Diphtheria

Overview

• Rosen's Emergency Medicine, p. 2582
• Robbins & Cotran Pathologic Basis of Disease, p. 344

Epidemiology

• Humans are the only reservoir. Spread is via respiratory droplets, direct contact with secretions, skin exudate, or rarely fomites/food.
• Crowded conditions favor transmission; carriers (symptomatic, convalescent, or asymptomatic) all spread the disease.
• US cases fell from 206,000 in 1921 to just 2 between 2004 and 2017 - a direct result of vaccination.
• More than 50% of adults over 40 in industrialized countries now lack protective antibodies, because widespread childhood vaccination reduces natural booster exposure.
• Recent outbreaks have occurred in Yemen, Venezuela, and cases linked to travelers in Spain (disrupted vaccination programs).
• WHO reported >5,000 global cases in 2022, with large outbreaks in areas with displaced populations.

Microbiology & Toxin Mechanism

1. The B (binding) fragment attaches to host cell receptors and enables entry.
2. The A (active) fragment catalyzes ADP-ribosylation of Elongation Factor-2 (EF-2) - irreversibly inactivating it.
3. This blocks mRNA translation (protein synthesis) in all host cells.
4. One toxin molecule can ADP-ribosylate >1 million EF-2 molecules, killing the cell.

Pathology & Morphology

• Composed of leukocytes, erythrocytes, fibrin, epithelial cells, and bacteria
• Forms from coagulation of fibrinopurulent exudate over necrotic, ulcerated mucosa
• Tough, dirty gray to black, leathery in texture
• Beneath it: intense neutrophilic infiltrate, vascular congestion, interstitial edema
• When the membrane sloughs off its vascularized bed: bleeding and asphyxiation may result

• Myocardium: fatty change, isolated myofiber necrosis
• Nerves: demyelination with degeneration of myelin sheaths and axis cylinders (polyneuritis)
• Liver, kidneys, adrenals: fatty change and focal necrosis (less common)

Clinical Forms

1. Faucial (Pharyngeal/Tonsillar) Diphtheria - Most Common

• Incubation: 2-4 days (range 1-8 days)
• Symptoms: sore throat, low-grade fever, malaise, dysphagia, weakness, headache, voice changes
• A membrane on the tonsils/pharynx is seen in >50% of patients
• Extent of membrane parallels clinical toxicity:
  • Limited to tonsils = mild disease
  • Covering entire pharynx = severe, abrupt onset
• "Bull neck": cervical lymphadenopathy + tissue infiltration so extensive it distorts the neck contour - sign of malignant diphtheria
• Malignant form: high fever, severe weakness, vomiting, diarrhea, restlessness, delirium

2. Laryngeal Diphtheria

• Classic "barking" cough, stridor, hoarseness, difficulty breathing
• Marked neck edema ("bull neck")
• High risk of airway obstruction

3. Nasal Diphtheria

• Serous or serosanguineous nasal discharge
• Usually mild; membrane on nasal septum
• Acts as source of spread

4. Cutaneous Diphtheria

• Chronic, non-healing ulcers with a dirty gray membrane
• Primary or secondary infection of pre-existing wounds
• Does not cause systemic toxin damage
• Least toxicity of all forms

Complications

Cardiac (appears 1-2 weeks post-onset, earlier in severe cases)

• ECG changes (myocarditis pattern): up to 2/3 of patients
• Clinical myocarditis: 10-25% of cases
• Can cause fatal cardiac failure

Neurological

• ~5% of respiratory infection cases develop polyneuritis
• 75% of patients with severe disease have some neuropathy
• Palatal muscles affected first (nasal voice, regurgitation)
• Then: cranial nerves, peripheral nerves, spinal cord (dorsal root + ventral horn ganglia)
• Cortical cells are spared
• Proximal muscle groups affected first
• Severe cases: paralysis within first few days
• Duration: typically <10 days, up to 3 months; complete recovery is the rule

Respiratory

• Membrane extension causing obstruction
• Diaphragmatic paralysis (from neuritis) leading to death

Diagnosis

• Clinical: characteristic pseudomembrane + systemic toxicity
• Confirmation: culture of nasopharyngeal swab - isolation of C. diphtheriae
• Culture requires special media (Loeffler's or tellurite medium)
• Toxigenicity confirmed by Elek test or PCR for the tox gene

Treatment

• Isolation is mandatory. Patient remains infectious until 2 consecutive negative cultures.

Prevention & Vaccination

• Toxoid vaccine (formalin-fixed toxin) stimulates neutralizing antibodies
• Part of DTP/DTaP (with tetanus, pertussis) series
• Standard childhood schedule: 3 primary doses + boosters
• Booster as Td or Tdap in adults every 10 years
• Immunization dramatically reduced global incidence (see global trend data from WHO 1980-2016)

Key Memory Points

Diagnostic Criteria & ED Management Timeline for Diphtheria

The Core Principle

Diagnostic Classification (CDC Framework)

Suspect Case (minimum threshold to begin treatment)

• Pharyngitis, nasopharyngitis, tonsillitis, laryngitis, or tracheitis (any combination)
• Absent or low-grade fever (high fever is actually atypical)
• Grayish adherent pseudomembrane present
• Membrane bleeds when manipulated or dislodged - this is a key distinguishing feature from other exudates

Probable Case

Laboratory Confirmed Case

• Positive culture of C. diphtheriae or C. ulcerans
• PLUS positive Elek test (toxin detection) OR
• PCR positive for tox gene (subunit A and B)

Important: A positive group A beta-hemolytic strep culture does not exclude diphtheria - up to 30% of diphtheria patients co-test positive for strep, which can mislead the clinician.

Differential Diagnosis to Work Through in the ED

• Streptococcal pharyngitis (exudate is white/yellow, not gray-black; does not bleed)
• Viral pharyngitis (EBV, adenovirus, HSV)
• Tonsillitis
• Gonococcal pharyngitis
• Acute necrotizing ulcerative gingivitis (ANUG) - involves gingivae, spared in diphtheria
• Acute epiglottitis - more rapid onset; laryngoscopy shows erythematous epiglottis without membrane
• Infectious mononucleosis
• Candida (thrush) - white patches, less adherent, immunocompromised patient

Diagnostic Workup in the ED

Specimen Collection (do before starting antibiotics)

• Throat AND nasopharyngeal swabs for respiratory diphtheria
• Membrane material itself if present - send a piece
• Skin lesion swab/biopsy for cutaneous form
• Notify the lab explicitly - routine throat culture media will miss C. diphtheriae; tellurite selective medium is required

Labs

ED Treatment Timeline

Immediate (0-15 minutes) - Simultaneously

• Assess immediately on arrival
• Early intubation for any laryngeal involvement - do not wait for obstruction to develop
• Membrane can detach and cause acute asphyxiation

• Place in respiratory isolation immediately upon suspicion
• Patient is infectious until 2 consecutive negative cultures

• Patients are often dehydrated (fever + dysphagia + neurologic impairment)
• Assess for fluid responsiveness - the myocardial toxin effect can cause heart failure; over-aggressive fluids can worsen it

Early (within 1 hour) - Do Not Delay

• Mandatory reportable disease - contact state/local health department immediately
• They facilitate access to DAT (held at CDC in the US)

• Test for equine serum hypersensitivity (conjunctival or intradermal test)
• Have epinephrine at bedside - anaphylaxis risk

The longer the delay from symptom onset to DAT administration, the higher the dose required and the worse the outcome.

• Erythromycin 500 mg IV/PO q6h x 14 days (preferred)
• Penicillin G 100,000-150,000 units/kg/day IV in divided doses x 14 days (alternative)
• Duration: 14 days total; confirm eradication with 2 negative cultures after completion

Ongoing (first 24-48 hours) - In-Hospital

• Continuous ECG monitoring for all patients with pharyngeal diphtheria
• Serial troponin and echo
• Cardiology consult for myocarditis - pacemaker may be needed for high-degree AV block

• Assess palatal function (nasal voice, regurgitation = soft palate neuropathy = first sign)
• Monitor for respiratory muscle weakness; early ICU/ventilator planning if cranial neuropathy progresses

• All close contacts: culture + prophylactic antibiotics (erythromycin x 7-10 days OR single dose benzathine penicillin G)
• Unimmunized contacts: give diphtheria toxoid
• Contacts with incomplete vaccination: booster dose

Mortality Reference Points

Summary: The ED Decision Tree

Sore throat + low-grade fever + adherent gray membrane
            ↓
Does membrane bleed when touched?
            ↓ YES
SUSPECT DIPHTHERIA
            ↓
→ Isolate immediately
→ Airway assessment (intubate if laryngeal involvement)
→ Swab cultures (before antibiotics)
→ ECG + troponin
→ Call public health for DAT access
→ Test for equine hypersensitivity → Administer DAT
→ Start erythromycin or penicillin G
→ Admit to ICU/monitored bed
DO NOT WAIT FOR CULTURE CONFIRMATION