George Christopher
Michigan, United States

The Voyages and Adventures of Captain Hatteras (1866) is a fictional account of an Arctic expedition set in 1860–1861 written by Jules Verne, the master of nineteenth-century science fiction. In one of the novel’s many dramatic episodes, the crew’s physician, Dr. Clawbonny, cured Bell, the ship’s carpenter, of diphtheria by applying ice to the oral cavity. Verne portrayed the resolution of local edema and the pharyngeal “false membrane” (pseudomembrane, the characteristic lesion of diphtheria) within hours and complete recovery by the next day.

Diphtheria is an acute exotoxin-mediated disease of the upper aerodigestive tract, conjunctivae, or skin caused by Corynebacterium diphtheriae. Complications may include upper airway obstruction due to severe edema and the formation of a pseudomembrane consisting of necrotic cellular debris. Toxemia can cause myocarditis and consequent heart failure; hepatic and renal injury; and peripheral neuropathy. The fatality rate of diphtheria was estimated at 50 to 80% during the nineteenth century¹ and is currently estimated at 29% among unvaccinated, untreated individuals.²

Although the clinical syndrome and pathology of diphtheria were characterized by Pierre Bretonneau by 1821,^3,4 the etiologic role of C. diphtheriae was not discovered until 1883–1884 through the work of Klebs and Loeffler.⁴ Therapies that were used during the nineteenth century included topical applications of disinfectants such as aqueous solutions of boric and phenolic acid, glycerine or salicylic acid, or calomel irrigation.⁵ Although the local application of ice was used to reduce edema and pain from other diseases since antiquity and was used as anesthesia by French military surgeons under the direction of Napoleon’s surgeon, Baron Dominique Larrey while performing amputations during the retreat of the Grande Armée from Russia (1812),⁶ it was not (to my knowledge) described as a treatment of diphtheria during the pre-antibiotic era. Two lifesaving interventions to relieve the upper airway obstruction of diphtheria were in practice by 1860–1861. Bretonneau successfully introduced tracheotomy as a treatment for diphtheria in 1825. Endotracheal intubation was promoted as a safer alternative by Eugene Bouchet during the 1850s, and was subsequently adopted at the Hôpital des Enfants-Malades in Paris, where it supplanted tracheotomy by 1867 and relegated it to a treatment of last resort.⁵ Antitoxin and antibiotic therapies were introduced in 1895 and the 1940s, respectively; the fielding of toxoid vaccine in 1923 constituted the key breakthrough in reducing the disease burden of a devastating malady.

In retrospect, Dr. Clawbonny’s fictional use of ice to treat an acute bacterial infection would almost certainly be ineffective, as it would not exert direct antibacterial activity, while cold-induced vasoconstriction would impede the delivery of immune effector cells, antibodies, complement component proteins, and oxygen, likely exacerbating the infection and hastening the patient’s demise. However, this episode presaged modern topical cryotherapy (application of extreme cold, enabled by the introductions of liquified air, carbon dioxide, and nitrogen during the late nineteenth and early twentieth centuries⁷) as an effective treatment of selected cutaneous and mucosal infections.

The anti-infective mechanisms of action of cryotherapy include destruction of infected and adjacent cells, thereby halting the replication of intracellular pathogens, and immune modulation. The most prevalent anti-infective use of cryotherapy today is the treatment of lesional human papilloma virus (HPV) infections of the skin—common warts. Of special note is the role of cryotherapy in the prevention of cancers caused by HPV, which comprise 5% of malignancies in humans.⁸ HPV-related premalignant lesions that respond to cryotherapy include cervical atypia/dysplasia (a disorder that may progress to cervical cancer, the fourth most common cancer in women that caused an estimated 660,000 cases and 350,000 deaths worldwide in 2022⁹) and anogenital warts. Cryotherapy is also a therapeutic option for initial stage (intraepithelial) HPV-related cervical and anogenital cancers.

Other viral-induced diseases that are treated with cryotherapy include molluscum contagiosum (caused by an orthopoxvirus) and Kaposi’s sarcoma,¹⁰ an endothelial neoplasm caused by human herpesvirus 8. Cryotherapy has also emerged as a treatment of localized cutaneous leishmaniasis, either as a monotherapy or in combination with intralesional injections of pentavalent antimonials.^11-13 Its utility in cutaneous fungal infections is suggested by success in 12 of 21 patients with refractory chronic intertrigo due to Candida spp.¹⁴ and use as an adjunctive therapy in a case of sporotrichosis.¹⁵

An innovative adaptation of cryotherapy has been its incorporation into bronchoscopy and subsequent application as an adjunctive therapy of pulmonary infections. Bronchoscopic cryotherapy represents a safer alternative to laser and argon coagulation to treat bronchial stenoses that may complicate tuberculosis,¹⁶ while bronchoscopic cryotherapy uses a probe to freeze and remove bronchial casts in cases of severe pneumonia.¹⁷

Cryotherapy is widely available, easily administered, nontoxic, and inexpensive. Side effects (due to local inflammation; i.e., pain, redness, blistering) are usually brief and self-limited. Skin dyspigmentation is the most common chronic complication.

In addition to predicting technological advances that included submarines, aircraft, and spacecraft, Jules Verne anticipated medical advances such as telemedicine, treatment of decompression sickness, and proactive preventive medicine on both individual and societal levels.¹⁸ Although Verne’s fictional use of ice to cure diphtheria was unrealistic, it reminds us that the first step in developing innovative therapies is imagination.

References

1. Chen RT, Hardy IR, Rhodes PH, Tyshchenko DK, Moiseeva AV, Marievsky VF. Ukraine, 1992: first assessment of diphtheria vaccine effectiveness during the recent resurgence of diphtheria in the former Soviet Union. J Infect Dis. 2000;181 Suppl 1:S178-S183. doi:10.1086/315561
2. Truelove SA, Keegan LT, Moss WJ, Chaisson LH, Macher E, Azman AS, Lessler J. Clinical and epidemiological aspects of diphtheria: A systematic review and pooled analysis. Clin Infect Dis. 2020 Jun 24;71(1):89-97. doi: 10.1093/cid/ciz808
3. Vicent Rodilla. El Garrotillo: On diphtheria and Goya. Hek Int. 2019:11(2): Frontispiece. Available at: https://hekint.org/2018/11/30/el-garrotillo-on-diphtheria-and-goya/. Accessed July 28, 2025.
4. Kyle RA, Steensma DP, Shampo MA. Friedrich August Johannes Löffler (Loeffler), German Bacteriologist. Mayo Clin Proc. 2015;90(12):e135. doi:10.1016/j.mayocp.2015.07.032
5. Opinel A, Gachelin G. French 19th century contributions to the development of treatments for diphtheria. J R Soc Med. 2011;104(4):173-178. doi:10.1258/jrsm.2010.10k069
6. Allan R, Malone J, Alexander J, et al. Cold for centuries: a brief history of cryotherapies to improve health, injury and post-exercise recovery. Eur J Appl Physiol. 2022;122(5):1153-1162. doi:10.1007/s00421-022-04915-5
7. Freiman A, Bouganim N. History of cryotherapy. Dermatol Online J. 2005;11(2):9. Published 2005 Aug 1.
8. Darvishi M, Nouri M, Zahir M, Asli M, Hejripoor SZ, Karimi E. Overview of human papillomavirus infection. Infect Disord Drug Targets. 2024;24(2):e031123223107. doi:10.2174/0118715265257105231025112708
9. World Health Organization. Cervical Cancer. 5 March, 2024. Available at: https://www.who.int/news-room/fact-sheets/detail/cervical-cancer. Accessed July 25, 2025.
10. İlchan S, Bayramgürler D, Demirbaş A, et al. Efficacy of pro-yellow laser versus cryotherapy in treating cutaneous lesions of Kaposi’s sarcoma: A comparative study. Arch Dermatol Res. 2025;317(1):627. Published 2025 Mar 24. doi:10.1007/s00403-025-04154-6
11. Tilahun Zewdu F, Misganaw Geremew B, Gadisa Belachew E, Alemu Gelay K. Effectiveness of carbon dioxide cryotherapy for the treatment of cutaneous leishmaniasis: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2025;19(1):e0012741. Published 2025 Jan 6. doi:10.1371/journal.pntd.0012741
12. López-Carvajal L, Cardona-Arias JA, Zapata-Cardona MI, Sánchez-Giraldo V, Vélez ID. Efficacy of cryotherapy for the treatment of cutaneous leishmaniasis: meta-analyses of clinical trials. BMC Infect Dis. 2016;16:360. Published 2016 Jul 26. doi:10.1186/s12879-016-1663-3
13. Saad KA, Ageehal HA, Elgrari AS, Ammar SA. The burden of cutaneous leishmaniasis in Libya (2019-2022): Epidemiological insights and treatment practices. Open Vet J. 2025;15(4):1685-1694. doi:10.5455/OVJ.2025.v15.i4.20
14. Zawar V, Pawar M, Reddy RR, Chuh A. Liquid nitrogen cryotherapy for chronic recalcitrant interdigital candidiasis of toe spaces-an uncontrolled pilot study. J Am Acad Dermatol. 2018;78(5):1004-1005. doi:10.1016/j.jaad.2017.10.016
15. Pudasaini P, Paudel S, Sagar GC, Adhikari S. Cryotherapy for treatment of sporotrichosis-rapid cure with adjuvant cryotherapy: Case report. J Med Case Rep. 2025;19(1):173. doi:10.1186/s13256-024-04955-9
16. Popevic S, Maric N, Belic S, et al. Bronchoscopy procedures in diagnostics and treatment of endobronchial tuberculosis. J Infect Dev Ctries. 2025;19(5):636-640. doi:10.3855/jidc.20444
17. Ma X, Tian L, Xu S, Shang J. Tigecycline combined with bronchoscopic interventions in the treatment of macrolide-unresponsive Mycoplasma pneumoniae pneumonia: A case report. Heliyon. 2024;10(21):e40058. doi:10.1016/j.heliyon.2024.e40058
18. Jules Verne’s Novels. Hektoen Int. 2025;17(2):Literary Vignettes. Available at: https://hekint.org/2025/05/07/jules-vernes-novels/. Published 2025 May 7. Accessed July 24, 2025.