Infectious Diseases

Sporotrichosis is an implantation mycosis that classically manifests as a localized skin and subcutaneous fungal infection but may disseminate to other parts of the body.¹ It is caused by several species within the Sporothrix genus² and is associated with varying clinical manifestations, geographic distributions, virulence profiles, and antifungal susceptibility patterns.^3,4 Transmission of the fungus can involve inoculation from wild or domestic animals (eg, cats).^5,6 Occupations such as landscaping and gardening or elements in the environment (eg, soil, plant fragments) also can be sources of exposure.^7,8

Sporotrichosis is recognized by the World Health Organization as a neglected tropical disease that warrants global advocacy to prevent infections and improve patient outcomes.^9,10 It carries substantial stigma and socioeconomic burden.^11,12 Diagnostics, species identification, and antifungal susceptibility testing often are limited, particularly in resource-limited settings.¹³ In this article, we outline steps to diagnose and manage sporotrichosis to improve care for affected patients globally.

Epidemiology

Sporotrichosis occurs worldwide but is most common in tropical and subtropical regions.^14,15 Outbreaks and clusters of sporotrichosis have been observed across North, Central, and South America as well as in southern Africa and Asia. The estimated annual incidence is 40,000 cases worldwide,^16-20 but global case counts likely are underestimated due to limited surveillance data and diagnostic capability.²¹

On the Asian subcontinent, Sporothrix globosa is the predominant causative species of sporotrichosis, typically via contaminated plant material²²; however, at least 1 outbreak has been associated with severe flooding.²³ In Africa, infections are most commonly caused by Sporothrix schenckii sensu stricto through a similar transmission route. Across Central America, S schenckii sensu stricto is the predominant causative species; however, Sporothrix brasiliensis is the predominant species in some countries in South America, particularly Brazil.²⁰   

Data describing the current geographic distribution and prevalence of sporotrichosis in the United States are limited. Historically, the disease was reported most commonly in Midwestern states and was associated with outbreaks related to handling Sphagnum moss.^24,25 Epidemiologic studies using health insurance data indicate an average annual incidence of 2.0 cases per million individuals in the United States, with a higher prevalence among women and a median age at diagnosis of 54 years.²⁶ A review of sporotrichosis-associated hospitalizations across the United States from 2000 to 2013 indicated an average hospitalization rate of 0.35 cases per 1 million individuals; rates were higher (0.45 cases per million) in the West and lower (0.15 per million) in the Northeast and in men (0.40 per million).²⁷ Type 2 diabetes, immune-mediated inflammatory disease, and chronic obstructive pulmonary disease are associated with an increased risk for infection and hospitalization.²⁷

Causative Organisms

Sporothrix species are thermally dimorphic fungi that can grow as mold in the environment and as yeast in human tissue. Sporothrix brasiliensis is the only thermodimorphic fungus known to be transmitted directly in its yeast form.²⁸ In other species, inoculation usually occurs after contact with contaminated soil or plant material during gardening, carpentry, or agricultural practices.⁷

Zoonotic transmission of sporotrichosis from animals to humans has been reported from a range of domestic and wild animals and birds but historically has been rare.^5,7,29,30 Recently, the importance of both cat-to-cat (epizootic) and cat-to-human (zoonotic) transmission of S brasiliensis has been recognized, with infection typically following traumatic inoculation after a scratch or bite; less frequently, transmission occurs due to exposure to respiratory droplets or contact with feline exudates.^5,29,31Sporothrix brasiliensis is responsible for zoonotic epidemics in South America, primarily in Brazil. Transmission occurs among humans, cats, and canines, with felines serving as the primary vector.³² Transmission of this species is particularly common in stray and unneutered male cats that exhibit aggressive behaviors.³³ This species also is thought to be the most virulent Sporothrix species.²¹

Sporothrix brasiliensis can persist on nondisinfected inanimate surfaces, which suggests that fomite transmission can lead to human infection.³¹ The epidemiology of sporotrichosis has transformed in regions where S brasiliensis circulates, with epidemic spread resulting in thousands of cases, whereas in other areas without S brasilinesis, sporotrichosis predominantly occurs sporadically with rare clusters.^1,2,7,15

Sporotrichosis has been the subject of a taxonomic debate in the mycology community.²¹Sporothrix schenckii sensu lato originally was believed to be the sole fungal pathogen causing sporotrichosis³⁴ but was later divided into S schenckii sensu stricto, Sporothrix globosa, and S brasiliensis.³⁵ More than 60 distinct species now have been described within the Sporothrix genus,^36,37 but the primary species causing human sporotrichosis include S schenckii sensu stricto, S brasiliensis, S globosa, Sporothrix mexicana, and Sporothrix luriei.³⁵ Both S schenckii and S brasiliensis have greater virulence than other Sporothrix species⁴; however, S schenckii causes infections that typically are localized and are milder, while S brasiliensis can lead to more atypical, severe, and disseminated infections^38,39 and can spread epidemically.

Clinical Manifestations

Sporotrichosis has 4 main clinical presentations: cutaneous lymphatic, fixed cutaneous, cutaneous or systemic disseminated, and extracutaneous.^40,41 The most common clinical manifestation is the cutaneous lymphatic form, which predominantly affects the hands and forearms in adults and the face in children.⁷ The primary lesion usually manifests as a unilateral papule, nodule, or pustule that may ulcerate (sporotrichotic chancre), but multiple sites of inoculation are possible. Subsequent lesions may appear in a linear distribution along a regional lymphatic path (sporotrichoid spread). Systemic symptoms and regional lymphadenopathy are uncommon and usually are mild.

The second most common clinical manifestation is the fixed cutaneous form, typically affecting the face, neck, trunk, or legs with a single papule, nodule, or verrucous lesion with no lymphangitic spread.⁷ Usually confined to the inoculation site, the primary lesion may be accompanied by satellite lesions and often presents a diagnostic challenge.

Disseminated sporotrichosis (either cutaneous or systemic) is rare. Disseminated cutaneous sporotrichosis manifests with multiple noncontiguous skin lesions caused by lymphatic and possible hematogenous spread. Lesions may include a combination of papules, pustules, follicular eruptions, crusted plaques, and ulcers that may mimic other systemic infections. Immunoreactive changes such as erythema nodosum, erythema multiforme, or arthritis may accompany skin lesions, most commonly with S brasiliensis infections. Nearly 10% of S brasiliensis infections involve the ocular adnexa, and Parinaud oculoglandular syndrome is commonly described in cases reported in Brazil.^42,43 Disseminated disease usually occurs in immunocompromised hosts; however, despite a focus on HIV co-infection,^8,44 prior epidemiologic research has suggested that diabetes and alcoholism are the most common predisposing factors.⁴⁵ Systemic disseminated sporotrichosis by definition affects at least 2 body systems, most commonly the central nervous system, lungs, and musculoskeletal system (including joints and bone marrow).⁴⁵

Extracutaneous sporotrichosis is rare and often is difficult to diagnose. Risk factors include chronic obstructive pulmonary disease, alcoholism, use of steroid medications, AIDS, solid organ transplantation, and use of tumor necrosis factor α inhibitors. It usually affects bony structures through hematogenous spread in immunocompromised hosts and is associated with a high risk for osteomyelitis due to delayed diagnosis.²

Clinical progression of sporotrichosis usually is slow, and lesions may persist for months or years if untreated. Sporotrichosis should always be considered for atypical, persistent, or treatment-resistant manifestations of nodular or ulcerated skin lesions in endemic regions or acute illness with these symptoms following exposure. Preventing secondary bacterial infection is an important consideration as it can exacerbate disease severity, extend the treatment duration, prolong hospitalization, and increase mortality risk.⁴⁶

Diagnosis

In regions endemic for S brasiliensis, it may be acceptable to commence treatment on clinical suspicion without a definitive diagnosis,²¹ but caution is necessary, as lesions easily can be mistaken for other conditions such as Mycobacterium marinum infections (sporotrichoid lesions) or cutaneous leishmaniasis. Limited availability of molecular diagnostic tools in routine clinical laboratories affects the diagnosis of sporotrichosis and species identification. Direct microscopy on a 10% to 30% potassium hydroxide wet mount has low diagnostic sensitivity and is not recommended⁴⁷; findings typically include cigar-shaped yeast cells (eFigure 1). Biopsy and histopathology also are useful, although in many infections (other than those due to S brasiliensis) there are very few detectable organisms in the tissue. Fluorescent staining of fungi with optical brighteners (eg, Calcofluor, Blankophor) is a useful technique with high sensitivity in clinical specimens on histopathologic and direct examination.⁴⁸

Fungal culture has higher sensitivity and specificity than microscopy and is the gold-standard approach for diagnosis of sporotrichosis (eFigure 2); however, culture cannot differentiate between Sporothrix species and may take more than a month to yield a positive result.⁷ No reliable serologic test for sporotrichosis has been validated, and a standardized antigen assay currently is unavailable.⁴⁹ Serology may be more useful for patients who present with systemic disease or have persistently negative culture results despite a high index of suspicion. 

A recent study evaluated the effectiveness of a lateral flow assay for detecting anti-Sporothrix antibodies, demonstrating the potential for its use as a rapid diagnostic test.⁵⁰ Investigating different molecular methods to increase the sensitivity and specificity of diagnosis and distinguish Sporothrix species has been a focus of recent research, with a preference for polymerase chain reaction (PCR)–based genotypic methods.^13,51 Recent advances in diagnostic testing include the development of multiplex PCR,⁵² culture-independent PCR techniques,⁵³ and matrix-assisted laser desorption/ionization–time of flight mass spectrometry,⁵⁴ each with varying clinical and practical applicability. Specialized testing can be beneficial for patients who have a poor therapeutic response to standard treatment, guide antifungal treatment choices, and identify epidemiologic disease and transmission patterns.²¹

Although rarely performed, antifungal susceptibility testing may be useful in guiding therapy to improve patient outcomes, particularly in the context of treatment failure, which has been documented with isolates exhibiting high minimal inhibitory concentrations (MICs) to first-line therapy and a poor clinical response.^55,56 Proposed mechanisms of resistance include increased cellular melanin ­production, which protects against oxidative stress and reduces antifungal activity.⁵⁶ Antifungal susceptibility profiles for therapeutics vary across Sporothrix species; for example, S brasiliensis generally shows lower MICs to itraconazole and terbinafine compared with S schenckii and S globosa, and S schenckii has shown a high MIC to itraconazole, as reflected in MIC distribution studies and epidemiologic cutoff values for antifungal agents.^55,57-59 However, specific breakpoints for different Sporothrix species have not been determined.⁶⁰ Robust clinical studies are needed to determine the correlation of in vitro MICs to clinical outcomes to assess the utility of antifungal susceptibility testing for Sporothrix species.

Management

Treatment of sporotrichosis is guided by clinical presentation, host immune status, and species identification. Management can be challenging in cases with an atypical or delayed diagnosis and limited access to molecular testing methods. Itraconazole is the first-line therapy for management of cutaneous sporotrichosis. It is regarded as safe, effective, well tolerated, and easily administered, with doses ranging from 100 mg in mild cases to 400 mg (with daily or twice-daily dosing).⁶¹ Treatment usually is for 3 to 6 months and should continue for 1 month after complete clinical resolution is achieved⁶²; however, some cases of S brasiliensis infection require longer treatment, and complex or disseminated cases may require therapy for up to 12 months.⁶¹ Itraconazole is contraindicated in pregnancy and has many drug interactions (through cytochrome P450 inhibition) that may preclude administration, particularly in elderly populations. Therapeutic drug monitoring is recommended for prolonged or high-dose therapy, with periodic liver function testing to reduce the risk for toxicity. Itraconazole should be administered with food, and concurrent use of antacids or proton pump inhibitors should be avoided.⁶¹

Oral terbinafine (250 mg daily) can be considered as an effective alternative to treat cutaneous disease.⁶³ Particularly in resource-limited settings, potassium iodide is an affordable and effective treatment for cutaneous sporotrichosis, administered as a saturated oral solution,⁶⁴ but due to adverse effects such as severe nausea, the daily dose should be increased slowly each day to ensure tolerance.

Amphotericin B is the treatment of choice for severe and treatment-resistant cases of sporotrichosis as well as for immunocompromised patients.^21,61 In patients with HIV, a longer treatment course is recommended with oversight from an infectious diseases specialist and usually is followed by a 12-month course of itraconazole after completion of initial therapy.⁶¹ Surgical excision infrequently is recommended but can be used in combination with another treatment modality and may be useful with a slow or incomplete response to medical therapy. Thermotherapy involves direct application of heat to cutaneous lesions and may be considered for small and localized lesions, particularly if antifungal agents are contraindicated or poorly tolerated.⁶¹ Public health measures include promoting case detection through practitioner education and patient awareness in endemic regions, as well as zoonotic control of infected animals to manage sporotrichosis.

Final Thoughts

Sporotrichosis is a fungal infection with growing public health significance. While the global disease burden is unknown, rising case numbers and geographic spread likely reflect a complex interaction between humans, the environment, and animals, exemplified by the spread of feline-associated infection due to S brasiliensis in South America.²⁸ Cases of S brasiliensis infection after importation of an affected cat have been detected outside South America, and clinicians should be alert for introduction to the United States. Strengthening genotypic and phenotypic diagnostic capabilities will allow species identification and guide treatment and management. Disease surveillance and operational research will inform public health approaches to control sporotrichosis worldwide.

Sporotrichosis is an implantation mycosis that classically manifests as a localized skin and subcutaneous fungal infection but may disseminate to other parts of the body.¹ It is caused by several species within the Sporothrix genus² and is associated with varying clinical manifestations, geographic distributions, virulence profiles, and antifungal susceptibility patterns.^3,4 Transmission of the fungus can involve inoculation from wild or domestic animals (eg, cats).^5,6 Occupations such as landscaping and gardening or elements in the environment (eg, soil, plant fragments) also can be sources of exposure.^7,8

Sporotrichosis is recognized by the World Health Organization as a neglected tropical disease that warrants global advocacy to prevent infections and improve patient outcomes.^9,10 It carries substantial stigma and socioeconomic burden.^11,12 Diagnostics, species identification, and antifungal susceptibility testing often are limited, particularly in resource-limited settings.¹³ In this article, we outline steps to diagnose and manage sporotrichosis to improve care for affected patients globally.

Epidemiology

Sporotrichosis occurs worldwide but is most common in tropical and subtropical regions.^14,15 Outbreaks and clusters of sporotrichosis have been observed across North, Central, and South America as well as in southern Africa and Asia. The estimated annual incidence is 40,000 cases worldwide,^16-20 but global case counts likely are underestimated due to limited surveillance data and diagnostic capability.²¹

On the Asian subcontinent, Sporothrix globosa is the predominant causative species of sporotrichosis, typically via contaminated plant material²²; however, at least 1 outbreak has been associated with severe flooding.²³ In Africa, infections are most commonly caused by Sporothrix schenckii sensu stricto through a similar transmission route. Across Central America, S schenckii sensu stricto is the predominant causative species; however, Sporothrix brasiliensis is the predominant species in some countries in South America, particularly Brazil.²⁰   

Data describing the current geographic distribution and prevalence of sporotrichosis in the United States are limited. Historically, the disease was reported most commonly in Midwestern states and was associated with outbreaks related to handling Sphagnum moss.^24,25 Epidemiologic studies using health insurance data indicate an average annual incidence of 2.0 cases per million individuals in the United States, with a higher prevalence among women and a median age at diagnosis of 54 years.²⁶ A review of sporotrichosis-associated hospitalizations across the United States from 2000 to 2013 indicated an average hospitalization rate of 0.35 cases per 1 million individuals; rates were higher (0.45 cases per million) in the West and lower (0.15 per million) in the Northeast and in men (0.40 per million).²⁷ Type 2 diabetes, immune-mediated inflammatory disease, and chronic obstructive pulmonary disease are associated with an increased risk for infection and hospitalization.²⁷

Causative Organisms

Sporothrix species are thermally dimorphic fungi that can grow as mold in the environment and as yeast in human tissue. Sporothrix brasiliensis is the only thermodimorphic fungus known to be transmitted directly in its yeast form.²⁸ In other species, inoculation usually occurs after contact with contaminated soil or plant material during gardening, carpentry, or agricultural practices.⁷

Zoonotic transmission of sporotrichosis from animals to humans has been reported from a range of domestic and wild animals and birds but historically has been rare.^5,7,29,30 Recently, the importance of both cat-to-cat (epizootic) and cat-to-human (zoonotic) transmission of S brasiliensis has been recognized, with infection typically following traumatic inoculation after a scratch or bite; less frequently, transmission occurs due to exposure to respiratory droplets or contact with feline exudates.^5,29,31Sporothrix brasiliensis is responsible for zoonotic epidemics in South America, primarily in Brazil. Transmission occurs among humans, cats, and canines, with felines serving as the primary vector.³² Transmission of this species is particularly common in stray and unneutered male cats that exhibit aggressive behaviors.³³ This species also is thought to be the most virulent Sporothrix species.²¹

Sporothrix brasiliensis can persist on nondisinfected inanimate surfaces, which suggests that fomite transmission can lead to human infection.³¹ The epidemiology of sporotrichosis has transformed in regions where S brasiliensis circulates, with epidemic spread resulting in thousands of cases, whereas in other areas without S brasilinesis, sporotrichosis predominantly occurs sporadically with rare clusters.^1,2,7,15

Sporotrichosis has been the subject of a taxonomic debate in the mycology community.²¹Sporothrix schenckii sensu lato originally was believed to be the sole fungal pathogen causing sporotrichosis³⁴ but was later divided into S schenckii sensu stricto, Sporothrix globosa, and S brasiliensis.³⁵ More than 60 distinct species now have been described within the Sporothrix genus,^36,37 but the primary species causing human sporotrichosis include S schenckii sensu stricto, S brasiliensis, S globosa, Sporothrix mexicana, and Sporothrix luriei.³⁵ Both S schenckii and S brasiliensis have greater virulence than other Sporothrix species⁴; however, S schenckii causes infections that typically are localized and are milder, while S brasiliensis can lead to more atypical, severe, and disseminated infections^38,39 and can spread epidemically.

Clinical Manifestations

Sporotrichosis has 4 main clinical presentations: cutaneous lymphatic, fixed cutaneous, cutaneous or systemic disseminated, and extracutaneous.^40,41 The most common clinical manifestation is the cutaneous lymphatic form, which predominantly affects the hands and forearms in adults and the face in children.⁷ The primary lesion usually manifests as a unilateral papule, nodule, or pustule that may ulcerate (sporotrichotic chancre), but multiple sites of inoculation are possible. Subsequent lesions may appear in a linear distribution along a regional lymphatic path (sporotrichoid spread). Systemic symptoms and regional lymphadenopathy are uncommon and usually are mild.

The second most common clinical manifestation is the fixed cutaneous form, typically affecting the face, neck, trunk, or legs with a single papule, nodule, or verrucous lesion with no lymphangitic spread.⁷ Usually confined to the inoculation site, the primary lesion may be accompanied by satellite lesions and often presents a diagnostic challenge.

Disseminated sporotrichosis (either cutaneous or systemic) is rare. Disseminated cutaneous sporotrichosis manifests with multiple noncontiguous skin lesions caused by lymphatic and possible hematogenous spread. Lesions may include a combination of papules, pustules, follicular eruptions, crusted plaques, and ulcers that may mimic other systemic infections. Immunoreactive changes such as erythema nodosum, erythema multiforme, or arthritis may accompany skin lesions, most commonly with S brasiliensis infections. Nearly 10% of S brasiliensis infections involve the ocular adnexa, and Parinaud oculoglandular syndrome is commonly described in cases reported in Brazil.^42,43 Disseminated disease usually occurs in immunocompromised hosts; however, despite a focus on HIV co-infection,^8,44 prior epidemiologic research has suggested that diabetes and alcoholism are the most common predisposing factors.⁴⁵ Systemic disseminated sporotrichosis by definition affects at least 2 body systems, most commonly the central nervous system, lungs, and musculoskeletal system (including joints and bone marrow).⁴⁵

Extracutaneous sporotrichosis is rare and often is difficult to diagnose. Risk factors include chronic obstructive pulmonary disease, alcoholism, use of steroid medications, AIDS, solid organ transplantation, and use of tumor necrosis factor α inhibitors. It usually affects bony structures through hematogenous spread in immunocompromised hosts and is associated with a high risk for osteomyelitis due to delayed diagnosis.²

Clinical progression of sporotrichosis usually is slow, and lesions may persist for months or years if untreated. Sporotrichosis should always be considered for atypical, persistent, or treatment-resistant manifestations of nodular or ulcerated skin lesions in endemic regions or acute illness with these symptoms following exposure. Preventing secondary bacterial infection is an important consideration as it can exacerbate disease severity, extend the treatment duration, prolong hospitalization, and increase mortality risk.⁴⁶

Diagnosis

In regions endemic for S brasiliensis, it may be acceptable to commence treatment on clinical suspicion without a definitive diagnosis,²¹ but caution is necessary, as lesions easily can be mistaken for other conditions such as Mycobacterium marinum infections (sporotrichoid lesions) or cutaneous leishmaniasis. Limited availability of molecular diagnostic tools in routine clinical laboratories affects the diagnosis of sporotrichosis and species identification. Direct microscopy on a 10% to 30% potassium hydroxide wet mount has low diagnostic sensitivity and is not recommended⁴⁷; findings typically include cigar-shaped yeast cells (eFigure 1). Biopsy and histopathology also are useful, although in many infections (other than those due to S brasiliensis) there are very few detectable organisms in the tissue. Fluorescent staining of fungi with optical brighteners (eg, Calcofluor, Blankophor) is a useful technique with high sensitivity in clinical specimens on histopathologic and direct examination.⁴⁸

Fungal culture has higher sensitivity and specificity than microscopy and is the gold-standard approach for diagnosis of sporotrichosis (eFigure 2); however, culture cannot differentiate between Sporothrix species and may take more than a month to yield a positive result.⁷ No reliable serologic test for sporotrichosis has been validated, and a standardized antigen assay currently is unavailable.⁴⁹ Serology may be more useful for patients who present with systemic disease or have persistently negative culture results despite a high index of suspicion. 

A recent study evaluated the effectiveness of a lateral flow assay for detecting anti-Sporothrix antibodies, demonstrating the potential for its use as a rapid diagnostic test.⁵⁰ Investigating different molecular methods to increase the sensitivity and specificity of diagnosis and distinguish Sporothrix species has been a focus of recent research, with a preference for polymerase chain reaction (PCR)–based genotypic methods.^13,51 Recent advances in diagnostic testing include the development of multiplex PCR,⁵² culture-independent PCR techniques,⁵³ and matrix-assisted laser desorption/ionization–time of flight mass spectrometry,⁵⁴ each with varying clinical and practical applicability. Specialized testing can be beneficial for patients who have a poor therapeutic response to standard treatment, guide antifungal treatment choices, and identify epidemiologic disease and transmission patterns.²¹

Although rarely performed, antifungal susceptibility testing may be useful in guiding therapy to improve patient outcomes, particularly in the context of treatment failure, which has been documented with isolates exhibiting high minimal inhibitory concentrations (MICs) to first-line therapy and a poor clinical response.^55,56 Proposed mechanisms of resistance include increased cellular melanin ­production, which protects against oxidative stress and reduces antifungal activity.⁵⁶ Antifungal susceptibility profiles for therapeutics vary across Sporothrix species; for example, S brasiliensis generally shows lower MICs to itraconazole and terbinafine compared with S schenckii and S globosa, and S schenckii has shown a high MIC to itraconazole, as reflected in MIC distribution studies and epidemiologic cutoff values for antifungal agents.^55,57-59 However, specific breakpoints for different Sporothrix species have not been determined.⁶⁰ Robust clinical studies are needed to determine the correlation of in vitro MICs to clinical outcomes to assess the utility of antifungal susceptibility testing for Sporothrix species.

Management

Treatment of sporotrichosis is guided by clinical presentation, host immune status, and species identification. Management can be challenging in cases with an atypical or delayed diagnosis and limited access to molecular testing methods. Itraconazole is the first-line therapy for management of cutaneous sporotrichosis. It is regarded as safe, effective, well tolerated, and easily administered, with doses ranging from 100 mg in mild cases to 400 mg (with daily or twice-daily dosing).⁶¹ Treatment usually is for 3 to 6 months and should continue for 1 month after complete clinical resolution is achieved⁶²; however, some cases of S brasiliensis infection require longer treatment, and complex or disseminated cases may require therapy for up to 12 months.⁶¹ Itraconazole is contraindicated in pregnancy and has many drug interactions (through cytochrome P450 inhibition) that may preclude administration, particularly in elderly populations. Therapeutic drug monitoring is recommended for prolonged or high-dose therapy, with periodic liver function testing to reduce the risk for toxicity. Itraconazole should be administered with food, and concurrent use of antacids or proton pump inhibitors should be avoided.⁶¹

Oral terbinafine (250 mg daily) can be considered as an effective alternative to treat cutaneous disease.⁶³ Particularly in resource-limited settings, potassium iodide is an affordable and effective treatment for cutaneous sporotrichosis, administered as a saturated oral solution,⁶⁴ but due to adverse effects such as severe nausea, the daily dose should be increased slowly each day to ensure tolerance.

Amphotericin B is the treatment of choice for severe and treatment-resistant cases of sporotrichosis as well as for immunocompromised patients.^21,61 In patients with HIV, a longer treatment course is recommended with oversight from an infectious diseases specialist and usually is followed by a 12-month course of itraconazole after completion of initial therapy.⁶¹ Surgical excision infrequently is recommended but can be used in combination with another treatment modality and may be useful with a slow or incomplete response to medical therapy. Thermotherapy involves direct application of heat to cutaneous lesions and may be considered for small and localized lesions, particularly if antifungal agents are contraindicated or poorly tolerated.⁶¹ Public health measures include promoting case detection through practitioner education and patient awareness in endemic regions, as well as zoonotic control of infected animals to manage sporotrichosis.

Final Thoughts

Sporotrichosis is a fungal infection with growing public health significance. While the global disease burden is unknown, rising case numbers and geographic spread likely reflect a complex interaction between humans, the environment, and animals, exemplified by the spread of feline-associated infection due to S brasiliensis in South America.²⁸ Cases of S brasiliensis infection after importation of an affected cat have been detected outside South America, and clinicians should be alert for introduction to the United States. Strengthening genotypic and phenotypic diagnostic capabilities will allow species identification and guide treatment and management. Disease surveillance and operational research will inform public health approaches to control sporotrichosis worldwide.

Sporotrichosis is an implantation mycosis that classically manifests as a localized skin and subcutaneous fungal infection but may disseminate to other parts of the body.¹ It is caused by several species within the Sporothrix genus² and is associated with varying clinical manifestations, geographic distributions, virulence profiles, and antifungal susceptibility patterns.^3,4 Transmission of the fungus can involve inoculation from wild or domestic animals (eg, cats).^5,6 Occupations such as landscaping and gardening or elements in the environment (eg, soil, plant fragments) also can be sources of exposure.^7,8

Sporotrichosis is recognized by the World Health Organization as a neglected tropical disease that warrants global advocacy to prevent infections and improve patient outcomes.^9,10 It carries substantial stigma and socioeconomic burden.^11,12 Diagnostics, species identification, and antifungal susceptibility testing often are limited, particularly in resource-limited settings.¹³ In this article, we outline steps to diagnose and manage sporotrichosis to improve care for affected patients globally.

Epidemiology

Sporotrichosis occurs worldwide but is most common in tropical and subtropical regions.^14,15 Outbreaks and clusters of sporotrichosis have been observed across North, Central, and South America as well as in southern Africa and Asia. The estimated annual incidence is 40,000 cases worldwide,^16-20 but global case counts likely are underestimated due to limited surveillance data and diagnostic capability.²¹

On the Asian subcontinent, Sporothrix globosa is the predominant causative species of sporotrichosis, typically via contaminated plant material²²; however, at least 1 outbreak has been associated with severe flooding.²³ In Africa, infections are most commonly caused by Sporothrix schenckii sensu stricto through a similar transmission route. Across Central America, S schenckii sensu stricto is the predominant causative species; however, Sporothrix brasiliensis is the predominant species in some countries in South America, particularly Brazil.²⁰   

Data describing the current geographic distribution and prevalence of sporotrichosis in the United States are limited. Historically, the disease was reported most commonly in Midwestern states and was associated with outbreaks related to handling Sphagnum moss.^24,25 Epidemiologic studies using health insurance data indicate an average annual incidence of 2.0 cases per million individuals in the United States, with a higher prevalence among women and a median age at diagnosis of 54 years.²⁶ A review of sporotrichosis-associated hospitalizations across the United States from 2000 to 2013 indicated an average hospitalization rate of 0.35 cases per 1 million individuals; rates were higher (0.45 cases per million) in the West and lower (0.15 per million) in the Northeast and in men (0.40 per million).²⁷ Type 2 diabetes, immune-mediated inflammatory disease, and chronic obstructive pulmonary disease are associated with an increased risk for infection and hospitalization.²⁷

Causative Organisms

Sporothrix species are thermally dimorphic fungi that can grow as mold in the environment and as yeast in human tissue. Sporothrix brasiliensis is the only thermodimorphic fungus known to be transmitted directly in its yeast form.²⁸ In other species, inoculation usually occurs after contact with contaminated soil or plant material during gardening, carpentry, or agricultural practices.⁷

Zoonotic transmission of sporotrichosis from animals to humans has been reported from a range of domestic and wild animals and birds but historically has been rare.^5,7,29,30 Recently, the importance of both cat-to-cat (epizootic) and cat-to-human (zoonotic) transmission of S brasiliensis has been recognized, with infection typically following traumatic inoculation after a scratch or bite; less frequently, transmission occurs due to exposure to respiratory droplets or contact with feline exudates.^5,29,31Sporothrix brasiliensis is responsible for zoonotic epidemics in South America, primarily in Brazil. Transmission occurs among humans, cats, and canines, with felines serving as the primary vector.³² Transmission of this species is particularly common in stray and unneutered male cats that exhibit aggressive behaviors.³³ This species also is thought to be the most virulent Sporothrix species.²¹

Sporothrix brasiliensis can persist on nondisinfected inanimate surfaces, which suggests that fomite transmission can lead to human infection.³¹ The epidemiology of sporotrichosis has transformed in regions where S brasiliensis circulates, with epidemic spread resulting in thousands of cases, whereas in other areas without S brasilinesis, sporotrichosis predominantly occurs sporadically with rare clusters.^1,2,7,15

Sporotrichosis has been the subject of a taxonomic debate in the mycology community.²¹Sporothrix schenckii sensu lato originally was believed to be the sole fungal pathogen causing sporotrichosis³⁴ but was later divided into S schenckii sensu stricto, Sporothrix globosa, and S brasiliensis.³⁵ More than 60 distinct species now have been described within the Sporothrix genus,^36,37 but the primary species causing human sporotrichosis include S schenckii sensu stricto, S brasiliensis, S globosa, Sporothrix mexicana, and Sporothrix luriei.³⁵ Both S schenckii and S brasiliensis have greater virulence than other Sporothrix species⁴; however, S schenckii causes infections that typically are localized and are milder, while S brasiliensis can lead to more atypical, severe, and disseminated infections^38,39 and can spread epidemically.

Clinical Manifestations

Sporotrichosis has 4 main clinical presentations: cutaneous lymphatic, fixed cutaneous, cutaneous or systemic disseminated, and extracutaneous.^40,41 The most common clinical manifestation is the cutaneous lymphatic form, which predominantly affects the hands and forearms in adults and the face in children.⁷ The primary lesion usually manifests as a unilateral papule, nodule, or pustule that may ulcerate (sporotrichotic chancre), but multiple sites of inoculation are possible. Subsequent lesions may appear in a linear distribution along a regional lymphatic path (sporotrichoid spread). Systemic symptoms and regional lymphadenopathy are uncommon and usually are mild.

The second most common clinical manifestation is the fixed cutaneous form, typically affecting the face, neck, trunk, or legs with a single papule, nodule, or verrucous lesion with no lymphangitic spread.⁷ Usually confined to the inoculation site, the primary lesion may be accompanied by satellite lesions and often presents a diagnostic challenge.

Disseminated sporotrichosis (either cutaneous or systemic) is rare. Disseminated cutaneous sporotrichosis manifests with multiple noncontiguous skin lesions caused by lymphatic and possible hematogenous spread. Lesions may include a combination of papules, pustules, follicular eruptions, crusted plaques, and ulcers that may mimic other systemic infections. Immunoreactive changes such as erythema nodosum, erythema multiforme, or arthritis may accompany skin lesions, most commonly with S brasiliensis infections. Nearly 10% of S brasiliensis infections involve the ocular adnexa, and Parinaud oculoglandular syndrome is commonly described in cases reported in Brazil.^42,43 Disseminated disease usually occurs in immunocompromised hosts; however, despite a focus on HIV co-infection,^8,44 prior epidemiologic research has suggested that diabetes and alcoholism are the most common predisposing factors.⁴⁵ Systemic disseminated sporotrichosis by definition affects at least 2 body systems, most commonly the central nervous system, lungs, and musculoskeletal system (including joints and bone marrow).⁴⁵

Extracutaneous sporotrichosis is rare and often is difficult to diagnose. Risk factors include chronic obstructive pulmonary disease, alcoholism, use of steroid medications, AIDS, solid organ transplantation, and use of tumor necrosis factor α inhibitors. It usually affects bony structures through hematogenous spread in immunocompromised hosts and is associated with a high risk for osteomyelitis due to delayed diagnosis.²

Clinical progression of sporotrichosis usually is slow, and lesions may persist for months or years if untreated. Sporotrichosis should always be considered for atypical, persistent, or treatment-resistant manifestations of nodular or ulcerated skin lesions in endemic regions or acute illness with these symptoms following exposure. Preventing secondary bacterial infection is an important consideration as it can exacerbate disease severity, extend the treatment duration, prolong hospitalization, and increase mortality risk.⁴⁶

Diagnosis

In regions endemic for S brasiliensis, it may be acceptable to commence treatment on clinical suspicion without a definitive diagnosis,²¹ but caution is necessary, as lesions easily can be mistaken for other conditions such as Mycobacterium marinum infections (sporotrichoid lesions) or cutaneous leishmaniasis. Limited availability of molecular diagnostic tools in routine clinical laboratories affects the diagnosis of sporotrichosis and species identification. Direct microscopy on a 10% to 30% potassium hydroxide wet mount has low diagnostic sensitivity and is not recommended⁴⁷; findings typically include cigar-shaped yeast cells (eFigure 1). Biopsy and histopathology also are useful, although in many infections (other than those due to S brasiliensis) there are very few detectable organisms in the tissue. Fluorescent staining of fungi with optical brighteners (eg, Calcofluor, Blankophor) is a useful technique with high sensitivity in clinical specimens on histopathologic and direct examination.⁴⁸

Fungal culture has higher sensitivity and specificity than microscopy and is the gold-standard approach for diagnosis of sporotrichosis (eFigure 2); however, culture cannot differentiate between Sporothrix species and may take more than a month to yield a positive result.⁷ No reliable serologic test for sporotrichosis has been validated, and a standardized antigen assay currently is unavailable.⁴⁹ Serology may be more useful for patients who present with systemic disease or have persistently negative culture results despite a high index of suspicion. 

A recent study evaluated the effectiveness of a lateral flow assay for detecting anti-Sporothrix antibodies, demonstrating the potential for its use as a rapid diagnostic test.⁵⁰ Investigating different molecular methods to increase the sensitivity and specificity of diagnosis and distinguish Sporothrix species has been a focus of recent research, with a preference for polymerase chain reaction (PCR)–based genotypic methods.^13,51 Recent advances in diagnostic testing include the development of multiplex PCR,⁵² culture-independent PCR techniques,⁵³ and matrix-assisted laser desorption/ionization–time of flight mass spectrometry,⁵⁴ each with varying clinical and practical applicability. Specialized testing can be beneficial for patients who have a poor therapeutic response to standard treatment, guide antifungal treatment choices, and identify epidemiologic disease and transmission patterns.²¹

Although rarely performed, antifungal susceptibility testing may be useful in guiding therapy to improve patient outcomes, particularly in the context of treatment failure, which has been documented with isolates exhibiting high minimal inhibitory concentrations (MICs) to first-line therapy and a poor clinical response.^55,56 Proposed mechanisms of resistance include increased cellular melanin ­production, which protects against oxidative stress and reduces antifungal activity.⁵⁶ Antifungal susceptibility profiles for therapeutics vary across Sporothrix species; for example, S brasiliensis generally shows lower MICs to itraconazole and terbinafine compared with S schenckii and S globosa, and S schenckii has shown a high MIC to itraconazole, as reflected in MIC distribution studies and epidemiologic cutoff values for antifungal agents.^55,57-59 However, specific breakpoints for different Sporothrix species have not been determined.⁶⁰ Robust clinical studies are needed to determine the correlation of in vitro MICs to clinical outcomes to assess the utility of antifungal susceptibility testing for Sporothrix species.

Management

Treatment of sporotrichosis is guided by clinical presentation, host immune status, and species identification. Management can be challenging in cases with an atypical or delayed diagnosis and limited access to molecular testing methods. Itraconazole is the first-line therapy for management of cutaneous sporotrichosis. It is regarded as safe, effective, well tolerated, and easily administered, with doses ranging from 100 mg in mild cases to 400 mg (with daily or twice-daily dosing).⁶¹ Treatment usually is for 3 to 6 months and should continue for 1 month after complete clinical resolution is achieved⁶²; however, some cases of S brasiliensis infection require longer treatment, and complex or disseminated cases may require therapy for up to 12 months.⁶¹ Itraconazole is contraindicated in pregnancy and has many drug interactions (through cytochrome P450 inhibition) that may preclude administration, particularly in elderly populations. Therapeutic drug monitoring is recommended for prolonged or high-dose therapy, with periodic liver function testing to reduce the risk for toxicity. Itraconazole should be administered with food, and concurrent use of antacids or proton pump inhibitors should be avoided.⁶¹

Oral terbinafine (250 mg daily) can be considered as an effective alternative to treat cutaneous disease.⁶³ Particularly in resource-limited settings, potassium iodide is an affordable and effective treatment for cutaneous sporotrichosis, administered as a saturated oral solution,⁶⁴ but due to adverse effects such as severe nausea, the daily dose should be increased slowly each day to ensure tolerance.

Amphotericin B is the treatment of choice for severe and treatment-resistant cases of sporotrichosis as well as for immunocompromised patients.^21,61 In patients with HIV, a longer treatment course is recommended with oversight from an infectious diseases specialist and usually is followed by a 12-month course of itraconazole after completion of initial therapy.⁶¹ Surgical excision infrequently is recommended but can be used in combination with another treatment modality and may be useful with a slow or incomplete response to medical therapy. Thermotherapy involves direct application of heat to cutaneous lesions and may be considered for small and localized lesions, particularly if antifungal agents are contraindicated or poorly tolerated.⁶¹ Public health measures include promoting case detection through practitioner education and patient awareness in endemic regions, as well as zoonotic control of infected animals to manage sporotrichosis.

Final Thoughts

Sporotrichosis is a fungal infection with growing public health significance. While the global disease burden is unknown, rising case numbers and geographic spread likely reflect a complex interaction between humans, the environment, and animals, exemplified by the spread of feline-associated infection due to S brasiliensis in South America.²⁸ Cases of S brasiliensis infection after importation of an affected cat have been detected outside South America, and clinicians should be alert for introduction to the United States. Strengthening genotypic and phenotypic diagnostic capabilities will allow species identification and guide treatment and management. Disease surveillance and operational research will inform public health approaches to control sporotrichosis worldwide.

THE DIAGNOSIS: Kaposi Varicelliform Eruption

Genital erosions tested positive for herpes simplex virus (HSV) 2 via PCR, confirming a Kaposi varicelliform eruption (KVE) in a patient with mycosis fungoides. The medical team began antiviral therapy with intravenous (IV) acyclovir; however, susceptibility testing during the hospital admission confirmed acyclovir resistance, requiring a transition to cidofovir cream 1% and IV foscarnet.¹ Subsequent concerns by the care team about chemical burns, dysuria, and renal impairment led to discontinuation of both the cidofovir and foscarnet, considerably narrowing the treatment options.¹ The patient’s condition was complicated by polymicrobial bacteremia. Additionally, worsening acidosis and acute kidney injury required initiation of continuous renal replacement therapy.¹ Considering these conditions, the patient was enrolled in a promising clinical trial for pritelivir, a novel antiviral medication; however, due to the development of oliguria and the progression of renal failure, this course of treatment had to be discontinued. Faced with potential viral encephalitis, the infectious disease team concluded that, despite previous adverse reactions, resumption of IV foscarnet treatment would present more benefits than risks, given the patient’s critical situation.¹

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma of CD4+ cells that primarily affects the skin. Clinically, it often is characterized by pruritic scaly patches or plaques with sharply demarcated borders, the enduring nature of which consistently poses a therapeutic challenge due to their noted resistance to preliminary lines of treatment. Presently, potential cures are limited to allogeneic stem cell transplantation and unilesional radiotherapy for advanced MF; however, no treatment has been found to notably improve survival rates.¹ Mycosis fungoides can result in various complications including diffuse spread of a skin infection caused by HSV, known as KVE.¹ Kaposi varicelliform eruption usually manifests clinically with painful skin vesicles that often are accompanied by systemic signs such as fever and malaise. The vesicles rapidly progress into pustules or erosions, predominantly affecting regions such as the head, neck, groin, and upper torso (Figure 1).² Kaposi varicelliform eruption is considered a dermatologic emergency due to its potential to precipitate serious complications such as life-threatening secondary bacterial infection, HSV viremia, and multiorgan involvement; it also carries the risk of instigating ocular complications, such as keratitis, conjunctivitis, blepharitis, uveitis, and potential vision loss.²

Kaposi varicelliform eruption usually is diagnosed through clinical examination supported by polymerase chain reaction, viral culture, histopathology, HSV serology, and Tzanck smear.² The differential diagnosis includes varicella, atypical varicella, herpes genitalis, herpes zoster, allergic or irritant contact dermatitis, or MF, which may result in painful skin ulcers.^2-4 If an HSV superinfection is suspected, a polymerase chain reaction test ideally should be conducted within the first 72 hours of symptom onset.² Herpes simplex virus infection may be reinforced by histologic features such as intraepidermal blistering, acantholysis, keratinocyte ballooning degeneration, and multinuclear giant cells with intranuclear inclusions. Given its severe nature, immediate empiric antiviral treatment for KVE is essential, even while awaiting confirmatory tests. The recommended treatment protocol involves acyclovir (400 mg orally 3 times daily or 10 mg/kg IV) or valacyclovir (500 mg orally twice daily), continued until KVE resolves.²

Herpes genitalis caused by HSV-2 is estimated to affect approximately 45 million adults in the United States.² First-line treatment for HSV-2 includes acyclovir and its derivatives, which are viral nucleoside analogs that inhibit viral DNA polymerases.^5,6 However, over the past 2 decades, increasing HSV resistance to acyclovir and its derivatives has been noted among immunocompromised patients.^5,6 Second-line agents, such as IV foscarnet and cidofovir, require close laboratory monitoring for nephrotoxicity and are contraindicated in those with renal insufficiency, thus limiting their use.⁵ To combat acyclovir resistance, novel antivirals such as pritelivir are being developed. Pritelivir targets the HSV helicase-primase complex and has been shown to outperform acyclovir in in-vitro animal models.⁷ Due to its unique mechanism of action (Figure 2), pritelivir is effective against acyclovir-resistant HSV strains, and clinical trials suggest its serum half-life may allow for daily dosing. A phase 2 study showed pritelivir reduced viral shedding days, sped up genital lesion healing in adults infected with HSV-2, and exhibited a good safety profile.⁷ Our patient participated in ongoing open-label trials of pritelivir that aimed to assess its efficacy and safety in immunocompromised patients. Given the limited alternative treatments for acyclovir-resistant HSV-2, clinicians need to stay updated on antiviral agents under development.

THE DIAGNOSIS: Kaposi Varicelliform Eruption

Genital erosions tested positive for herpes simplex virus (HSV) 2 via PCR, confirming a Kaposi varicelliform eruption (KVE) in a patient with mycosis fungoides. The medical team began antiviral therapy with intravenous (IV) acyclovir; however, susceptibility testing during the hospital admission confirmed acyclovir resistance, requiring a transition to cidofovir cream 1% and IV foscarnet.¹ Subsequent concerns by the care team about chemical burns, dysuria, and renal impairment led to discontinuation of both the cidofovir and foscarnet, considerably narrowing the treatment options.¹ The patient’s condition was complicated by polymicrobial bacteremia. Additionally, worsening acidosis and acute kidney injury required initiation of continuous renal replacement therapy.¹ Considering these conditions, the patient was enrolled in a promising clinical trial for pritelivir, a novel antiviral medication; however, due to the development of oliguria and the progression of renal failure, this course of treatment had to be discontinued. Faced with potential viral encephalitis, the infectious disease team concluded that, despite previous adverse reactions, resumption of IV foscarnet treatment would present more benefits than risks, given the patient’s critical situation.¹

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma of CD4+ cells that primarily affects the skin. Clinically, it often is characterized by pruritic scaly patches or plaques with sharply demarcated borders, the enduring nature of which consistently poses a therapeutic challenge due to their noted resistance to preliminary lines of treatment. Presently, potential cures are limited to allogeneic stem cell transplantation and unilesional radiotherapy for advanced MF; however, no treatment has been found to notably improve survival rates.¹ Mycosis fungoides can result in various complications including diffuse spread of a skin infection caused by HSV, known as KVE.¹ Kaposi varicelliform eruption usually manifests clinically with painful skin vesicles that often are accompanied by systemic signs such as fever and malaise. The vesicles rapidly progress into pustules or erosions, predominantly affecting regions such as the head, neck, groin, and upper torso (Figure 1).² Kaposi varicelliform eruption is considered a dermatologic emergency due to its potential to precipitate serious complications such as life-threatening secondary bacterial infection, HSV viremia, and multiorgan involvement; it also carries the risk of instigating ocular complications, such as keratitis, conjunctivitis, blepharitis, uveitis, and potential vision loss.²

Kaposi varicelliform eruption usually is diagnosed through clinical examination supported by polymerase chain reaction, viral culture, histopathology, HSV serology, and Tzanck smear.² The differential diagnosis includes varicella, atypical varicella, herpes genitalis, herpes zoster, allergic or irritant contact dermatitis, or MF, which may result in painful skin ulcers.^2-4 If an HSV superinfection is suspected, a polymerase chain reaction test ideally should be conducted within the first 72 hours of symptom onset.² Herpes simplex virus infection may be reinforced by histologic features such as intraepidermal blistering, acantholysis, keratinocyte ballooning degeneration, and multinuclear giant cells with intranuclear inclusions. Given its severe nature, immediate empiric antiviral treatment for KVE is essential, even while awaiting confirmatory tests. The recommended treatment protocol involves acyclovir (400 mg orally 3 times daily or 10 mg/kg IV) or valacyclovir (500 mg orally twice daily), continued until KVE resolves.²

Herpes genitalis caused by HSV-2 is estimated to affect approximately 45 million adults in the United States.² First-line treatment for HSV-2 includes acyclovir and its derivatives, which are viral nucleoside analogs that inhibit viral DNA polymerases.^5,6 However, over the past 2 decades, increasing HSV resistance to acyclovir and its derivatives has been noted among immunocompromised patients.^5,6 Second-line agents, such as IV foscarnet and cidofovir, require close laboratory monitoring for nephrotoxicity and are contraindicated in those with renal insufficiency, thus limiting their use.⁵ To combat acyclovir resistance, novel antivirals such as pritelivir are being developed. Pritelivir targets the HSV helicase-primase complex and has been shown to outperform acyclovir in in-vitro animal models.⁷ Due to its unique mechanism of action (Figure 2), pritelivir is effective against acyclovir-resistant HSV strains, and clinical trials suggest its serum half-life may allow for daily dosing. A phase 2 study showed pritelivir reduced viral shedding days, sped up genital lesion healing in adults infected with HSV-2, and exhibited a good safety profile.⁷ Our patient participated in ongoing open-label trials of pritelivir that aimed to assess its efficacy and safety in immunocompromised patients. Given the limited alternative treatments for acyclovir-resistant HSV-2, clinicians need to stay updated on antiviral agents under development.

THE DIAGNOSIS: Kaposi Varicelliform Eruption

Genital erosions tested positive for herpes simplex virus (HSV) 2 via PCR, confirming a Kaposi varicelliform eruption (KVE) in a patient with mycosis fungoides. The medical team began antiviral therapy with intravenous (IV) acyclovir; however, susceptibility testing during the hospital admission confirmed acyclovir resistance, requiring a transition to cidofovir cream 1% and IV foscarnet.¹ Subsequent concerns by the care team about chemical burns, dysuria, and renal impairment led to discontinuation of both the cidofovir and foscarnet, considerably narrowing the treatment options.¹ The patient’s condition was complicated by polymicrobial bacteremia. Additionally, worsening acidosis and acute kidney injury required initiation of continuous renal replacement therapy.¹ Considering these conditions, the patient was enrolled in a promising clinical trial for pritelivir, a novel antiviral medication; however, due to the development of oliguria and the progression of renal failure, this course of treatment had to be discontinued. Faced with potential viral encephalitis, the infectious disease team concluded that, despite previous adverse reactions, resumption of IV foscarnet treatment would present more benefits than risks, given the patient’s critical situation.¹

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma of CD4+ cells that primarily affects the skin. Clinically, it often is characterized by pruritic scaly patches or plaques with sharply demarcated borders, the enduring nature of which consistently poses a therapeutic challenge due to their noted resistance to preliminary lines of treatment. Presently, potential cures are limited to allogeneic stem cell transplantation and unilesional radiotherapy for advanced MF; however, no treatment has been found to notably improve survival rates.¹ Mycosis fungoides can result in various complications including diffuse spread of a skin infection caused by HSV, known as KVE.¹ Kaposi varicelliform eruption usually manifests clinically with painful skin vesicles that often are accompanied by systemic signs such as fever and malaise. The vesicles rapidly progress into pustules or erosions, predominantly affecting regions such as the head, neck, groin, and upper torso (Figure 1).² Kaposi varicelliform eruption is considered a dermatologic emergency due to its potential to precipitate serious complications such as life-threatening secondary bacterial infection, HSV viremia, and multiorgan involvement; it also carries the risk of instigating ocular complications, such as keratitis, conjunctivitis, blepharitis, uveitis, and potential vision loss.²

Kaposi varicelliform eruption usually is diagnosed through clinical examination supported by polymerase chain reaction, viral culture, histopathology, HSV serology, and Tzanck smear.² The differential diagnosis includes varicella, atypical varicella, herpes genitalis, herpes zoster, allergic or irritant contact dermatitis, or MF, which may result in painful skin ulcers.^2-4 If an HSV superinfection is suspected, a polymerase chain reaction test ideally should be conducted within the first 72 hours of symptom onset.² Herpes simplex virus infection may be reinforced by histologic features such as intraepidermal blistering, acantholysis, keratinocyte ballooning degeneration, and multinuclear giant cells with intranuclear inclusions. Given its severe nature, immediate empiric antiviral treatment for KVE is essential, even while awaiting confirmatory tests. The recommended treatment protocol involves acyclovir (400 mg orally 3 times daily or 10 mg/kg IV) or valacyclovir (500 mg orally twice daily), continued until KVE resolves.²

Herpes genitalis caused by HSV-2 is estimated to affect approximately 45 million adults in the United States.² First-line treatment for HSV-2 includes acyclovir and its derivatives, which are viral nucleoside analogs that inhibit viral DNA polymerases.^5,6 However, over the past 2 decades, increasing HSV resistance to acyclovir and its derivatives has been noted among immunocompromised patients.^5,6 Second-line agents, such as IV foscarnet and cidofovir, require close laboratory monitoring for nephrotoxicity and are contraindicated in those with renal insufficiency, thus limiting their use.⁵ To combat acyclovir resistance, novel antivirals such as pritelivir are being developed. Pritelivir targets the HSV helicase-primase complex and has been shown to outperform acyclovir in in-vitro animal models.⁷ Due to its unique mechanism of action (Figure 2), pritelivir is effective against acyclovir-resistant HSV strains, and clinical trials suggest its serum half-life may allow for daily dosing. A phase 2 study showed pritelivir reduced viral shedding days, sped up genital lesion healing in adults infected with HSV-2, and exhibited a good safety profile.⁷ Our patient participated in ongoing open-label trials of pritelivir that aimed to assess its efficacy and safety in immunocompromised patients. Given the limited alternative treatments for acyclovir-resistant HSV-2, clinicians need to stay updated on antiviral agents under development.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

THE DIAGNOSIS: Mpox

Histologic examination demonstrated dense aggregates of necrotic cellular debris composed of karyorrhectic nuclear fragments intermixed with neutrophils, lymphocytes, and histiocytes. Eosinophilic intracytoplasmic inclusions also were observed (Figure 1). The bacterial, fungal, and mycobacterial histologic special stains and cultures were negative. Three weeks after the initial visit with dermatology, the patient was admitted to the hospital for worsening symptoms of fever, chills, and painful erythema surrounding the skin lesions. Serology and viral workup revealed a positive mpox polymerase chain reaction test, suggesting a diagnosis of mpox. Following the Centers for Disease Control and Prevention protocol, the patient was started on oral tecovirimat 200 mg twice daily for 3 weeks and intravenous infusions of cidofovir 345 mg once weekly for 2 weeks. After treatment was initiated, the skin lesions showed rapid improvement (Figure 2), and he was discharged from the hospital after finishing the second dose of cidofovir. Four months after the initial dermatology consultation, the lesions had resolved completely with residual scarring. At that time, the patient had full movement of the right eye.

Mpox virus is a member of the Poxviridae family of zoonotic viruses, which are transmitted from animals to humans. The mpox virus is brick-shaped (rectangular) and has a genome of linear double-stranded DNA encoding 180 proteins.¹ Primates and rodents are the typical host reservoirs for viral circulation of mpox.² Animal-to-human transmission occurs through direct contact with mucous membranes, bodily fluids, or tissues of an infected animal. Human-to-human transmission occurs through direct contact with infected mucous membranes, bodily fluids, respiratory droplets, and contaminated fomites.²

Symptoms typically occur within 1 week of exposure to the mpox virus. Prodromal symptoms of fever, sore throat, body aches, and headaches last for 3 days.¹ Many patients experience a facial rash that spreads to the arms and legs over a period of 2 to 4 weeks. The rash initially manifests as small papules that progress to painful pustules and vesicles measuring 0.5 to 1.0 cm in diameter.³ The mpox virus is transmitted through these skin lesions until they crust over and re-epithelialize.¹ The case fatality rate for mpox infection remains low (0.18%).⁴

Mpox outbreaks mainly were limited to central and western Africa prior to 2022. From May 17, 2022, through October 6, 2022, 26,384 cases of mpox were reported in the United States.⁵ During this outbreak, immunocompromised patients diagnosed with HIV and men who have sex with men were disproportionately affected.⁵

Due to the similarities between the smallpox virus and other orthopoxviruses, certain smallpox vaccines have been indicated for pre-exposure prophylaxis.⁶ The efficacy of prophylactic vaccination is believed to stem from the production of neutralizing antibodies that are cross-protective against other orthopoxviruses, including mpox.⁷ The 2 vaccines approved in the United States for mpox prophylaxis are JYNNEOS and ACAM2000, which are both live attenuated vaccines. Pre-exposure prophylaxis is indicated for patients at risk for severe disease, including men who have sex with men, individuals diagnosed with HIV or other immunosuppressive disorders, and individuals with recent diagnoses of one or more sexually transmitted diseases.⁸

Most mpox cases resolve within 2 to 4 weeks and only require supportive care (eg, nonsteroidal anti-inflammatory drugs, topical steroids, topical anesthetics) to treat pain.⁸ For patients at risk for severe disease, antiviral medications are warranted. Tecovirimat, brincidofovir, and cidofovir are antiviral medications used to treat smallpox that are thought to be effective against mpox.^8,9 Tecovirimat and cidofovir have been shown to be effective against mpox in animal trials, but randomized or nonrandomized trials have not been performed in humans.^9-11 Tecovirimat currently is available for the treatment of severe mpox in patients who meet the Centers for Disease Control and Prevention’s Investigational New Drug protocol; for these patients, a 200-mg course is administered orally or intravenously every 12 hours for 2 weeks.⁸

THE DIAGNOSIS: Mpox

Histologic examination demonstrated dense aggregates of necrotic cellular debris composed of karyorrhectic nuclear fragments intermixed with neutrophils, lymphocytes, and histiocytes. Eosinophilic intracytoplasmic inclusions also were observed (Figure 1). The bacterial, fungal, and mycobacterial histologic special stains and cultures were negative. Three weeks after the initial visit with dermatology, the patient was admitted to the hospital for worsening symptoms of fever, chills, and painful erythema surrounding the skin lesions. Serology and viral workup revealed a positive mpox polymerase chain reaction test, suggesting a diagnosis of mpox. Following the Centers for Disease Control and Prevention protocol, the patient was started on oral tecovirimat 200 mg twice daily for 3 weeks and intravenous infusions of cidofovir 345 mg once weekly for 2 weeks. After treatment was initiated, the skin lesions showed rapid improvement (Figure 2), and he was discharged from the hospital after finishing the second dose of cidofovir. Four months after the initial dermatology consultation, the lesions had resolved completely with residual scarring. At that time, the patient had full movement of the right eye.

Mpox virus is a member of the Poxviridae family of zoonotic viruses, which are transmitted from animals to humans. The mpox virus is brick-shaped (rectangular) and has a genome of linear double-stranded DNA encoding 180 proteins.¹ Primates and rodents are the typical host reservoirs for viral circulation of mpox.² Animal-to-human transmission occurs through direct contact with mucous membranes, bodily fluids, or tissues of an infected animal. Human-to-human transmission occurs through direct contact with infected mucous membranes, bodily fluids, respiratory droplets, and contaminated fomites.²

Symptoms typically occur within 1 week of exposure to the mpox virus. Prodromal symptoms of fever, sore throat, body aches, and headaches last for 3 days.¹ Many patients experience a facial rash that spreads to the arms and legs over a period of 2 to 4 weeks. The rash initially manifests as small papules that progress to painful pustules and vesicles measuring 0.5 to 1.0 cm in diameter.³ The mpox virus is transmitted through these skin lesions until they crust over and re-epithelialize.¹ The case fatality rate for mpox infection remains low (0.18%).⁴

Mpox outbreaks mainly were limited to central and western Africa prior to 2022. From May 17, 2022, through October 6, 2022, 26,384 cases of mpox were reported in the United States.⁵ During this outbreak, immunocompromised patients diagnosed with HIV and men who have sex with men were disproportionately affected.⁵

Due to the similarities between the smallpox virus and other orthopoxviruses, certain smallpox vaccines have been indicated for pre-exposure prophylaxis.⁶ The efficacy of prophylactic vaccination is believed to stem from the production of neutralizing antibodies that are cross-protective against other orthopoxviruses, including mpox.⁷ The 2 vaccines approved in the United States for mpox prophylaxis are JYNNEOS and ACAM2000, which are both live attenuated vaccines. Pre-exposure prophylaxis is indicated for patients at risk for severe disease, including men who have sex with men, individuals diagnosed with HIV or other immunosuppressive disorders, and individuals with recent diagnoses of one or more sexually transmitted diseases.⁸

Most mpox cases resolve within 2 to 4 weeks and only require supportive care (eg, nonsteroidal anti-inflammatory drugs, topical steroids, topical anesthetics) to treat pain.⁸ For patients at risk for severe disease, antiviral medications are warranted. Tecovirimat, brincidofovir, and cidofovir are antiviral medications used to treat smallpox that are thought to be effective against mpox.^8,9 Tecovirimat and cidofovir have been shown to be effective against mpox in animal trials, but randomized or nonrandomized trials have not been performed in humans.^9-11 Tecovirimat currently is available for the treatment of severe mpox in patients who meet the Centers for Disease Control and Prevention’s Investigational New Drug protocol; for these patients, a 200-mg course is administered orally or intravenously every 12 hours for 2 weeks.⁸

THE DIAGNOSIS: Mpox

Histologic examination demonstrated dense aggregates of necrotic cellular debris composed of karyorrhectic nuclear fragments intermixed with neutrophils, lymphocytes, and histiocytes. Eosinophilic intracytoplasmic inclusions also were observed (Figure 1). The bacterial, fungal, and mycobacterial histologic special stains and cultures were negative. Three weeks after the initial visit with dermatology, the patient was admitted to the hospital for worsening symptoms of fever, chills, and painful erythema surrounding the skin lesions. Serology and viral workup revealed a positive mpox polymerase chain reaction test, suggesting a diagnosis of mpox. Following the Centers for Disease Control and Prevention protocol, the patient was started on oral tecovirimat 200 mg twice daily for 3 weeks and intravenous infusions of cidofovir 345 mg once weekly for 2 weeks. After treatment was initiated, the skin lesions showed rapid improvement (Figure 2), and he was discharged from the hospital after finishing the second dose of cidofovir. Four months after the initial dermatology consultation, the lesions had resolved completely with residual scarring. At that time, the patient had full movement of the right eye.

Mpox virus is a member of the Poxviridae family of zoonotic viruses, which are transmitted from animals to humans. The mpox virus is brick-shaped (rectangular) and has a genome of linear double-stranded DNA encoding 180 proteins.¹ Primates and rodents are the typical host reservoirs for viral circulation of mpox.² Animal-to-human transmission occurs through direct contact with mucous membranes, bodily fluids, or tissues of an infected animal. Human-to-human transmission occurs through direct contact with infected mucous membranes, bodily fluids, respiratory droplets, and contaminated fomites.²

Symptoms typically occur within 1 week of exposure to the mpox virus. Prodromal symptoms of fever, sore throat, body aches, and headaches last for 3 days.¹ Many patients experience a facial rash that spreads to the arms and legs over a period of 2 to 4 weeks. The rash initially manifests as small papules that progress to painful pustules and vesicles measuring 0.5 to 1.0 cm in diameter.³ The mpox virus is transmitted through these skin lesions until they crust over and re-epithelialize.¹ The case fatality rate for mpox infection remains low (0.18%).⁴

Mpox outbreaks mainly were limited to central and western Africa prior to 2022. From May 17, 2022, through October 6, 2022, 26,384 cases of mpox were reported in the United States.⁵ During this outbreak, immunocompromised patients diagnosed with HIV and men who have sex with men were disproportionately affected.⁵

Due to the similarities between the smallpox virus and other orthopoxviruses, certain smallpox vaccines have been indicated for pre-exposure prophylaxis.⁶ The efficacy of prophylactic vaccination is believed to stem from the production of neutralizing antibodies that are cross-protective against other orthopoxviruses, including mpox.⁷ The 2 vaccines approved in the United States for mpox prophylaxis are JYNNEOS and ACAM2000, which are both live attenuated vaccines. Pre-exposure prophylaxis is indicated for patients at risk for severe disease, including men who have sex with men, individuals diagnosed with HIV or other immunosuppressive disorders, and individuals with recent diagnoses of one or more sexually transmitted diseases.⁸

Most mpox cases resolve within 2 to 4 weeks and only require supportive care (eg, nonsteroidal anti-inflammatory drugs, topical steroids, topical anesthetics) to treat pain.⁸ For patients at risk for severe disease, antiviral medications are warranted. Tecovirimat, brincidofovir, and cidofovir are antiviral medications used to treat smallpox that are thought to be effective against mpox.^8,9 Tecovirimat and cidofovir have been shown to be effective against mpox in animal trials, but randomized or nonrandomized trials have not been performed in humans.^9-11 Tecovirimat currently is available for the treatment of severe mpox in patients who meet the Centers for Disease Control and Prevention’s Investigational New Drug protocol; for these patients, a 200-mg course is administered orally or intravenously every 12 hours for 2 weeks.⁸

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.