A 7-year-old unvaccinated boy from rural Maharashtra presents with a 3-day history of sore throat, low-grade fever (38.2°C), and progressive difficulty swallowing. On examination, he has a thick, greyish-white pseudomembrane covering both tonsils and extending into the pharynx. The membrane does not bleed on gentle scraping. His neck shows marked lymphadenopathy with "bull neck" appearance due to soft tissue edema. A throat swab is sent for culture. Which toxin produced by the causative organism is responsible for the systemic manifestations observed in this patient?

Explanation

## Pathophysiology of Diphtheria **Key Point:** Diphtheria toxin is an A-B toxin produced by *Corynebacterium diphtheriae* lysogenized by a β-phage carrying the *tox* gene. Only toxigenic strains cause systemic disease. ### Mechanism of Diphtheria Toxin The toxin consists of: - **Fragment A (catalytic domain):** ADP-ribosylates elongation factor 2 (EF-2), permanently inactivating it and halting protein synthesis in host cells. - **Fragment B (binding domain):** Binds to heparin-binding EGF-like growth factor precursor (HB-EGF) on cell surface, allowing internalization. ### Systemic Manifestations Caused by Toxin | Organ System | Manifestation | Mechanism | | --- | --- | --- | | **Cardiac** | Myocarditis, arrhythmias, heart block | Toxin damages myocardial cells → conduction defects | | **Neurological** | Cranial nerve palsies (CN III, IV, VI), peripheral neuropathy | Demyelination of nerves; toxin affects Schwann cells | | **Renal** | Acute kidney injury | Tubular necrosis from toxin | | **Cutaneous** | Skin diptheria (rare) | Toxin production in skin lesions | **Clinical Pearl:** The "bull neck" appearance and systemic toxicity distinguish diphtheria from streptococcal pharyngitis. The pseudomembrane itself is not the primary cause of systemic disease—the toxin is. **High-Yield:** Diphtheria toxin is one of the most potent bacterial toxins known. A single molecule of Fragment A can kill a cell. Antitoxin (passive immunization) must be given early before toxin binds irreversibly to cells. ### Why Toxin Production Matters - **Gravis biotype:** High toxin production → severe disease - **Mitis biotype:** Lower toxin production → milder disease - **Intermedius biotype:** Variable toxin production **Mnemonic:** **EF-2** = **E**longation **F**actor **2**; diphtheria toxin **A**DP-ribosylates it → **A**bsolute halt in protein synthesis. [cite:Robbins 10e Ch 8]