| Domain | Key facts | Quantitative/current evidence | Suggested ontology terms |
|---|---|---|---|
| Etiology / transmission | Acute toxin-mediated bacterial infection classically caused by toxigenic *Corynebacterium diphtheriae*; other CdSC species, especially *C. ulcerans* and rarely *C. pseudotuberculosis*, can produce diphtheria toxin. Transmission is mainly respiratory droplets for respiratory disease and direct/indirect contact for cutaneous disease; zoonotic transmission is important for *C. ulcerans*. Incubation usually 2–5 days. (pqac-00000002, pqac-00000013, pqac-00000014, pqac-00000015) | 2024 review reported 27,991 suspected cases and 828 deaths across 5 African countries; untreated contagious period 2–3 weeks vs ~1 day after antibiotics in cited review synthesis. In French cutaneous cohort, 39% of isolates were toxigenic; species were *C. diphtheriae* 77% and *C. ulcerans* 23%. (pqac-00000002, pqac-00000014) | MONDO: diphtheria; MeSH: Diphtheria; NCIT: Infectious Process; NCBITaxon: *C. diphtheriae*, *C. ulcerans* |
| Phenotypes | Core respiratory phenotype: sore throat/pharyngitis, low-grade fever, adherent gray-white pseudomembrane, cervical lymphadenopathy, “bull neck,” dysphagia, airway obstruction. Cutaneous phenotype: chronic ulcer or nonhealing wound, often on limbs, sometimes with gray membrane. Major complications: myocarditis, neuritis/polyneuropathy, respiratory failure. (pqac-00000004, pqac-00000014, pqac-00000015, pqac-00000016) | In French cutaneous cohort: lower limbs 86.9%, ulcerations 82%, polymicrobial lesions 88.9%. In a 2024 pediatric mortality study, myocarditis and airway obstruction were significantly associated with death; airway obstruction carried ~13-fold higher mortality odds. (pqac-00000014, pqac-00000016) | HPO: HP:0030247 Pseudomembranous pharyngitis; HP:0002039 Dysphagia; HP:0001644 Dilated cardiomyopathy / myocarditis-related cardiac dysfunction; HP:0001257 Spasticity not appropriate—prefer HP:0009830 Peripheral neuropathy; HP:0012735 Cutaneous ulcer; HP:0000456 Neck swelling |
| Mechanism / pathophysiology | Disease has two linked layers: local mucosal/skin infection and systemic toxemia. Diphtheria toxin is phage-encoded, secreted by lysogenized strains; receptor-binding domain binds HB-EGF/proHB-EGF, toxin enters via receptor-mediated endocytosis, acidic endosome enables translocation, catalytic domain ADP-ribosylates EF-2, blocking protein synthesis and causing cell death. Toxin expression is regulated in part by DtxR and iron availability. (pqac-00000006, pqac-00000013, pqac-00000017) | DT is a 535-aa, ~58 kDa polypeptide with catalytic, transmembrane, and receptor-binding domains. Genome studies show acquisition of tox plus iron-uptake, adhesin, and fimbrial determinants. NTTB strains exist and may be tox-positive but non-expressing. (pqac-00000006, pqac-00000013, pqac-00000017) | GO:0006412 translation; GO:0042776 mitochondrial ATP synthesis not central—prefer GO:0017148 negative regulation of translation by toxin not standard; GO:0009405 pathogenesis; GO:0019219 regulation of nucleobase-containing compound metabolic process; GO:0006886 intracellular protein transport |
| Anatomy / cells | Primary sites are upper respiratory tract mucosa (tonsils, pharynx, larynx, trachea) and skin. Secondary systemic injury affects myocardium and peripheral nerves; kidneys can also be affected. Cell-level involvement includes mucosal epithelial cells, keratinocytes, cardiomyocytes, and peripheral neurons/Schwann-cell-associated tissues. (pqac-00000002, pqac-00000006, pqac-00000015, pqac-00000017) | Respiratory obstruction from pseudomembrane can cause fatal asphyxia; in cutaneous French series, lower limbs predominated. Human toxin complications reflect hematogenous spread to distant organs. (pqac-00000014, pqac-00000017) | UBERON: pharynx, palatine tonsil, larynx, trachea, skin, heart, peripheral nerve; CL: epithelial cell, keratinocyte, cardiomyocyte, neuron, Schwann cell |
| Diagnostics | Diagnosis is clinical first when compatible membrane/airway disease is present; confirm with culture, species identification, and toxigenicity testing. Culture may use tellurite media; current workflows commonly add tox PCR and reference-lab confirmation; Elek test remains classical phenotypic toxin-expression assay. Serology is useful for population immunity studies, not acute diagnosis. (pqac-00000001, pqac-00000004, pqac-00000014) | In French Guiana, 61 *C. diphtheriae* isolates included 5 tox-gene positive, all Elek-negative. In Kitamura 2023, ELISA cutoffs corresponding to TNT 0.01 IU/mL were 0.060 IU/mL (serum) and 0.044 IU/mL (DBS); applying 0.06 IU/mL to a Vietnam serosurvey classified 54% as susceptible, while multiple-imputation estimate was 35%. (pqac-00000001, pqac-00000008, pqac-00000009, pqac-00000010) | NCIT: Polymerase Chain Reaction; LOINC concepts for bacterial culture and antitoxin serology; MeSH: Elek Test |
| Treatment | Immediate therapy should not await lab confirmation when respiratory diphtheria is suspected. Mainstays: diphtheria antitoxin/antiserum to neutralize circulating toxin, antibiotics (classically penicillin or erythromycin), isolation, airway management, cardiac monitoring, and update of immunization after recovery. (pqac-00000000, pqac-00000005, pqac-00000016) | Historical/modern reviews report overall fatality commonly 5–10%, higher in young children; untreated/unvaccinated severe cases may approach ~29% in review synthesis. 2024 pediatric cohorts identify airway obstruction and myocarditis as major mortality drivers. (pqac-00000000, pqac-00000006, pqac-00000016) | NCIT: Antitoxin Therapy; Penicillin; Erythromycin; Anti-Bacterial Agent; Airway Management; Cardiac Monitoring |
| Prevention / public health | Prevention is dominated by diphtheria toxoid-containing vaccination, booster maintenance, rapid case recognition, isolation, prophylaxis and vaccination of close contacts, and surveillance. Cutaneous disease also requires wound/contact control; zoonotic *C. ulcerans* requires animal-human interface management. (pqac-00000000, pqac-00000002, pqac-00000014, pqac-00000015) | Vaccination gaps and disrupted immunization services are repeatedly linked to resurgence. In the French cutaneous cohort, immunization rate was 44%; in companion-animal work, authors emphasized tox-gene testing and management of animal contacts. (pqac-00000014, pqac-00000015, pqac-00000016) | NCIT: Vaccination; Diphtheria Toxoid Vaccine; Contact Tracing; Chemoprophylaxis; Isolation Precaution |
| Epidemiology / prognosis | Disease burden is now concentrated in under-immunized populations and humanitarian/health-system-fragile settings. Respiratory disease remains the classic severe form, while cutaneous disease is increasingly recognized and epidemiologically important. Prognosis worsens with delayed antitoxin, airway obstruction, myocarditis, incomplete immunization, and young age. (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000014, pqac-00000016) | French Guiana incidence rose from 0.7/100,000 in 2016 to 7.7/100,000 in 2021; mean age 30.4 years; male:female 1.7:1; 95% of cases were cutaneous. Nigeria early 2023 review cited 733 suspected cases and 89 deaths Jan–Mar 2023. In recent French cutaneous series, 68.3% were men and 56.7% had traveled outside mainland France. (pqac-00000001, pqac-00000003, pqac-00000014) | MeSH: Incidence; Prevalence; Mortality; UBERON/HPO terms for complications |
| Veterinary reservoirs / models | *C. ulcerans* is a major zoonotic reservoir species in companion animals and other mammals; horses can carry tox-positive *C. diphtheriae*. Animal and experimental systems have been central to toxin biology and antitoxin development. Classical toxin-neutralization and intoxication studies use guinea pigs; rodents are naturally resistant unless engineered to express the receptor. (pqac-00000015, pqac-00000017, pqac-00000006) | Companion-animal survey screened 18,308 animals and found 51 *C. ulcerans* cases (24 toxigenic), plus 2 horses with tox-positive *C. diphtheriae* and 11 *C. rouxii* infections. Phase 1 monoclonal antitoxin program cites prior guinea-pig potency work. (pqac-00000015, pqac-00000011) | NCBITaxon: dog, cat, horse, rat, *C. ulcerans*; NCIT: Animal Model; UBERON: skin, nasal cavity |
| Human genetics / omics applicability notes | Diphtheria is not primarily a Mendelian human genetic disease; there are no established causal human germline genes or inheritance patterns for “having diphtheria.” Relevant genetics are mostly pathogen-side (tox, phage carriage, DtxR-regulated virulence programs) and host receptor biology used mechanistically. Human omics for routine diagnosis are limited; serology and pathogen genomics are more actionable than host genomics. (pqac-00000006, pqac-00000013, pqac-00000017) | Recent practical advances center on pathogen genomic surveillance, tox-gene detection, and serosurveys rather than WES/WGS for host diagnosis. Clinical trials include anti-toxin mAb S315 (NCT04075175; completed, n=41) and new DTaP-containing vaccine studies such as NCT06184542 (recruiting, target n=460). (pqac-00000011, pqac-00000012) | SO/NCIT not applicable for causal human variant annotation; NCIT: Whole Genome Sequencing (pathogen surveillance context), Serologic Test, Monoclonal Antibody Therapy |


*Table: This compact table summarizes the most actionable disease-knowledge-base facts for diphtheria across clinical, mechanistic, epidemiologic, veterinary, and implementation domains. It is designed to support structured curation with recent evidence and ontology term suggestions.*