] It has been found on catheters in patients who are neutropenic and have malignancies and has been recovered from the blood of patients with pleuropulmonary infections, endocarditis, and peritonitis. C striatum found in 11 hospitalized patients with COPD exacerbations and pneumonia was found to be multidrug resistant. [13]
In one heart transplant patient, C striatum was repeatedly cultured from sputum and bronchial lavage fluid. [39] One case of C striatum meningitis was also reported recently. [40]
C pseudodiphtheriticum infection is also found in immunocompromised hosts, associated with both native and prosthetic valve endocarditis, pneumonia, lung abscesses, tracheobronchitis, and suppurative lymphadenitis. In 1995, Manzella and colleagues reviewed the clinical and microbiological features of 17 cases of bronchitis and pneumonia due to C pseudodiphtheriticum that required hospitalization. [41] A more recent study from Brazil found C pseudodiphtheriticum caused urinary tract infections in 29%, respiratory infections in 27%, and intravenous access site infections in 19%. [42]
Group JK can be found on the skin of healthy people. Patients with prolonged hospitalization, neutropenia, or on a prolonged course of antibiotics have a high prevalence for highly resistant JK bacteria. The most common manifestation is endocarditis with bacteremia, often associated with indwelling catheters or artificial valves. A recent review of C JK endocarditis demonstrated that most were treated with many weeks of combined antibiotic therapies, including vancomycin, erythryomycin, ceftazidime, rifampin and doxycycline. [14]
Corynebacteria is often found in the semen of men with inflammatory prostatitis; Türk et al found that more than half of these were isolates were Corynebacterium seminale. [43] However, diphtheroids can be found in the semen of both healthy men and those with chronic prostatitis syndrome. [44]
Moazzez et al (2007) found that 16% of breast abscesses in an urban county hospital were due to diphtheroids. [23] Granulomatous mastitis due to Corynebacterium group G, diagnosed by fine-needle aspirate and culture, was reported by Mathelin et al (2005). [45] More recently, Williams et al (2021) [9] found that 52% (22/44) of bacteria in granulomatous mastitis were diphtheroids; corynebacteria and cutibacteria species. In this review, clarithryomycin as the most commonly used antibiotic.
Cases of Corynebacterium macginleyikeratitis following eye surgery have been reported. [46] In these cases, the bacteria was relatively resistant to extended-spectrum penicillins and fluoroquinolones.
Corynebacterium resistens is a newly described, multidrug-resistant species associated with fatal bacteremia in immunocompromised patients in Japan. [47]
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The corynebacterial tox gene is regulated by the corynebacterial iron-binding repressor, labeled DtxR. Binding of ferrous iron to the DtxR molecule forms a complex that binds to the tox gene operator and inhibits transcription. Depletion of iron from the system removes the repression and allows the toxin to be produced.
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The characteristic thick membrane of diphtheria infection in the posterior pharynx.
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Cervical edema and cervical lymphadenopathy from diphtheria infection produce a bullneck appearance in this child. Courtesy of Immunize.org, formerly Immunization Action Coalition (IAC) [https://www.immunize.org/].
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Final case classification of corynebacteria infections. Courtesy of the World Health Organization (WHO) [Surveillance standards for vaccine-preventable diseases, 2nd ed, 2018, https://apps.who.int/iris/handle/10665/275754].
