PracticalDermatology

Dermatology is often noted for the outsized role of visual-based diagnosis as a cornerstone of daily practice. Among the five senses, vision may reign supreme for the clinical dermatologist, but little has been noted of the diagnostic utility of an astute sense of smell when examining a patient in the clinic or hospital setting. In the general medical literature, this topic has a long history, with the ancient Sanskrit text Susrata Samhita noting that, “by the sense of smell we can recognize the peculiar perspiration of many diseases, which has an important bearing on their identification.” The phenomenon Maharshi Sushruta described thousands of years ago remains equally true in the present day: associating characteristic smells with their underlying disease is a simple yet valuable source of information to utilize when treating patients. A better understanding of the odors of cutaneous disorders will enhance the diagnostic abilities of the practicing dermatologist. In this review, we explore the role smell has in the work-up of different dermatologic conditions with a focus on five categories of ailments: general medicine, metabolic and genetic, infectious and inflammatory, malignancies, and systemic disorders with cutaneous manifestations.

General Medicine

Scrofula. Tuberculosis is an infectious disease caused by the bacteria Mycobacterium tuberculosis and is found most commonly in developing countries. Scrofula is the Latin term for tuberculosis infection of the cervical lymph nodes and skin of the neck, and often presents as firm, rubbery, or matted nodes with possible swelling, ulceration, and fistula formation.¹ These ulcerations have been noted to have a “stale beer” odor.² While there is no clear microbial link between infected tissue and fermentation yeast, the common scent is most likely due the chemical odorants activating olfactory receptors in similar ways.³

Typhoid. Typhoid fever is caused by infection of the gastrointestinal tract with the bacteria Salmonella typhi. Salmonella typhi is the notorious culprit of the Typhoid Mary super-spreader event of the early 1900s in which numerous restaurant-goers were infected by NYC chef Mary Mallon.4 The intestinal manifestations of Salmonella typhi infection include constipation and diarrhea, and can progress to intestinal ulceration and hemorrhage. Typhoid fever includes these gastrointestinal symptoms as well as a fever and “rose spots” found on the abdomen. Patients with typhoid fever often have a musty that which is sometimes described as a “baked bread” odor.^5,6

Rubella. While Rubella has been eradicated from the US for more than 15 years—largely attributed to widespread vaccination efforts—recent anti-vaccination movements have raised concern for a resurgence of measles, mumps, and rubella. Rubella poses a threat to children in underdeveloped areas that lack proper sanitation and resources. In these parts of the world, medical supplies are also limited, and olfactory diagnosis may play a larger role in diagnosis than in the US. Rubella has been described as having the odor of a “freshly plucked feather.”⁷ While it is difficult to characterize this scent, it is possible that in areas where rubella is prevalent, this odor is defined and encountered.

Diphtheria. Diphtheria is caused by bacterial infection with Corynebacterium diphtheria. Diphtheria is spread by respiratory droplets, and has a classic presentation of a grey pseudomembranous pharyngitis but can affect the larynx or respiratory tract. Individuals with diphtheria have been found to have a sweet or putrid odor to their breath that is often described as “sickening.”³

Metabolic and Genetic Diseases

Darier Disease. Darier disease is an autosomal dominant genodermatosis caused by a mutation in ATP2A2 encoding a sarco/endoplasmic reticulum calcium ATPase pump (SERCA2) featuring hyperkeratotic papules, characteristic V-shaped nail nicking, and sometimes crusted areas reminiscent of seborrheic dermatitis. The condition is known for a signature foul-smelling odor associated with secondary bacterial colonization of the skin.8 It may be treated with anti-microbial cleansers while showering, mupirocin, metronidazole, and courses of systemic antibiotics.

Hailey-Hailey Disease. Similar to Darier disease, Hailey-Hailey is a rare familial disorder with crusted erosions that develop in the axillae, chest, and groin that may have a foul smell.⁹ It is an autosomal dominant disorder caused by a mutation in ATP2C1 that leads to impairment of normal calcium storage ability in keratinocytes. Consequently, keratinocyte adhesion is weakened, which increases vulnerability towards damage, creating characteristic erosions usually in skin fold areas. A wide variety of treatments is available, including corticosteroids, dapsone, and photodynamic therapy.

Trimethylaminuria. Trimethylaminuria, also known as fish odor syndrome, is a disorder in which a patient emits a foul odor resembling rotting fish. The disease is due to an inherited deficiency in flavin monooxygenase, which normally metabolizes trimethylamine (TMA).¹⁰ The increase of TMA in sweat glands, breath, and urine causes the fishy smell. The diagnosis is often overlooked and can have devastating psychosocial impacts on its sufferers.¹⁰ Patients may attempt to self-treat with measures such as frequent bathing, which can delay diagnosis as the smell may not be as obvious to clinicians. Diagnosis is based on clinical presentation and urinalysis, which can be analyzed for concentrations of both TMA and trimethylamine-N-oxide.¹⁰ While there is no single treatment regimen that has been found to be universally efficacious, treatment options with various results include having patients wash frequently with acidic soap (pH 5.5-6.5), laundering clothes on a regular basis, diet modification, sequestering agents such as oral activated charcoal, and antibiotic therapy.^10–15

Phenylketonuria. Phenylketonuria is an autosomal recessive inborn error of phenylalanine metabolism. The condition is due to a deficiency of phenylalanine hydroxylase (PAH), which leads to a buildup of phenylalanine, causing a musty body odor from the skin and urine.¹⁶ Other symptoms include growth failure, poor skin pigmentation, eczema, microcephaly, seizures, global developmental delay, and severe intellectual impairment.¹⁷ Newborns in the US are screened one to two days after birth, leading to early detection and treatment with life-long dietary therapy focused on reducing phenylalanine levels and increasing tyrosine intake.¹⁶

Infectious and Inflammatory Diseases

Hidradenitis Suppurativa. Hidradenitis Suppurativa is a chronic inflammatory disease of apocrine gland-bearing skin that may present with abscesses, painful lesions, fibrosis, and scarring.^18,19 It is considered a multifactorial condition that is influenced by genetic and environmental factors. Common areas affected are the axilla as well as the inguinal and inframammary regions. Early signs of Hidradenitis Suppurativa are tender subcutaneous nodules, including boils or pimples, sometimes accompanied by burning, pain, pruritus, warmth, or hyperhidrosis.¹⁹ Ruptured nodules have a characteristic purulent, foul-smelling discharge. Topical antibacterial agents, such as clindamycin, may suffice for milder cases, while biologics such as adalimumab and infliximab are often used for moderate-to-severe disease.¹⁹

Staphylococcus Aureus.Staphylococcus aureus is an infectious pathogen and a common cause of skin infections in those with atopic dermatitis.²⁰ Methicillin-resistant S. aureus strains (MRSA) are even more problematic and can cause widespread infections throughout hospitals and the community.²¹ Cases have been reported in which patients with atopic dermatitis are infected with MRSA and develop generalized erythema along with a peculiar fishy odor.²⁰ Both the erythema and odor disappeared after a course of Vancomycin was administered. With increasing emphasis being placed on S. aureus as a primary driver of atopic dermatitis, detecting the odor may help with sub-typing those patients who may favorably respond to an antimicrobial approach.

Pasteurella Multocida.Pasteurella multocida is a gram-negative coccobacillus commonly transmitted through cat and dog bites. Two cases were reported in which a Pasteurella-infected wound was associated with a seminal fluid-like odor.²² The specific bacteria isolated was Pasteurella multocida subspecies septica. Recommended treatment includes penicillin, ampicillin, amoxicillin, cefuroxime, doxycycline, and fluoroquinolones.²³

Pseudomonas.Pseudomonas aeruginosa is a motile, gram negative bacillus that can lead to dermatologic complications, including green nail syndrome, toe web infection, and ecthyma gangrenosum that typically presents as lesions on the buttocks or extremities while sparing palmar, plantar, and mucosal surfaces.²⁴ Superficial Pseudomonas aeruginosa infections typically present with a bluish green appearance, accompanied by a grape juice or mousey aromatic smell.²⁴ Drug resistance is a concerning issue regarding treatment of Pseudomonas aeruginosa, but monotherapies such as ceftolozane/tazobactam have been reported to achieve good clinical outcomes for skin and soft tissue infections.²⁵

Malignancies

Smell can also be a useful tool when examining patients with malignancies. The profile of volatile organic compounds (VOCs) released from the body changes in the setting of skin cancer, and dogs have been shown to accurately distinguish melanoma from basal cell carcinoma, benign nevi, and healthy skin.²⁶ There have also been multiple cases of canine olfactory detection of malignant melanoma, given the animals’ extraordinary sense of smell.^28–30 The role in VOCs in olfactory differentiation has been further confirmed by gas chromatography-mass spectrometry (GC-MS) and gas sensors.^31,32 Along with skin cancer, sense of smell has been shown to be useful in the setting of breast cancer diagnosis, as dogs have demonstrated the ability to accurately distinguish breast cancer samples purely using their olfactory sensation.²⁷ Canine olfactory detection has shown promise with additional cancers as well including bladder cancer, ovarian cancer, and colorectal cancer.³³

Systemic Disorders with Cutaneous Manifestations

Renal Disease. Uremia is a clinical syndrome seen in renal failure characterized by nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, and/or changes in mental status. Uremia is due to an excess of nitrogenous waste products, such as urea, in the bloodstream.³⁴ The syndrome can produce an ammonia or urine-like odor in the breath due to the breakdown of urea to ammonia and trimethylamine in saliva.³⁵ Dermatological findings of uremia include pruritus and uremic frost, characterized by white urea crystals on the skin, although this manifestation is rarely seen.³⁶ Other skin manifestations in patients with renal disease include xerosis, pigmentation changes, nail changes, perforating disorders, calcifying disorders, bullous dermatoses, and nephrogenic systemic fibrosis.³⁷

Diabetes. Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of uncontrolled diabetes resulting from pathologically high serum and urine concentrations of ketone bodies, namely acetone, acetoacetate, and beta-hydroxybutyrate.³⁸ Due to increased acetone, patients may have a distinct fruity odor to their breath. Other symptoms include polyuria, polydipsia, weight loss, vomiting, weakness, and mentation changes.³⁸ While skin changes are not part of DKA’s clinical picture, cutaneous manifestations of diabetes mellitus are quite common and may be a presenting symptom.³⁹ The most common skin manifestations in diabetes include cutaneous infection, xerosis, and inflammatory skin diseases.³⁹ While skin manifestations are more common in those with type 2 diabetes, DKA more commonly presents in patients with type 1 diabetes.^38,39

Scurvy. Scurvy is the clinical syndrome of a vitamin C deficiency. While historically seen in sailors with no access to fruits and vegetables, today vitamin C deficiency can be seen in patients with alcoholism, infants fed with only cow’s milk, and seniors consuming a “tea and toast diet.”40 It has been noted that those with scurvy produce sweat with a putrid odor.33 Vitamin C has a key role in collagen synthesis, and deficiency leads to classic dermatological findings including poor wound healing, gingival swelling with loss of teeth, mucocutaneous petechiae, ecchymosis, and hyperkeratosis. Corkscrew and swan-neck hairs can occur, as well as nail findings including koilonychia and splinter hemorrhages.⁴⁰

Toxins. Cyanide poisoning can result from fires, industrial exposures, or medical exposures, such as to sodium nitroprusside.⁴¹ A bitter almond odor on the breath is present in the majority of patients with cyanide poisoning and may be accompanied by hypotension, bradycardia, and a cherry red color to the skin due to increased oxygen in the blood.⁴¹ Arsenic poisoning, which can result from contaminated drinking water from wells, mining, or other industrial processes, presents with garlic breath.⁴² Hyperpigmentation and keratosis are the most common dermatological findings in arsenic poisoning, supported by observations of arsenic-affected villages.⁴³

Conclusion

Olfaction is a powerful yet overlooked tool in physicians’ arsenals that should be more actively considered while examining patients. Table 1 provides a concise overview of the discussed odors as well as their strongly associated disease states. Animals such as canines may prove to be a valuable asset to the field in the near future as their well-adapted olfaction pathway enhances their ability to differentiate smells several times greater than humans. As technological advances continue to push medicine forward through improved diagnostic equipment and procedures, it is important to not disregard basic skills like olfaction while providing optimal medical care for patients.

1. Duarte I. [Scrofula in the 19th century]. Rev Chil Infectol organo Of la Soc Chil Infectol. 2017;34(1):55-59. doi:10.4067/S0716-10182017000100008

2. Olsson MJ, Lundström JN, Kimball BA, et al. The scent of disease: human body odor contains an early chemosensory cue of sickness. Psychol Sci. 2014;25(3):817-823. doi:10.1177/0956797613515681

3. Stitt WZ, Goldsmith A. Scratch and sniff. The dynamic duo. Arch Dermatol. 1995;131(9):997-999.

4. Marineli F, Tsoucalas G, Karamanou M, Androutsos G. Mary Mallon (1869-1938) and the history of typhoid fever. Ann Gastroenterol. 2013;26(2):132-134.

5. Pavlou AK, Turner AP. Sniffing out the truth: clinical diagnosis using the electronic nose. Clin Chem Lab Med. 2000;38(2):99-112. doi:10.1515/CCLM.2000.016

6. Liddell K. Smell as a diagnostic marker. Postgrad Med J. 1976;52(605):136-138. doi:10.1136/pgmj.52.605.136

7. Hayden GF. Olfactory diagnosis in medicine. Postgrad Med. 1980;67(4):110-115,118. doi:10.1080/00325481.1980.11715427

8. Mathews D, Perera LP, Irion LD, Carley F. Darier disease: beware the cyst that smells. Ophthal Plast Reconstr Surg. 2010;26(3):206-207. doi:10.1097/IOP.0b013e3181b8dd86

9. Nanda KB, Saldanha CS, Jacintha M, Kamath G. Hailey-hailey disease responding to thalidomide. Indian J Dermatol. 2014;59(2):190-192. doi:10.4103/0019-5154.127684

10. Messenger J, Clark S, Massick S, Bechtel M. A review of trimethylaminuria: (fish odor syndrome). J Clin Aesthet Dermatol. 2013;6(11):45-48.

11. Wilcken B. Acid soaps in the fish odour syndrome. BMJ Br Med J. 1993;307(6917):1497.

12. Blau N, Duran M, Gibson KM. Laboratory Guide to the Methods in Biochemical Genetics. Springer; 2008.

13. Yamazaki H, Fujieda M, Togashi M, et al. Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients. Life Sci. 2004;74(22):2739-2747. doi:10.1016/j.lfs.2003.10.022

14. Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J Inherit Metab Dis. 2006;29(1):162-172. doi:10.1007/s10545-006-0158-6

15. Danks DM, Hammond J, Schlesinger P, Faull K, Burke D, Halpern B. Trimethylaminuria: diet does not always control the fishy odor. N Engl J Med. 1976;295(17):962.

16. Stone WL, Basit H, Los E. Phenylketonuria. In: StatPearls [Internet]. StatPearls Publishing; 2019.

17. Williams RA, Mamotte CDS, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008;29(1):31-41.

18. Buyukasik O, Osmanoglu CG, Polat Y, Kargici H, Kaya G. A life-threatening multilocalized hidradenitis suppurativa case. MedGenMed. 2005;7(4):19.

19. Napolitano M, Megna M, Timoshchuk EA, et al. Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment. Clin Cosmet Investig Dermatol. 2017;10:105-115. doi:10.2147/ccid.S111019

20. Hon KL, Leung AK, Kong AY, Leung TF, Ip M. Atopic dermatitis complicated by methicillin-resistant Staphylococcus aureus infection. J Natl Med Assoc. 2008;100(7):797-800. doi:10.1016/s0027-9684(15)31373-0

21. Krishna S, Miller LS. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin Immunopathol. 2012;34(2):261-280. doi:10.1007/s00281-011-0292-6

22. Arashima Y, Kumasaka K, Tutchiya T, Yanai M, Kawano K. [Two cases of pasteurellosis accompanied by exudate with semen-like odor from the wound]. Kansenshogaku Zasshi. 1999;73(6):623-625. doi:10.11150/kansenshogakuzasshi1970.73.623

23. David Weber, Sheldon, L, Kaplan J. Pasteurella infections. Published 2020. https://www.uptodate.com/contents/pasteurella-infections

24. Hall JH, Callaway JL, Tindall JP, Smith Jr. JG. Pseudomonas aeruginosa in Dermatology. Arch Dermatol. 1968;97(3):312-324. doi:10.1001/archderm.1968.01610090084015

25. Dietl B, Sánchez I, Arcenillas P, et al. Ceftolozane/tazobactam in the treatment of osteomyelitis and skin and soft-tissue infections due to extensively drug-resistant Pseudomonas aeruginosa: clinical and microbiological outcomes. Int J Antimicrob Agents. 2018;51(3):498-502. doi:10.1016/j.ijantimicag.2017.11.003

26. Willis CM, Britton LE, Swindells MA, et al. Invasive melanoma in vivo can be distinguished from basal cell carcinoma, benign naevi and healthy skin by canine olfaction: a proof-of-principle study of differential volatile organic compound emission. Br J Dermatol. 2016;175(5):1020-1029. doi:10.1111/bjd.14887

27. Thuleau A, Gilbert C, Bauër P, et al. A New Transcutaneous Method for Breast Cancer Detection with Dogs. Oncology. 2019;96(2):110-113. doi:10.1159/000492895

28. Campbell LF, Farmery L, George SMC, Farrant PBJ. Canine olfactory detection of malignant melanoma. BMJ Case Rep. 2013;2013. doi:10.1136/bcr-2013-008566

29. Williams H, Pembroke A. Sniffer dogs in the melanoma clinic? Lancet (London, England). 1989;1(8640):734. doi:10.1016/s0140-6736(89)92257-5

30. Srivastava R, John JJ, Reilly C, John AM, Rao BK. Sniffing out malignant melanoma: a case of canine olfactory detection. Cutis. 2019;104(3):E4-E6.

31. Pickel D, Manucy GP, Walker DB, Hall SB, Walker JC. Evidence for canine olfactory detection of melanoma. Appl Anim Behav Sci. 2004;89(1):107-116. doi:https://doi.org/10.1016/j.applanim.2004.04.008

32. Kwak J, Gallagher M, Ozdener MH, et al. Volatile biomarkers from human melanoma cells. J Chromatogr B, Anal Technol Biomed life Sci. 2013;931:90-96. doi:10.1016/j.jchromb.2013.05.007

33. Shirasu M, Touhara K. The scent of disease: volatile organic compounds of the human body related to disease and disorder. J Biochem. 2011;150(3):257-266. doi:10.1093/jb/mvr090

34. Zemaitis MR, Foris LA, Katta S, Bashir K. Uremia. StatPearls [Internet]. Published online 2020.

35. Simenhoff ML, Burke JF, Saukkonen JJ, Ordinario AT, Doty R. Biochemical profile or uremic breath. N Engl J Med. 1977;297(3):132-135. doi:10.1056/NEJM197707212970303

36. Raina S, Chauhan V, Sharma R, Sharma R. Uremic frost. Indian Dermatol Online J. 2014;5(Suppl 1):S58. doi:10.4103/2229-5178.144545

37. Blaha T, Nigwekar S, Combs S, Kaw U, Krishnappa V, Raina R. Dermatologic manifestations in end stage renal disease. Hemodial Int. 2019;23(1):3-18. doi:10.1111/hdi.12689

38. Ghimire P, Dhamoon AS. Ketoacidosis. In: StatPearls [Internet]. StatPearls Publishing; 2019.

39. Duff M, Demidova O, Blackburn S, Shubrook J. Cutaneous manifestations of diabetes mellitus. Clin Diabetes. 2015;33(1):40-48. doi:10.2337/diaclin.33.1.40

40. Maxfield L, Crane JS. Vitamin C deficiency (scurvy). In: StatPearls [Internet]. StatPearls Publishing; 2019.

41. Graham J, Traylor J. Cyanide toxicity. Published online 2018.

42. Ratnaike RN. Acute and chronic arsenic toxicity. Postgrad Med J. 2003;79(933):391-396. doi:10.1136/pmj.79.933.391

43. Dastgiri S, Mosaferi M, Fizi MAH, et al. Arsenic exposure, dermatological lesions, hypertension, and chromosomal abnormalities among people in a rural community of northwest Iran. J Health Popul Nutr. 2010;28(1):14-22. doi:10.3329/jhpn.v28i1.4519