WBR0291

Author	[[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Microbiology, MainCategory::Pathophysiology
Sub Category	SubCategory::General Principles, SubCategory::Infectious Disease
Prompt	[[Prompt::A 4-year-old boy is brought to the emergency department (ED) with fever, sore throat, and malaise. His mother states that the patient has no significant past medical history but has not received any childhood vaccinations. She denies any known allergies to medications or drugs. The family immigrated to the United States from Africa only 2 days ago. In the ED, his temperature is 38.5 °C (101.3 °F), blood pressure is 136/86 mmHg, and heart rate is 106/min. The patient is leaning forward on the hands and drooling saliva. Physical examination is remarkable for cervical lymphadenopathy, pharyngeal erythema, and presence of a grey-white exudative membrane that bleeds when scraped in the pharynx. The patient is immediately isolated and is managed promptly. Two days later, a club-shaped, gram-positive rod that contains red and blue granules grows on Loffler's media. What is the mechanism of virulence that characterizes the organism responsible for this patient's condition?]]
Answer A	AnswerA::It binds to MHC II and T-cell receptor, resulting in polyclonal T-cell activation
Answer A Explanation	[[AnswerAExp::Superantigens (SAG or SAg) are proteins of bacterial or viral origin that activate T-cell populations by simultaneously binding to T-cell receptors and MHC II of antigen presenting cells (APCs), resulting in the release of IFN-gamma and IL-2 that lead to shock. Examples include exfoliative toxin and enterotoxin of S. aureus and exotoxin A of S. pyogenes.]]
Answer B	AnswerB::It forms phospholipase that degrades tissue and cell membranes
Answer B Explanation	AnswerBExp::Alpha toxin of ''C. perfringens'' forms phospholipase that degrades tissue and cell membranes. It results in gas gangrene due to myonecrosis. On blood agar, ''C. perfringens'' demonstrates a double zone of hemolysis.
Answer C	AnswerC::It inhibits protein synthesis via stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2
Answer C Explanation	AnswerCExp::''C. diphtheriae'' exotoxin acts by inhibiting the cellular protein synthesis by stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2.
Answer D	AnswerD::It blocks GABA and glycine release from cells in the spinal cord
Answer D Explanation	AnswerDExp::''C. tetani'' produces tetanospasmin, which blocks GABA and glycine release from Renshaw cells in the spinal cord, resulting in spasticity, lockjaw, and risus sardonicus.
Answer E	AnswerE::Increases the concentration of cyclic AMP (cAMP) via calmodulin-activated adenylyl cyclase activity.
Answer E Explanation	AnswerEExp::Edema factor is an exotoxin of ''B. anthracis'', the bacteria responsible for anthrax. Edema factor has calmodulin (CaM)-activated adenylyl cyclase activity that increases the concentration of cyclic AMP (cAMP) to supraphysiological levels.
Right Answer	RightAnswer::C
Explanation	[[Explanation::Diphtheria is an acute infectious disease caused by Corynebacterium diphtheriae. C. diphtheriae is an exotoxin-producing, club-shaped, urease-negative, catalase-positive, gram-positive bacteria that is usually transmitted by direct contract or by aerosol. The most common manifestations of C. diphtheriae infection include an upper respiratory tract infection that often involves the posterior oral and the proximal pharyngeal regions, resulting in significant edema and formation of "pseudomembranes" (coalescence of the bacteria on the mucosal membranes and the outpouring of fibrinosuppurative exudates). The "pseudomembrane" is often described as dirty-looking and firmly attached to the mucosa, causing mucosal bleeding when scraped off the pharynx or palates. It is usually white-grey early in the disease and becomes necrotic green-black as the infection progresses. The bacteria contains diphtheria exotoxin, which acts by inhibiting the cellular protein synthesis by stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2. The toxigenicity of C. diphtheriae is derived from tox genes, three structural genes found in lysogenic corynebacteriophages that are eventually inserted into the bacterial genome. The bacteria regulates the expression of these genes in an iron-dependent manner (increased toxin production in low iron concentrations). Following excretion from the bacteria, these toxins undergo cleavage into 2 chains (A and B) held by a disulfide bond. Systemic manifestations of C. diphtheriae infection may also occur due to the absorption of diphtheria exotoxin into the blood. Cervical lymph nodes may become enlarged and hemorrhagic with a "bull neck" appearance. Potentially fatal complications include myocarditis and neuropathy. Cardiac failure develops due to myocardial distortions, granular degeneration with loss of striations, and cardiac conduction abnormalities. Patients with diphtheria and cardiac complications may eventually die of myocardiosclerosis within 1-2 weeks of disease progression. On autopsy, the heart will appear dilated and pale with a "streaky" appearance. Neuropathy first manifests with food regurgitation through the nose due to paralysis of the soft palate and the posterior pharyngeal wall. If left untreated, other cranial and peripheral motor and sensory neuropathies develop at a later stage. The diagnosis of diphtheria should be considered upon high clinical suspicion among young patients (usually < 5 years of age) with consistent manifestations (sore throat, drooling, and leaning forward on the hands or "tripod positioning" in attempt to breathe) and findings on physical examination (fever, cervical lymphadenopathy, pharyngeal edema, and pseudomembranes that bleed when scraped in the palate and the pharynx). Suspicion is confirmed with gram stain and culture from the throat, nose, secretions of the respiratory tract, or parts of the pseudomembranes. Gram stain may rapidly aid in the diagnosis, often demonstrating gram-positive rods with a "Chinese character" distribution. Metachromatic (red and blue) granules are observed on Loffler's media, whereas brown/black colonies with halo formation are observed on tellurite agar. Elek test (in vitro immunodiffusion technique) is a blood test that may be used to evaluate the toxigenicity of the infectious C. diphtheriae strain. Once diphtheria is suspected, management includes early isolation, empirical administration of anti-toxin and intravenous antibiotics (erythromycin or penicillin G), and careful monitoring for respiratory, cardiac, or neurological complications. With the introduction of toxoid vaccines against C. diphtheriae infection, the incidence of diphtheria has greatly been reduced; and diphtheria respiratory infection noawadays is rarely described in developed countries. However, cutaneous diphtheria is still a common source of wound and umbilical infections, often showing single/multiple, curved, punched-out ulcers with elevated margins. Educational Objective: C. diphtheriae exotoxin acts by inhibiting the cellular protein synthesis by stimulation of adenosine diphosphate (ADP) ribosylation and inactivation of protein synthesis elongation factor 2. References: Hadfield TL, McEvoy P, Polotsky Y, et al. The pathology of diphtheria. J Infect Dis. 2000;181 Suppl 1:S116-20. 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. Kneen R, Pham NG, Solomon T, et al. Penicillin vs. erythromycin in the treatment of diphtheria. Clin Infect Dis. 1998;27(4):845. Shen Y, Zhukovskaya NL, Zimmer MI, et al. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc Natl Acad Sci USA. 2004;101(9):3242-7. First Aid 2014 page 126]]
Approved	Approved::Yes
Keyword	WBRKeyword::Corynebacterium diphtheriae, WBRKeyword::C. diphtheriae, WBRKeyword::Diphtheria, WBRKeyword::Pseudomembranes, WBRKeyword::Loffler's media, WBRKeyword::Metachromatic granules, WBRKeyword::Fever, WBRKeyword::Sore throat, WBRKeyword::Vaccine, WBRKeyword::Immigrant, WBRKeyword::Mechanism of action, WBRKeyword::Exotoxin, WBRKeyword::Elongation factor 2, WBRKeyword::ADP ribosylation, WBRKeyword::Protein synthesis, WBRKeyword::Myocarditis, WBRKeyword::Neuropathy, WBRKeyword::Lymphadenopathy, WBRKeyword::Elek test, WBRKeyword::Toxigenicity, WBRKeyword::Diphtheria toxin
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