Difteri

01Pathophysiology

Diphtheria is caused by toxigenic strains of Corynebacterium diphtheriae, a gram-positive, club-shaped bacillus. Humans are the sole reservoir. Transmission occurs via respiratory droplets (coughing, sneezing) or direct contact with skin lesions or contaminated fomites.

The organism colonizes the mucosal surface of the upper respiratory tract, most commonly the pharynx, tonsils, and larynx. Once established, toxigenic strains produce diphtheria exotoxin, an AB toxin. The B subunit binds to heparin-binding epidermal growth factor (HB-EGF) receptors on host cells, allowing endocytosis. Once internalized, the A subunit catalyzes the ADP-ribosylation of Elongation Factor 2 (EF-2), which irreversibly halts protein synthesis. This leads to cell death.

Locally, this toxin-mediated necrosis produces a dense, fibrinous pseudomembrane composed of dead epithelial cells, fibrin, white blood cells, and bacteria. This membrane is tough, adherent, and characteristically bleeds when forcibly removed. The pseudomembrane can extend from the pharynx into the larynx and trachea, causing mechanical airway obstruction, which is a leading cause of death in children.

Systemically, the absorbed exotoxin has tropism for three organ systems, and understanding this explains the feared complications:

• Myocardium: The toxin causes myocarditis, which can manifest as conduction abnormalities (heart block, arrhythmias) and heart failure. This is the most common cause of death in treated patients and typically appears in the second week of illness.

• Nervous system: The toxin damages Schwann cells, causing demyelinating neuropathy. This often presents as palatal palsy (nasal regurgitation, nasal voice) early in the course, followed by cranial nerve palsies and later a descending peripheral polyneuropathy affecting limb and respiratory muscles.

• Kidneys: Tubular necrosis can lead to acute kidney injury, though this is less common than cardiac or neurologic sequelae.

The low-grade fever (< 38.5 °C) that characterizes diphtheria, as opposed to high-spiking fevers, is explained by the fact that the primary damage is toxin-mediated rather than from an invasive bacteremia. The organism largely remains on the mucosal surface.

02Classification and Clinical Manifestation

By Anatomical Site

Case Classification (Kemenkes 2017)

A single suspect case of diphtheria is already declared an outbreak (KLB) and must be reported within 24 hours.

03Diagnostic Workup

Clinical diagnosis comes first. Diphtheria is a clinical diagnosis, and treatment with ADS and antibiotics must never be delayed while awaiting laboratory confirmation. The Kemenkes 2017 guideline explicitly states that management begins immediately based on symptoms and exam findings.

Specimen collection involves two swabs: one throat swab and one nasal swab, both placed in Amies transport medium. Critically, specimens must be collected before the patient receives antibiotics, as antibiotic administration reduces culture sensitivity. Specimens should be transported at 2-8 °C and arrive at the laboratory within 48 hours of collection. Close contacts who are suspected carriers must also be swabbed.

At the reference laboratory, the specimen is inoculated onto Hoyle medium (potassium tellurite medium, where C. diphtheriae forms characteristic dark gray-black colonies) and Columbia agar. Colonies are Gram stained (gram-positive rods in "Chinese letter" or "V" and "L" arrangements), then purified and subjected to biochemical screening tests (PYZ, cystinase, urease, nitrate) and sugar fermentation tests to determine the biotype. Simultaneously, the Elek test is performed to confirm toxin production.

An important exam concept: microscopy alone (Gram stain, Albert stain, Neisser stain, Loeffler stain) is not recommended for establishing a diagnosis of diphtheria.

04Management & Treatment

ADS Dosing Table

The dose is the same for children and adults and is determined by disease severity and duration, not by body weight.

Antibiotic Therapy

Contact Prophylaxis

Step 1: Isolate the patient. All suspect diphtheria cases must be admitted and placed in contact and droplet isolation (single room or cohorting). Negative-pressure ventilation is not required. Isolation continues for a minimum of 48 hours after antibiotic initiation.

Step 2: Airway management. If there is evidence of laryngeal or extensive pharyngeal membrane causing airway obstruction, a tracheostomy should be performed. Corticosteroids (prednisone 2 mg/kg/day for 2 weeks, then tapered) may be given for upper airway obstruction or if myocarditis develops.

Step 3: Administer ADS immediately. Before giving ADS, a skin hypersensitivity test must be performed (0.1 mL of ADS in 1:1,000 saline, injected intradermally; positive if induration > 10 mm within 20 minutes). If positive, ADS is given by desensitization (Besredka method). If negative, ADS is given as a single IV dose diluted in normal saline or 100 mL of 5% dextrose, infused over 1-2 hours. The patient is monitored for anaphylaxis during infusion and for 2 hours afterward. Anaphylaxis risk is approximately 0.6%, febrile reactions occur in about 4%, and serum sickness develops in about 8.8% at 7-10 days.

Step 4: Begin antibiotics. Either penicillin procaine IM or erythromycin (oral or IV) for 14 days. Antibiotics eliminate the organism and stop further toxin production, but they do not neutralize toxin already bound to tissues. This is why ADS must be given first and as early as possible.

Step 5: Monitor for complications. Observe continuously for myocarditis (ECG monitoring, cardiac enzymes), neurologic deficits (palatal palsy, limb weakness), and renal dysfunction.

Step 6: Post-recovery immunization. Patients who recover from diphtheria are NOT necessarily immune. If previously unimmunized, they should receive one dose of Td toxoid during convalescence, and then complete a primary series of at least 3 doses. Patients who received ADS should be immunized 4-6 weeks after ADS administration to avoid interference.

Contact management: All close contacts (household members, classmates, healthcare workers) must be identified and monitored daily for 7 days. They receive prophylactic erythromycin for 7 days and have throat/nasal swabs taken before starting antibiotics. If a contact tests positive (carrier), and remains positive after the 7-day course, another 7-day course is given. If still positive, antibiotic sensitivity testing is performed and the regimen is adjusted accordingly. A designated medication supervisor (PMO) is assigned during prophylaxis.

Outbreak Response Immunization (ORI): Performed immediately at the sub-district level (minimum), regardless of prior immunization status, in 3 rounds at intervals of 0-1-6 months. Vaccine selection: DPT-HB-Hib for ages 1 to < 5 years, DT for ages 5 to < 7 years, Td for ages 7 years and older. Target coverage is at least 90%.

05Differential Diagnosis & Distractors

The single most reliable discriminator for diphtheria is the adherent grayish-white pseudomembrane on the pharynx or tonsils that bleeds when you attempt to remove it, combined with a low-grade fever (< 38.5 °C). Most bacterial pharyngitis mimics produce high fevers. The combination of relatively mild systemic symptoms with a disproportionately alarming-looking throat should trigger the diagnosis.

06Traps & High-Yield Pearls

The most common way students lose points on diphtheria questions falls into three categories.

Trap 1: Waiting for lab confirmation before treating. The exam will present a classic vignette (unimmunized child, sore throat, pseudomembrane, low-grade fever) and ask for the next best step. The answer is administer ADS immediately after the hypersensitivity skin test, not "order a throat culture and wait." Culture is performed in parallel, but treatment is never delayed. Per the Kemenkes guideline, management begins without laboratory confirmation.

Trap 2: Confusing the mechanism of death. Students often answer "airway obstruction" for all diphtheria deaths. While airway obstruction from the membrane is the primary cause of death in untreated or early disease, in treated patients the leading killer is myocarditis (typically in the second week). A vignette describing a patient who initially improved on ADS and antibiotics but then develops new-onset arrhythmia or heart failure at day 10-14 is testing your knowledge of toxin-mediated myocarditis.

Trap 3: Misidentifying the gold standard test. PCR for the toxin gene is rapid but is not the gold standard on its own. The gold standard for confirming toxigenicity is the Elek test (modified immunodiffusion). PCR-positive results must be confirmed with the Elek test. Microscopic staining methods (Gram, Albert, Neisser, Loeffler) are explicitly not recommended for diagnosis according to the Kemenkes guideline.

Additional pearls: The ADS dose is based on disease severity and duration of illness, not on patient weight. A patient presenting late (> 72 hours) receives the highest dose (80,000-100,000 IU) regardless of anatomical location. Carriers are managed with erythromycin and repeat cultures; they must avoid contact with unimmunized individuals and use surgical masks to prevent droplet transmission. Recovery from clinical diphtheria does not guarantee immunity, so patients must be immunized during convalescence. Finally, a single suspect case of diphtheria constitutes an outbreak declaration and triggers a mandatory report within 24 hours and an Outbreak Response Immunization campaign.