Dirk M. Elston, MD

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Characteristics

The ubiquitous human flea, Pulex irritans, is a hematophagous wingless ectoparasite in the order Siphonaptera (wingless siphon) that survives by consuming the blood of its mammalian and avian hosts. Due to diseases such as the bubonic plague, fleas have claimed more victims than all the wars ever fought; in the 14th century, the Black Death caused more than 200 million deaths. Fleas fossilized in amber have been found to be 200 million years old and closely resemble the modern human flea, demonstrating the resilience of the species.

The adult human flea is a small, reddish brown, laterally compressed, wingless insect that is approximately 2- to 3.5-mm long (females, 2.5–3.5 mm; males, 2–2.5 mm) and enclosed by a tough cuticle. Compared to the dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis), P irritans has no combs or ctenidia (Figure 1). Fleas have large powerful hind legs enabling them to jump horizontally or vertically 200 times their body length (equivalent to a 6-foot human jumping 1200 feet) using stored muscle energy in a pad on the hind legs composed of the elastic protein resilin.¹ They feed off a wide variety of hosts, including humans, pigs, cats, dogs, goats, sheep, cattle, chickens, owls, foxes, rabbits, mice, and feral cats. The flea’s mouthparts are highly specialized for piercing the skin and sucking its blood meal via direct capillary cannulation.

Life Cycle

There are 4 stages of the flea life cycle: egg, larva, pupa, and adult. Most adult flea species mate on the host; the female will lay an average of 4 to 8 small white eggs on the host after each blood meal, laying more than 400 eggs during her lifetime. The eggs then drop from the host and hatch in approximately 4 to 6 days to become larvae. The active larvae feed on available organic matter in their environment, such as their parents’ feces and detritus, while undergoing 3 molts within 1 week to several months.² The larva then spins a silken cocoon from modified salivary glands to form the pupa. In favorable conditions, the pupa lasts only a few weeks; however, it can last for a year or more in unfavorable conditions. Triggers for emergence of the adult flea from the pupa include high humidity, warm temperatures, increased levels of carbon dioxide, and vibrations including sound. An adult P irritans flea can live for a few weeks to more than 1.5 years in favorable conditions of lower air temperature, high relative humidity, and access to a host.³

Related Diseases

Pulex irritans can be a vector for several human diseases. Yersinia pestis is a gram-negative bacteria that causes plague, a highly virulent disease that killed millions of people during its 3 largest human pandemics. The black rat (Rattus rattus) and the oriental rat flea (Xenopsylla cheopis) have been implicated as initial vectors; however, transmission may be human-to-human with pneumonic plague, and septicemic plague may be spread via Pulex fleas or body lice.^4,5 In 1971, Y pestis was isolated from P irritans on a dog in the home of a plague patient in Kayenta, Arizona.⁶Yersinia pestis bacterial DNA also was extracted from P irritans during a plague outbreak in Madagascar in 2014⁷ and was implicated in epidemiologic studies of plague in Tanzania from 1986 to 2004, suggesting it also plays a role in endemic disease.⁸

Bartonellosis is an emerging disease caused by different species of the gram-negative intracellular bacteria of the genus Bartonella transmitted by lice, ticks, and fleas. Bartonella quintana causes trench fever primarily transmitted by the human body louse, Pediculus humanus corporis, and resulted in more than 1 million cases during World War I. Trench fever is characterized by headache, fever, dizziness, and shin pain that lasts 1 to 3 days and recurs in cycles every 4 to 6 days. Other clinical manifestations of B quintana include chronic bacteremia, endocarditis, lymphadenopathy, and bacillary angiomatosis.⁹Bartonella henselae causes cat scratch fever, characterized by lymphadenopathy, fever, headache, joint pain, and lethargy from infected cat scratches or the bite of an infected flea. Bartonella rochalimae also has been found to cause a trench fever–like bacteremia.¹⁰Bartonella species have been found in P irritans, and the flea is implicated as a vector of bartonellosis in humans.^11-15

Rickettsioses are worldwide diseases caused by the gram-negative intracellular bacteria of the genus Rickettsia transmitted to humans via hematophagous arthropods. The rickettsiae traditionally have been classified into the spotted fever or typhus groups. The spotted fever group (ie, Rocky Mountain spotted fever, Mediterranean spotted fever) is transmitted via ticks. The typhus group is transmitted via lice (epidemic typhus) and fleas (endemic or murine typhus). Murine typhus can be caused by Rickettsia typhi in warm coastal areas around the world where the main mammal reservoir is the rat and the rat flea vector X cheopis. Clinical signs of infection are abrupt onset of fever, headaches, myalgia, malaise, and chills, with a truncal maculopapular rash progressing peripherally several days after the initial clinical signs. Rash is present in up to 50% of cases.¹⁶Rickettsia felis is an emerging flea-borne pathogen causing an acute febrile illness usually transmitted via the cat flea C felis.¹⁷Rickettsia species DNA have been found to be present in P irritans from dogs¹⁸ and livestock¹⁹ and pose a risk for causing rickettsioses in humans.

Environmental Treatment and Prevention

Flea bites present as intense, pruritic, urticarial to vesicular papules that usually are located on the lower extremities but also can be present on exposed areas of the upper extremities and hands (Figure 2). Human fleas infest clothing, and bites can be widespread. Topical antipruritics and corticosteroids can be used for controlling itch and the intense cutaneous inflammatory response. The flea host should be identified in areas of the home, school, farm, work, or local environment. House pets should be examined and treated by a veterinarian. The pet’s bedding should be washed and dried at high temperatures, and carpets and floors should be routinely vacuumed or cleaned to remove eggs, larvae, flea feces, and/or pupae. The killing of adult fleas with insecticidal products (eg, imidacloprid, fipronil, spinosad, selamectin, lufenuron, ivermectin) is the primary method of flea control. Use of insect growth regulators such as pyriproxyfen inhibits adult reproduction and blocks the organogenesis of immature larval stages via hormonal or enzymatic actions.²⁰ The combination of an insecticide and an insect growth regulator appears to be most effective in their synergistic actions against adult fleas and larvae. There have been reports of insecticidal resistance in the flea population, especially with pyrethroids.^21,22 A professional exterminator and veterinarian should be consulted. In recalcitrant cases, evaluation for other wild mammals or birds should be performed in unoccupied areas of the home such as the attic, crawl spaces, and basements, as well as inside walls.

Conclusion

The human flea, P irritans, is an important vector in the transmission of human diseases such as the bubonic plague, bartonellosis, and rickettsioses. Flea bites present as intensely pruritic, urticarial to vesicular papules that most commonly present on the lower extremities. Flea bites can be treated with topical steroids, and fleas can be controlled by a combination of insecticidal products and insect growth regulators.

Characteristics

The ubiquitous human flea, Pulex irritans, is a hematophagous wingless ectoparasite in the order Siphonaptera (wingless siphon) that survives by consuming the blood of its mammalian and avian hosts. Due to diseases such as the bubonic plague, fleas have claimed more victims than all the wars ever fought; in the 14th century, the Black Death caused more than 200 million deaths. Fleas fossilized in amber have been found to be 200 million years old and closely resemble the modern human flea, demonstrating the resilience of the species.

The adult human flea is a small, reddish brown, laterally compressed, wingless insect that is approximately 2- to 3.5-mm long (females, 2.5–3.5 mm; males, 2–2.5 mm) and enclosed by a tough cuticle. Compared to the dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis), P irritans has no combs or ctenidia (Figure 1). Fleas have large powerful hind legs enabling them to jump horizontally or vertically 200 times their body length (equivalent to a 6-foot human jumping 1200 feet) using stored muscle energy in a pad on the hind legs composed of the elastic protein resilin.¹ They feed off a wide variety of hosts, including humans, pigs, cats, dogs, goats, sheep, cattle, chickens, owls, foxes, rabbits, mice, and feral cats. The flea’s mouthparts are highly specialized for piercing the skin and sucking its blood meal via direct capillary cannulation.

Life Cycle

There are 4 stages of the flea life cycle: egg, larva, pupa, and adult. Most adult flea species mate on the host; the female will lay an average of 4 to 8 small white eggs on the host after each blood meal, laying more than 400 eggs during her lifetime. The eggs then drop from the host and hatch in approximately 4 to 6 days to become larvae. The active larvae feed on available organic matter in their environment, such as their parents’ feces and detritus, while undergoing 3 molts within 1 week to several months.² The larva then spins a silken cocoon from modified salivary glands to form the pupa. In favorable conditions, the pupa lasts only a few weeks; however, it can last for a year or more in unfavorable conditions. Triggers for emergence of the adult flea from the pupa include high humidity, warm temperatures, increased levels of carbon dioxide, and vibrations including sound. An adult P irritans flea can live for a few weeks to more than 1.5 years in favorable conditions of lower air temperature, high relative humidity, and access to a host.³

Related Diseases

Pulex irritans can be a vector for several human diseases. Yersinia pestis is a gram-negative bacteria that causes plague, a highly virulent disease that killed millions of people during its 3 largest human pandemics. The black rat (Rattus rattus) and the oriental rat flea (Xenopsylla cheopis) have been implicated as initial vectors; however, transmission may be human-to-human with pneumonic plague, and septicemic plague may be spread via Pulex fleas or body lice.^4,5 In 1971, Y pestis was isolated from P irritans on a dog in the home of a plague patient in Kayenta, Arizona.⁶Yersinia pestis bacterial DNA also was extracted from P irritans during a plague outbreak in Madagascar in 2014⁷ and was implicated in epidemiologic studies of plague in Tanzania from 1986 to 2004, suggesting it also plays a role in endemic disease.⁸

Bartonellosis is an emerging disease caused by different species of the gram-negative intracellular bacteria of the genus Bartonella transmitted by lice, ticks, and fleas. Bartonella quintana causes trench fever primarily transmitted by the human body louse, Pediculus humanus corporis, and resulted in more than 1 million cases during World War I. Trench fever is characterized by headache, fever, dizziness, and shin pain that lasts 1 to 3 days and recurs in cycles every 4 to 6 days. Other clinical manifestations of B quintana include chronic bacteremia, endocarditis, lymphadenopathy, and bacillary angiomatosis.⁹Bartonella henselae causes cat scratch fever, characterized by lymphadenopathy, fever, headache, joint pain, and lethargy from infected cat scratches or the bite of an infected flea. Bartonella rochalimae also has been found to cause a trench fever–like bacteremia.¹⁰Bartonella species have been found in P irritans, and the flea is implicated as a vector of bartonellosis in humans.^11-15

Rickettsioses are worldwide diseases caused by the gram-negative intracellular bacteria of the genus Rickettsia transmitted to humans via hematophagous arthropods. The rickettsiae traditionally have been classified into the spotted fever or typhus groups. The spotted fever group (ie, Rocky Mountain spotted fever, Mediterranean spotted fever) is transmitted via ticks. The typhus group is transmitted via lice (epidemic typhus) and fleas (endemic or murine typhus). Murine typhus can be caused by Rickettsia typhi in warm coastal areas around the world where the main mammal reservoir is the rat and the rat flea vector X cheopis. Clinical signs of infection are abrupt onset of fever, headaches, myalgia, malaise, and chills, with a truncal maculopapular rash progressing peripherally several days after the initial clinical signs. Rash is present in up to 50% of cases.¹⁶Rickettsia felis is an emerging flea-borne pathogen causing an acute febrile illness usually transmitted via the cat flea C felis.¹⁷Rickettsia species DNA have been found to be present in P irritans from dogs¹⁸ and livestock¹⁹ and pose a risk for causing rickettsioses in humans.

Environmental Treatment and Prevention

Flea bites present as intense, pruritic, urticarial to vesicular papules that usually are located on the lower extremities but also can be present on exposed areas of the upper extremities and hands (Figure 2). Human fleas infest clothing, and bites can be widespread. Topical antipruritics and corticosteroids can be used for controlling itch and the intense cutaneous inflammatory response. The flea host should be identified in areas of the home, school, farm, work, or local environment. House pets should be examined and treated by a veterinarian. The pet’s bedding should be washed and dried at high temperatures, and carpets and floors should be routinely vacuumed or cleaned to remove eggs, larvae, flea feces, and/or pupae. The killing of adult fleas with insecticidal products (eg, imidacloprid, fipronil, spinosad, selamectin, lufenuron, ivermectin) is the primary method of flea control. Use of insect growth regulators such as pyriproxyfen inhibits adult reproduction and blocks the organogenesis of immature larval stages via hormonal or enzymatic actions.²⁰ The combination of an insecticide and an insect growth regulator appears to be most effective in their synergistic actions against adult fleas and larvae. There have been reports of insecticidal resistance in the flea population, especially with pyrethroids.^21,22 A professional exterminator and veterinarian should be consulted. In recalcitrant cases, evaluation for other wild mammals or birds should be performed in unoccupied areas of the home such as the attic, crawl spaces, and basements, as well as inside walls.

Conclusion

The human flea, P irritans, is an important vector in the transmission of human diseases such as the bubonic plague, bartonellosis, and rickettsioses. Flea bites present as intensely pruritic, urticarial to vesicular papules that most commonly present on the lower extremities. Flea bites can be treated with topical steroids, and fleas can be controlled by a combination of insecticidal products and insect growth regulators.

Characteristics

The ubiquitous human flea, Pulex irritans, is a hematophagous wingless ectoparasite in the order Siphonaptera (wingless siphon) that survives by consuming the blood of its mammalian and avian hosts. Due to diseases such as the bubonic plague, fleas have claimed more victims than all the wars ever fought; in the 14th century, the Black Death caused more than 200 million deaths. Fleas fossilized in amber have been found to be 200 million years old and closely resemble the modern human flea, demonstrating the resilience of the species.

The adult human flea is a small, reddish brown, laterally compressed, wingless insect that is approximately 2- to 3.5-mm long (females, 2.5–3.5 mm; males, 2–2.5 mm) and enclosed by a tough cuticle. Compared to the dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis), P irritans has no combs or ctenidia (Figure 1). Fleas have large powerful hind legs enabling them to jump horizontally or vertically 200 times their body length (equivalent to a 6-foot human jumping 1200 feet) using stored muscle energy in a pad on the hind legs composed of the elastic protein resilin.¹ They feed off a wide variety of hosts, including humans, pigs, cats, dogs, goats, sheep, cattle, chickens, owls, foxes, rabbits, mice, and feral cats. The flea’s mouthparts are highly specialized for piercing the skin and sucking its blood meal via direct capillary cannulation.

Life Cycle

There are 4 stages of the flea life cycle: egg, larva, pupa, and adult. Most adult flea species mate on the host; the female will lay an average of 4 to 8 small white eggs on the host after each blood meal, laying more than 400 eggs during her lifetime. The eggs then drop from the host and hatch in approximately 4 to 6 days to become larvae. The active larvae feed on available organic matter in their environment, such as their parents’ feces and detritus, while undergoing 3 molts within 1 week to several months.² The larva then spins a silken cocoon from modified salivary glands to form the pupa. In favorable conditions, the pupa lasts only a few weeks; however, it can last for a year or more in unfavorable conditions. Triggers for emergence of the adult flea from the pupa include high humidity, warm temperatures, increased levels of carbon dioxide, and vibrations including sound. An adult P irritans flea can live for a few weeks to more than 1.5 years in favorable conditions of lower air temperature, high relative humidity, and access to a host.³

Related Diseases

Pulex irritans can be a vector for several human diseases. Yersinia pestis is a gram-negative bacteria that causes plague, a highly virulent disease that killed millions of people during its 3 largest human pandemics. The black rat (Rattus rattus) and the oriental rat flea (Xenopsylla cheopis) have been implicated as initial vectors; however, transmission may be human-to-human with pneumonic plague, and septicemic plague may be spread via Pulex fleas or body lice.^4,5 In 1971, Y pestis was isolated from P irritans on a dog in the home of a plague patient in Kayenta, Arizona.⁶Yersinia pestis bacterial DNA also was extracted from P irritans during a plague outbreak in Madagascar in 2014⁷ and was implicated in epidemiologic studies of plague in Tanzania from 1986 to 2004, suggesting it also plays a role in endemic disease.⁸

Bartonellosis is an emerging disease caused by different species of the gram-negative intracellular bacteria of the genus Bartonella transmitted by lice, ticks, and fleas. Bartonella quintana causes trench fever primarily transmitted by the human body louse, Pediculus humanus corporis, and resulted in more than 1 million cases during World War I. Trench fever is characterized by headache, fever, dizziness, and shin pain that lasts 1 to 3 days and recurs in cycles every 4 to 6 days. Other clinical manifestations of B quintana include chronic bacteremia, endocarditis, lymphadenopathy, and bacillary angiomatosis.⁹Bartonella henselae causes cat scratch fever, characterized by lymphadenopathy, fever, headache, joint pain, and lethargy from infected cat scratches or the bite of an infected flea. Bartonella rochalimae also has been found to cause a trench fever–like bacteremia.¹⁰Bartonella species have been found in P irritans, and the flea is implicated as a vector of bartonellosis in humans.^11-15

Rickettsioses are worldwide diseases caused by the gram-negative intracellular bacteria of the genus Rickettsia transmitted to humans via hematophagous arthropods. The rickettsiae traditionally have been classified into the spotted fever or typhus groups. The spotted fever group (ie, Rocky Mountain spotted fever, Mediterranean spotted fever) is transmitted via ticks. The typhus group is transmitted via lice (epidemic typhus) and fleas (endemic or murine typhus). Murine typhus can be caused by Rickettsia typhi in warm coastal areas around the world where the main mammal reservoir is the rat and the rat flea vector X cheopis. Clinical signs of infection are abrupt onset of fever, headaches, myalgia, malaise, and chills, with a truncal maculopapular rash progressing peripherally several days after the initial clinical signs. Rash is present in up to 50% of cases.¹⁶Rickettsia felis is an emerging flea-borne pathogen causing an acute febrile illness usually transmitted via the cat flea C felis.¹⁷Rickettsia species DNA have been found to be present in P irritans from dogs¹⁸ and livestock¹⁹ and pose a risk for causing rickettsioses in humans.

Environmental Treatment and Prevention

Flea bites present as intense, pruritic, urticarial to vesicular papules that usually are located on the lower extremities but also can be present on exposed areas of the upper extremities and hands (Figure 2). Human fleas infest clothing, and bites can be widespread. Topical antipruritics and corticosteroids can be used for controlling itch and the intense cutaneous inflammatory response. The flea host should be identified in areas of the home, school, farm, work, or local environment. House pets should be examined and treated by a veterinarian. The pet’s bedding should be washed and dried at high temperatures, and carpets and floors should be routinely vacuumed or cleaned to remove eggs, larvae, flea feces, and/or pupae. The killing of adult fleas with insecticidal products (eg, imidacloprid, fipronil, spinosad, selamectin, lufenuron, ivermectin) is the primary method of flea control. Use of insect growth regulators such as pyriproxyfen inhibits adult reproduction and blocks the organogenesis of immature larval stages via hormonal or enzymatic actions.²⁰ The combination of an insecticide and an insect growth regulator appears to be most effective in their synergistic actions against adult fleas and larvae. There have been reports of insecticidal resistance in the flea population, especially with pyrethroids.^21,22 A professional exterminator and veterinarian should be consulted. In recalcitrant cases, evaluation for other wild mammals or birds should be performed in unoccupied areas of the home such as the attic, crawl spaces, and basements, as well as inside walls.

Conclusion

The human flea, P irritans, is an important vector in the transmission of human diseases such as the bubonic plague, bartonellosis, and rickettsioses. Flea bites present as intensely pruritic, urticarial to vesicular papules that most commonly present on the lower extremities. Flea bites can be treated with topical steroids, and fleas can be controlled by a combination of insecticidal products and insect growth regulators.

A dult Siphonaptera (fleas) are highly adapted to life on the surface of their hosts. Their small 2- to 10-mm bodies are laterally flattened and wingless. They utilize particularly strong hind legs for jumping up to 150 times their body length and backward-directed spines on their legs and bodies for moving forward through fur, hair, and feathers. Xenopsylla cheopis , the oriental rat flea, lacks pronotal and genal combs and has a mesopleuron divided by internal scleritinization (Figure). These features differentiate the species from its close relatives, Ctenocephalides (cat and dog fleas), which have both sets of combs, as well as Pulex irritans (human flea), which do not have a divided mesopleuron. ^1,2

Flea-borne infections are extremely important to public health and are present throughout the world. Further, humidity and warmth are essential for the life cycle of many species of fleas. Predicted global warming likely will increase their distribution, allowing the spread of diseases they carry into previously untouched areas.¹ Therefore, it is important to continue to examine species that carry particularly dangerous pathogens, such as X cheopis.

Disease Vector

Xenopsylla cheopis primarily is known for being a vector in the transmission of Yersinia pestis, the etiologic agent of the plague. Plague occurs in 3 forms: bubonic, pneumonic, and septicemic. It has caused major epidemics throughout history, the most widely known being the Black Death, which lasted for 130 years, beginning in the 1330s in China and spreading into Europe where it wiped out one-third of the population. However, bubonic plague is thought to have caused documented outbreaks as early as 320 bce, and it still remains endemic today.^3,4

Between January 2010 and December 2015, 3248 cases of plague in humans were reported, resulting in 584 deaths worldwide.⁵ It is thought that the plague originated in Central Asia, and this area still is a focus of disease. However, the at-risk population is reduced to breeders and hunters of gerbils and marmots, the main reservoirs in the area. In Africa, 4 countries still regularly report cases, with Madagascar being the most severely affected country in the world.⁵ The Democratic Republic of the Congo, Uganda, and Tanzania also are affected. The Americas also experience the plague. There are sporadic cases of bubonic plague in the northwest corner of Peru, mostly in rural areas. In the western United States, plague circulates among wild rodents, resulting in several reported cases each year, with the most recent confirmed case noted in California in August 2020.^5,6 Further adding to its relevance, Y pestis is one of several organisms most likely to be used as a biologic weapon.^3,4

Due to the historical and continued significance of Y pestis, many studies have been performed over the decades regarding its association with X cheopis. It has been discovered that fleas transmit the bacteria to the host in 2 ways. The most well-defined form of transmission occurs after an incubation period of Y pestis in the flea for 7 to 31 days. During this time, the bacteria form a dense biofilm on a valve in the flea foregut—the proventriculus—interfering with its function, which allows regurgitation of the blood and the bacteria it contains into the bite site and consequently disease transmission. The proventriculus can become completely blocked in some fleas, preventing any blood from reaching the midgut and causing starvation. In these scenarios, the flea will make continuous attempts to feed, increasing transmission.⁷ The hemin storage gene, hms, encoding the second messenger molecule cyclic di-GMP plays a critical role in biofilm formation and proventricular blockage.⁸ The phosphoheptose isomerase gene, GmhA, also has been elucidated as crucial in late transmission due to its role in biofilm formation.⁹ Early-phase transmission, or biofilm-independent transmission, has been documented to occur as early as 3 hours after infection of the flea but can occur for up to 4 days.¹⁰ Historically, the importance of early-phase transmission has been overlooked. Research has shown that it likely is crucial to the epizootic transmission of the plague.¹⁰ As a result, the search has begun for genes that contribute to the maintenance of Y pestis in the flea vector during the first 4 days of colonization. It is thought that a key evolutionary development was the selective loss-of-function mutation in a gene essential for the activity of urease, an enzyme that causes acute oral toxicity and mortality in fleas.^11,12 The Yersinia murine toxin gene, Ymt, also allows for early survival of Y pestis in the flea midgut by producing a phospholipase D that protects the bacteria from toxic by-products produced during digestion of blood.^11,13 In addition, gene products that function in lipid A modification are crucial for the ability of Y pestis to resist the action of cationic antimicrobial peptides it produces, such as cecropin A and polymyxin B.¹³

Murine typhus, an acute febrile illness caused by Rickettsia typhi, is another disease that can be spread by oriental rat fleas. It has a worldwide distribution. In the United States, R typhi–induced rickettsia mainly is concentrated in suburban areas of Texas and California where it is thought to be mainly spread by Ctenocephalides, but it also is found in Hawaii where spread by X cheopis has been documented.^14,15 The most common symptoms of rickettsia include fever, headache, arthralgia, and a characteristic rash that is pruritic and maculopapular, starting on the trunk and spreading peripherally but sparing the palms and soles. This rash occurs about a week after the onset of fever.¹⁴Rickettsia felis also has been isolated in the oriental rat flea. However, only a handful of cases of human disease caused by this bacterium have been reported throughout the world, with clinical similarity to murine typhus likely leading to underestimation of disease prevalence.¹⁵Bartonella and other species of bacteria also have been documented to be spread by X cheopis.¹⁶ Unfortunately, the interactions of X cheopis with these other bacteria are not as well studied as its relationship with Y pestis.

Adverse Reactions

A flea bite itself can cause discomfort. It begins as a punctate hemorrhagic area that develops a surrounding wheal within 30 minutes. Over the course of 1 to 2 days, a delayed reaction occurs and there is a transition to an extremely pruritic, papular lesion. Bites often occur in clusters and can persist for weeks.¹

Prevention and Treatment

Control of host animals via extermination and proper sanitation can secondarily reduce the population of X cheopis. Direct pesticide control of the flea population also has been suggested to reduce flea-borne disease. However, insecticides cause a selective pressure on the flea population, leading to populations that are resistant to them. For example, the flea population in Madagascar developed resistance to DDT (dichlorodiphenyltrichloroethane), dieldrin, deltamethrin, and cyfluthrin after their widespread use.¹⁷ Further, a recent study revealed resistance of X cheopis populations to alphacypermethrin, lambda-cyhalothrin, and etofenprox, none of which were used in mass vector control, indicating that some cross-resistance mechanism between these and the extensively used insecticides may exist. With the development of widespread resistance to most pesticides, flea control in endemic areas is difficult. Insecticide targeting to fleas on rodents (eg, rodent bait containing insecticide) can allow for more targeted insecticide treatment, limiting the development of resistance.¹⁷ Recent development of a maceration protocol used to detect zoonotic pathogens in fleas in the field also will allow management with pesticides to be targeted geographically and temporally where infected vectors are located.¹⁸ Research of the interaction between vector, pathogen, and insect microbiome also should continue, as it may allow for development of biopesticides, limiting the use of chemical pesticides all together. The strategy is based on the introduction of microorganisms that can reduce vector lifespan or their ability to transmit pathogens.¹⁷

When flea-transmitted diseases do occur, treatment with antibiotics is advised. Early treatment of the plague with effective antibiotics such as streptomycin, gentamicin, tetracycline, or chloramphenicol for a minimum of 10 days is critical for survival. Additionally, patients with bubonic plague should be isolated for at least 2 days after administration of antibiotics, while patients with the pneumonic form should be isolated for 4 days into therapy to prevent the spread of disease. Prophylactic therapy for individuals who come into contact with infected individuals also is advised.⁴ Patients with murine typhus typically respond to doxycycline, tetracycline, or fluoroquinolones. The few cases of R felis–induced disease have responded to doxycycline. Of note, short courses of treatment of doxycycline are appropriate and safe in young children. The short (3–7 day) nature of the course limits the chances of teeth staining.¹⁴

A dult Siphonaptera (fleas) are highly adapted to life on the surface of their hosts. Their small 2- to 10-mm bodies are laterally flattened and wingless. They utilize particularly strong hind legs for jumping up to 150 times their body length and backward-directed spines on their legs and bodies for moving forward through fur, hair, and feathers. Xenopsylla cheopis , the oriental rat flea, lacks pronotal and genal combs and has a mesopleuron divided by internal scleritinization (Figure). These features differentiate the species from its close relatives, Ctenocephalides (cat and dog fleas), which have both sets of combs, as well as Pulex irritans (human flea), which do not have a divided mesopleuron. ^1,2

Flea-borne infections are extremely important to public health and are present throughout the world. Further, humidity and warmth are essential for the life cycle of many species of fleas. Predicted global warming likely will increase their distribution, allowing the spread of diseases they carry into previously untouched areas.¹ Therefore, it is important to continue to examine species that carry particularly dangerous pathogens, such as X cheopis.

Disease Vector

Xenopsylla cheopis primarily is known for being a vector in the transmission of Yersinia pestis, the etiologic agent of the plague. Plague occurs in 3 forms: bubonic, pneumonic, and septicemic. It has caused major epidemics throughout history, the most widely known being the Black Death, which lasted for 130 years, beginning in the 1330s in China and spreading into Europe where it wiped out one-third of the population. However, bubonic plague is thought to have caused documented outbreaks as early as 320 bce, and it still remains endemic today.^3,4

Between January 2010 and December 2015, 3248 cases of plague in humans were reported, resulting in 584 deaths worldwide.⁵ It is thought that the plague originated in Central Asia, and this area still is a focus of disease. However, the at-risk population is reduced to breeders and hunters of gerbils and marmots, the main reservoirs in the area. In Africa, 4 countries still regularly report cases, with Madagascar being the most severely affected country in the world.⁵ The Democratic Republic of the Congo, Uganda, and Tanzania also are affected. The Americas also experience the plague. There are sporadic cases of bubonic plague in the northwest corner of Peru, mostly in rural areas. In the western United States, plague circulates among wild rodents, resulting in several reported cases each year, with the most recent confirmed case noted in California in August 2020.^5,6 Further adding to its relevance, Y pestis is one of several organisms most likely to be used as a biologic weapon.^3,4

Due to the historical and continued significance of Y pestis, many studies have been performed over the decades regarding its association with X cheopis. It has been discovered that fleas transmit the bacteria to the host in 2 ways. The most well-defined form of transmission occurs after an incubation period of Y pestis in the flea for 7 to 31 days. During this time, the bacteria form a dense biofilm on a valve in the flea foregut—the proventriculus—interfering with its function, which allows regurgitation of the blood and the bacteria it contains into the bite site and consequently disease transmission. The proventriculus can become completely blocked in some fleas, preventing any blood from reaching the midgut and causing starvation. In these scenarios, the flea will make continuous attempts to feed, increasing transmission.⁷ The hemin storage gene, hms, encoding the second messenger molecule cyclic di-GMP plays a critical role in biofilm formation and proventricular blockage.⁸ The phosphoheptose isomerase gene, GmhA, also has been elucidated as crucial in late transmission due to its role in biofilm formation.⁹ Early-phase transmission, or biofilm-independent transmission, has been documented to occur as early as 3 hours after infection of the flea but can occur for up to 4 days.¹⁰ Historically, the importance of early-phase transmission has been overlooked. Research has shown that it likely is crucial to the epizootic transmission of the plague.¹⁰ As a result, the search has begun for genes that contribute to the maintenance of Y pestis in the flea vector during the first 4 days of colonization. It is thought that a key evolutionary development was the selective loss-of-function mutation in a gene essential for the activity of urease, an enzyme that causes acute oral toxicity and mortality in fleas.^11,12 The Yersinia murine toxin gene, Ymt, also allows for early survival of Y pestis in the flea midgut by producing a phospholipase D that protects the bacteria from toxic by-products produced during digestion of blood.^11,13 In addition, gene products that function in lipid A modification are crucial for the ability of Y pestis to resist the action of cationic antimicrobial peptides it produces, such as cecropin A and polymyxin B.¹³

Murine typhus, an acute febrile illness caused by Rickettsia typhi, is another disease that can be spread by oriental rat fleas. It has a worldwide distribution. In the United States, R typhi–induced rickettsia mainly is concentrated in suburban areas of Texas and California where it is thought to be mainly spread by Ctenocephalides, but it also is found in Hawaii where spread by X cheopis has been documented.^14,15 The most common symptoms of rickettsia include fever, headache, arthralgia, and a characteristic rash that is pruritic and maculopapular, starting on the trunk and spreading peripherally but sparing the palms and soles. This rash occurs about a week after the onset of fever.¹⁴Rickettsia felis also has been isolated in the oriental rat flea. However, only a handful of cases of human disease caused by this bacterium have been reported throughout the world, with clinical similarity to murine typhus likely leading to underestimation of disease prevalence.¹⁵Bartonella and other species of bacteria also have been documented to be spread by X cheopis.¹⁶ Unfortunately, the interactions of X cheopis with these other bacteria are not as well studied as its relationship with Y pestis.

Adverse Reactions

A flea bite itself can cause discomfort. It begins as a punctate hemorrhagic area that develops a surrounding wheal within 30 minutes. Over the course of 1 to 2 days, a delayed reaction occurs and there is a transition to an extremely pruritic, papular lesion. Bites often occur in clusters and can persist for weeks.¹

Prevention and Treatment

Control of host animals via extermination and proper sanitation can secondarily reduce the population of X cheopis. Direct pesticide control of the flea population also has been suggested to reduce flea-borne disease. However, insecticides cause a selective pressure on the flea population, leading to populations that are resistant to them. For example, the flea population in Madagascar developed resistance to DDT (dichlorodiphenyltrichloroethane), dieldrin, deltamethrin, and cyfluthrin after their widespread use.¹⁷ Further, a recent study revealed resistance of X cheopis populations to alphacypermethrin, lambda-cyhalothrin, and etofenprox, none of which were used in mass vector control, indicating that some cross-resistance mechanism between these and the extensively used insecticides may exist. With the development of widespread resistance to most pesticides, flea control in endemic areas is difficult. Insecticide targeting to fleas on rodents (eg, rodent bait containing insecticide) can allow for more targeted insecticide treatment, limiting the development of resistance.¹⁷ Recent development of a maceration protocol used to detect zoonotic pathogens in fleas in the field also will allow management with pesticides to be targeted geographically and temporally where infected vectors are located.¹⁸ Research of the interaction between vector, pathogen, and insect microbiome also should continue, as it may allow for development of biopesticides, limiting the use of chemical pesticides all together. The strategy is based on the introduction of microorganisms that can reduce vector lifespan or their ability to transmit pathogens.¹⁷

When flea-transmitted diseases do occur, treatment with antibiotics is advised. Early treatment of the plague with effective antibiotics such as streptomycin, gentamicin, tetracycline, or chloramphenicol for a minimum of 10 days is critical for survival. Additionally, patients with bubonic plague should be isolated for at least 2 days after administration of antibiotics, while patients with the pneumonic form should be isolated for 4 days into therapy to prevent the spread of disease. Prophylactic therapy for individuals who come into contact with infected individuals also is advised.⁴ Patients with murine typhus typically respond to doxycycline, tetracycline, or fluoroquinolones. The few cases of R felis–induced disease have responded to doxycycline. Of note, short courses of treatment of doxycycline are appropriate and safe in young children. The short (3–7 day) nature of the course limits the chances of teeth staining.¹⁴

A dult Siphonaptera (fleas) are highly adapted to life on the surface of their hosts. Their small 2- to 10-mm bodies are laterally flattened and wingless. They utilize particularly strong hind legs for jumping up to 150 times their body length and backward-directed spines on their legs and bodies for moving forward through fur, hair, and feathers. Xenopsylla cheopis , the oriental rat flea, lacks pronotal and genal combs and has a mesopleuron divided by internal scleritinization (Figure). These features differentiate the species from its close relatives, Ctenocephalides (cat and dog fleas), which have both sets of combs, as well as Pulex irritans (human flea), which do not have a divided mesopleuron. ^1,2

Flea-borne infections are extremely important to public health and are present throughout the world. Further, humidity and warmth are essential for the life cycle of many species of fleas. Predicted global warming likely will increase their distribution, allowing the spread of diseases they carry into previously untouched areas.¹ Therefore, it is important to continue to examine species that carry particularly dangerous pathogens, such as X cheopis.

Disease Vector

Xenopsylla cheopis primarily is known for being a vector in the transmission of Yersinia pestis, the etiologic agent of the plague. Plague occurs in 3 forms: bubonic, pneumonic, and septicemic. It has caused major epidemics throughout history, the most widely known being the Black Death, which lasted for 130 years, beginning in the 1330s in China and spreading into Europe where it wiped out one-third of the population. However, bubonic plague is thought to have caused documented outbreaks as early as 320 bce, and it still remains endemic today.^3,4

Between January 2010 and December 2015, 3248 cases of plague in humans were reported, resulting in 584 deaths worldwide.⁵ It is thought that the plague originated in Central Asia, and this area still is a focus of disease. However, the at-risk population is reduced to breeders and hunters of gerbils and marmots, the main reservoirs in the area. In Africa, 4 countries still regularly report cases, with Madagascar being the most severely affected country in the world.⁵ The Democratic Republic of the Congo, Uganda, and Tanzania also are affected. The Americas also experience the plague. There are sporadic cases of bubonic plague in the northwest corner of Peru, mostly in rural areas. In the western United States, plague circulates among wild rodents, resulting in several reported cases each year, with the most recent confirmed case noted in California in August 2020.^5,6 Further adding to its relevance, Y pestis is one of several organisms most likely to be used as a biologic weapon.^3,4

Due to the historical and continued significance of Y pestis, many studies have been performed over the decades regarding its association with X cheopis. It has been discovered that fleas transmit the bacteria to the host in 2 ways. The most well-defined form of transmission occurs after an incubation period of Y pestis in the flea for 7 to 31 days. During this time, the bacteria form a dense biofilm on a valve in the flea foregut—the proventriculus—interfering with its function, which allows regurgitation of the blood and the bacteria it contains into the bite site and consequently disease transmission. The proventriculus can become completely blocked in some fleas, preventing any blood from reaching the midgut and causing starvation. In these scenarios, the flea will make continuous attempts to feed, increasing transmission.⁷ The hemin storage gene, hms, encoding the second messenger molecule cyclic di-GMP plays a critical role in biofilm formation and proventricular blockage.⁸ The phosphoheptose isomerase gene, GmhA, also has been elucidated as crucial in late transmission due to its role in biofilm formation.⁹ Early-phase transmission, or biofilm-independent transmission, has been documented to occur as early as 3 hours after infection of the flea but can occur for up to 4 days.¹⁰ Historically, the importance of early-phase transmission has been overlooked. Research has shown that it likely is crucial to the epizootic transmission of the plague.¹⁰ As a result, the search has begun for genes that contribute to the maintenance of Y pestis in the flea vector during the first 4 days of colonization. It is thought that a key evolutionary development was the selective loss-of-function mutation in a gene essential for the activity of urease, an enzyme that causes acute oral toxicity and mortality in fleas.^11,12 The Yersinia murine toxin gene, Ymt, also allows for early survival of Y pestis in the flea midgut by producing a phospholipase D that protects the bacteria from toxic by-products produced during digestion of blood.^11,13 In addition, gene products that function in lipid A modification are crucial for the ability of Y pestis to resist the action of cationic antimicrobial peptides it produces, such as cecropin A and polymyxin B.¹³

Murine typhus, an acute febrile illness caused by Rickettsia typhi, is another disease that can be spread by oriental rat fleas. It has a worldwide distribution. In the United States, R typhi–induced rickettsia mainly is concentrated in suburban areas of Texas and California where it is thought to be mainly spread by Ctenocephalides, but it also is found in Hawaii where spread by X cheopis has been documented.^14,15 The most common symptoms of rickettsia include fever, headache, arthralgia, and a characteristic rash that is pruritic and maculopapular, starting on the trunk and spreading peripherally but sparing the palms and soles. This rash occurs about a week after the onset of fever.¹⁴Rickettsia felis also has been isolated in the oriental rat flea. However, only a handful of cases of human disease caused by this bacterium have been reported throughout the world, with clinical similarity to murine typhus likely leading to underestimation of disease prevalence.¹⁵Bartonella and other species of bacteria also have been documented to be spread by X cheopis.¹⁶ Unfortunately, the interactions of X cheopis with these other bacteria are not as well studied as its relationship with Y pestis.

Adverse Reactions

A flea bite itself can cause discomfort. It begins as a punctate hemorrhagic area that develops a surrounding wheal within 30 minutes. Over the course of 1 to 2 days, a delayed reaction occurs and there is a transition to an extremely pruritic, papular lesion. Bites often occur in clusters and can persist for weeks.¹

Prevention and Treatment

Control of host animals via extermination and proper sanitation can secondarily reduce the population of X cheopis. Direct pesticide control of the flea population also has been suggested to reduce flea-borne disease. However, insecticides cause a selective pressure on the flea population, leading to populations that are resistant to them. For example, the flea population in Madagascar developed resistance to DDT (dichlorodiphenyltrichloroethane), dieldrin, deltamethrin, and cyfluthrin after their widespread use.¹⁷ Further, a recent study revealed resistance of X cheopis populations to alphacypermethrin, lambda-cyhalothrin, and etofenprox, none of which were used in mass vector control, indicating that some cross-resistance mechanism between these and the extensively used insecticides may exist. With the development of widespread resistance to most pesticides, flea control in endemic areas is difficult. Insecticide targeting to fleas on rodents (eg, rodent bait containing insecticide) can allow for more targeted insecticide treatment, limiting the development of resistance.¹⁷ Recent development of a maceration protocol used to detect zoonotic pathogens in fleas in the field also will allow management with pesticides to be targeted geographically and temporally where infected vectors are located.¹⁸ Research of the interaction between vector, pathogen, and insect microbiome also should continue, as it may allow for development of biopesticides, limiting the use of chemical pesticides all together. The strategy is based on the introduction of microorganisms that can reduce vector lifespan or their ability to transmit pathogens.¹⁷

When flea-transmitted diseases do occur, treatment with antibiotics is advised. Early treatment of the plague with effective antibiotics such as streptomycin, gentamicin, tetracycline, or chloramphenicol for a minimum of 10 days is critical for survival. Additionally, patients with bubonic plague should be isolated for at least 2 days after administration of antibiotics, while patients with the pneumonic form should be isolated for 4 days into therapy to prevent the spread of disease. Prophylactic therapy for individuals who come into contact with infected individuals also is advised.⁴ Patients with murine typhus typically respond to doxycycline, tetracycline, or fluoroquinolones. The few cases of R felis–induced disease have responded to doxycycline. Of note, short courses of treatment of doxycycline are appropriate and safe in young children. The short (3–7 day) nature of the course limits the chances of teeth staining.¹⁴

Lepidoptera is the second largest order of the class Insecta and comprises approximately 160,000 species of butterflies and moths classified among approximately 124 families and subfamilies. Venomous properties have been identified in 12 of these families, posing a serious threat to human health. ¹

The clinical manifestations from Lepidoptera envenomation can range from general systemic symptoms such as fever and abdominal distress; to more complex focal affections including hemorrhage, ophthalmologic lesions, and irritation of the respiratory tracts; to less severe reactions of the skin, which are the most common presentation.¹

Terminology

Lepidopterism is the term used to address a clinical spectrum of systemic manifestations from direct contact with venomous butterflies or moths and/or their products.² Conversely, erucism is a term used to describe localized cutaneous reactions after direct contact with toxins from caterpillars.

Lepidopterism is derived from the Greek roots lepis, meaning scale, and pteron, meaning wing. The term erucism stems from the Latin word eruca, which means larva.²

Ideally, lepidopterism should refer solely to reactions from butterflies and moths—adult forms of insects with scaly wings—while erucism should refer to reactions from contact with caterpillars—the larval form of butterflies and moths.

In common use, lepidopterism can describe any reaction from caterpillars, moths, or adult butterflies, as well as any case of Lepidoptera exposure with only systemic manifestations, regardless of cutaneous findings. Concurrently, erucism has been defined as either any reaction from caterpillars or any skin reaction from contact with caterpillars or moths.²

Because caterpillars are the larval form of butterflies and moths, caterpillar-associated skin reactions also have been conveniently denominated caterpillar dermatitis.¹ Henceforth in this article, both terms erucism and caterpillar dermatitis are used interchangeably.

Caterpillar Envenomation

Caterpillars cause the vast majority of adverse events from lepidopteran exposures.² Envenomation by caterpillars might stand as the world’s most common envenomation given the larvae proximity to humans.³ Although involvement of internal organs (eg, renal failure), cerebral hemorrhage, and joint lesions can occur, skin manifestations are more predominant with the majority of species. Initial localized pain, edema, and erythema usually are present at the site of direct contact and subsequently progress toward maculopapular to bullous lesions, erosions, petechiae, necrosis, and ulceration depending on the offending species.^1,4

Megalopyge opercularis

In the United States, more than 50 species of caterpillars have been identified as poisonous or venomous.⁵ Megalopyge opercularis (Figure 1), the larval form of the flannel moth, is an important cause of caterpillar-associated dermatitis in the southern United States.^6,7 Megalopyge opercularis also is commonly known as the puss caterpillar, opossum bug, wooly slug, el perrito, tree asp, or Italian asp.⁶ This lepidopteran insect is mainly found in the southeastern and southcentral United States, with noted particular abundance in Texas, Louisiana, and Florida.^6,8 The puss caterpillar has 2 generations per year; the first develops during the months of June to July, and the second develops from September to October, carrying seasonal health hazards.^6,8

Megalopyge opercularis is tapered at the ends and can measure 2.5 to 3.5×1 cm at maturity. It is covered by silky, long-streaked, wavy hairs that may appear single colored or as a mix of colors—from white to gray to brown—forming a mid-dorsal crest.⁶ Beneath this furry coat, rows of short sharp spines are hidden. Upon contact with the human skin, these spines will break and discharge venom.^1,6,8 Toxins contained within the hollow spines are thought to be produced by specialized basal cells, but there still is little knowledge about the dynamics and composition of the venom.¹

Clinical Manifestations

The severity of the reaction depends on the caterpillar’s size and the extent of contact.^1,4 Contact with M opercularis instantly presents with a throbbing or burning pain that may be followed by localized erythema and rash.^1,6 A characteristic gridlike pattern of erythematous macules develops, reflecting each site of puncture from the insect’s spines (Figure 2).^8,9 Skin lesions can progress from erythematous macules to hemorrhagic vesicles or pustules, usually self-resolving after a few days. The reaction also can present with radiating pain to regional lymph nodes and numbness of the affected area.^1,6,8 Moreover, some patients may report urticaria and pruritus.⁹

Envenomation by a puss caterpillar also can present with systemic manifestations including fever, headache, nausea, vomiting, shocklike symptoms, and seizures.^1,6,7 Anaphylactic reaction is rare but also can present.⁷ Uncommon cases have been reported with severe abdominal pain and muscle spasm mimicking acute appendicitis and latrodectism, respectively.^7,9

Diagnosis

The diagnosis of M opercularis envenomation is made clinically based on the morphology of the skin lesions and a history of probable exposure. Coexistent leukocytosis is likely, but laboratory testing is not warranted, as it is both nonspecific and insensitive.⁹

Management/Treatment

The most commonly reported immediate approaches to treatment involve attempts to remove the spines from the skin with tape (stripping), application of ice packs over the affected area, oral antihistamines, topical and intralesional anesthetics, regional nerve block, and oral analgesics.^6,9 There have been several cases detailing the successful use of parenteral calcium gluconate,^5,7 and diazepam has been used to treat severe muscle spasms. Anaphylactic reactions should be managed in a controlled monitored setting with subcutaneous epinephrine.⁷ Despite their common use, some data suggest that ice packs and mid- to high-potency topical steroids are ineffective.⁹

Incidence

From 2001 to 2005, a mean average of 94,552 annual cases of animal bites and stings were reported to poison control centers in the United States, of which 2094 were linked to caterpillars in this 5-year period.¹⁰ There were 3484 M opercularis caterpillar stings reported to the Texas Poison Center Network from 2000 to 2016.^5,6 Given their ability to sting throughout their life cycle, thousands of M opercularis caterpillar stings can occur each year.^1,6 Existing literature on M opercularis caterpillar stings mainly involves case reports with affections of the skin and oral mucosa, self-reported envenomation, and case studies.^5,6,8

Although multiple health concerns associated with caterpillar envenomation have been reported worldwide, the lack of official epidemiologic reports highly suggests that this problem remains underestimated. There also may be many unreported cases because certain reactions are mild or self-limited and can even go unnoticed.¹¹ Nonetheless, there is an evident rise of cases reported in the United States. According to the 2018 annual report of the American Association of Poison Control Centers, there were 2815 case mentions from caterpillar envenomation.¹²

In 1921 and 1952, some public schools in Texas were temporarily closed due to outbreaks of puss caterpillar–associated dermatitis.⁸ Similar outbreaks also have been reported in South Carolina, Virginia, and Oklahoma.⁹ Emerging data suggest that plant oil products and the pesticide cypermethrin may be helpful in controlling local infestations of the puss caterpillar.⁸

Lepidoptera is the second largest order of the class Insecta and comprises approximately 160,000 species of butterflies and moths classified among approximately 124 families and subfamilies. Venomous properties have been identified in 12 of these families, posing a serious threat to human health. ¹

The clinical manifestations from Lepidoptera envenomation can range from general systemic symptoms such as fever and abdominal distress; to more complex focal affections including hemorrhage, ophthalmologic lesions, and irritation of the respiratory tracts; to less severe reactions of the skin, which are the most common presentation.¹

Terminology

Lepidopterism is the term used to address a clinical spectrum of systemic manifestations from direct contact with venomous butterflies or moths and/or their products.² Conversely, erucism is a term used to describe localized cutaneous reactions after direct contact with toxins from caterpillars.

Lepidopterism is derived from the Greek roots lepis, meaning scale, and pteron, meaning wing. The term erucism stems from the Latin word eruca, which means larva.²

Ideally, lepidopterism should refer solely to reactions from butterflies and moths—adult forms of insects with scaly wings—while erucism should refer to reactions from contact with caterpillars—the larval form of butterflies and moths.

In common use, lepidopterism can describe any reaction from caterpillars, moths, or adult butterflies, as well as any case of Lepidoptera exposure with only systemic manifestations, regardless of cutaneous findings. Concurrently, erucism has been defined as either any reaction from caterpillars or any skin reaction from contact with caterpillars or moths.²

Because caterpillars are the larval form of butterflies and moths, caterpillar-associated skin reactions also have been conveniently denominated caterpillar dermatitis.¹ Henceforth in this article, both terms erucism and caterpillar dermatitis are used interchangeably.

Caterpillar Envenomation

Caterpillars cause the vast majority of adverse events from lepidopteran exposures.² Envenomation by caterpillars might stand as the world’s most common envenomation given the larvae proximity to humans.³ Although involvement of internal organs (eg, renal failure), cerebral hemorrhage, and joint lesions can occur, skin manifestations are more predominant with the majority of species. Initial localized pain, edema, and erythema usually are present at the site of direct contact and subsequently progress toward maculopapular to bullous lesions, erosions, petechiae, necrosis, and ulceration depending on the offending species.^1,4

Megalopyge opercularis

In the United States, more than 50 species of caterpillars have been identified as poisonous or venomous.⁵ Megalopyge opercularis (Figure 1), the larval form of the flannel moth, is an important cause of caterpillar-associated dermatitis in the southern United States.^6,7 Megalopyge opercularis also is commonly known as the puss caterpillar, opossum bug, wooly slug, el perrito, tree asp, or Italian asp.⁶ This lepidopteran insect is mainly found in the southeastern and southcentral United States, with noted particular abundance in Texas, Louisiana, and Florida.^6,8 The puss caterpillar has 2 generations per year; the first develops during the months of June to July, and the second develops from September to October, carrying seasonal health hazards.^6,8

Megalopyge opercularis is tapered at the ends and can measure 2.5 to 3.5×1 cm at maturity. It is covered by silky, long-streaked, wavy hairs that may appear single colored or as a mix of colors—from white to gray to brown—forming a mid-dorsal crest.⁶ Beneath this furry coat, rows of short sharp spines are hidden. Upon contact with the human skin, these spines will break and discharge venom.^1,6,8 Toxins contained within the hollow spines are thought to be produced by specialized basal cells, but there still is little knowledge about the dynamics and composition of the venom.¹

Clinical Manifestations

The severity of the reaction depends on the caterpillar’s size and the extent of contact.^1,4 Contact with M opercularis instantly presents with a throbbing or burning pain that may be followed by localized erythema and rash.^1,6 A characteristic gridlike pattern of erythematous macules develops, reflecting each site of puncture from the insect’s spines (Figure 2).^8,9 Skin lesions can progress from erythematous macules to hemorrhagic vesicles or pustules, usually self-resolving after a few days. The reaction also can present with radiating pain to regional lymph nodes and numbness of the affected area.^1,6,8 Moreover, some patients may report urticaria and pruritus.⁹

Envenomation by a puss caterpillar also can present with systemic manifestations including fever, headache, nausea, vomiting, shocklike symptoms, and seizures.^1,6,7 Anaphylactic reaction is rare but also can present.⁷ Uncommon cases have been reported with severe abdominal pain and muscle spasm mimicking acute appendicitis and latrodectism, respectively.^7,9

Diagnosis

The diagnosis of M opercularis envenomation is made clinically based on the morphology of the skin lesions and a history of probable exposure. Coexistent leukocytosis is likely, but laboratory testing is not warranted, as it is both nonspecific and insensitive.⁹

Management/Treatment

The most commonly reported immediate approaches to treatment involve attempts to remove the spines from the skin with tape (stripping), application of ice packs over the affected area, oral antihistamines, topical and intralesional anesthetics, regional nerve block, and oral analgesics.^6,9 There have been several cases detailing the successful use of parenteral calcium gluconate,^5,7 and diazepam has been used to treat severe muscle spasms. Anaphylactic reactions should be managed in a controlled monitored setting with subcutaneous epinephrine.⁷ Despite their common use, some data suggest that ice packs and mid- to high-potency topical steroids are ineffective.⁹

Incidence

From 2001 to 2005, a mean average of 94,552 annual cases of animal bites and stings were reported to poison control centers in the United States, of which 2094 were linked to caterpillars in this 5-year period.¹⁰ There were 3484 M opercularis caterpillar stings reported to the Texas Poison Center Network from 2000 to 2016.^5,6 Given their ability to sting throughout their life cycle, thousands of M opercularis caterpillar stings can occur each year.^1,6 Existing literature on M opercularis caterpillar stings mainly involves case reports with affections of the skin and oral mucosa, self-reported envenomation, and case studies.^5,6,8

Although multiple health concerns associated with caterpillar envenomation have been reported worldwide, the lack of official epidemiologic reports highly suggests that this problem remains underestimated. There also may be many unreported cases because certain reactions are mild or self-limited and can even go unnoticed.¹¹ Nonetheless, there is an evident rise of cases reported in the United States. According to the 2018 annual report of the American Association of Poison Control Centers, there were 2815 case mentions from caterpillar envenomation.¹²

In 1921 and 1952, some public schools in Texas were temporarily closed due to outbreaks of puss caterpillar–associated dermatitis.⁸ Similar outbreaks also have been reported in South Carolina, Virginia, and Oklahoma.⁹ Emerging data suggest that plant oil products and the pesticide cypermethrin may be helpful in controlling local infestations of the puss caterpillar.⁸

Lepidoptera is the second largest order of the class Insecta and comprises approximately 160,000 species of butterflies and moths classified among approximately 124 families and subfamilies. Venomous properties have been identified in 12 of these families, posing a serious threat to human health. ¹

The clinical manifestations from Lepidoptera envenomation can range from general systemic symptoms such as fever and abdominal distress; to more complex focal affections including hemorrhage, ophthalmologic lesions, and irritation of the respiratory tracts; to less severe reactions of the skin, which are the most common presentation.¹

Terminology

Lepidopterism is the term used to address a clinical spectrum of systemic manifestations from direct contact with venomous butterflies or moths and/or their products.² Conversely, erucism is a term used to describe localized cutaneous reactions after direct contact with toxins from caterpillars.

Lepidopterism is derived from the Greek roots lepis, meaning scale, and pteron, meaning wing. The term erucism stems from the Latin word eruca, which means larva.²

Ideally, lepidopterism should refer solely to reactions from butterflies and moths—adult forms of insects with scaly wings—while erucism should refer to reactions from contact with caterpillars—the larval form of butterflies and moths.

In common use, lepidopterism can describe any reaction from caterpillars, moths, or adult butterflies, as well as any case of Lepidoptera exposure with only systemic manifestations, regardless of cutaneous findings. Concurrently, erucism has been defined as either any reaction from caterpillars or any skin reaction from contact with caterpillars or moths.²

Because caterpillars are the larval form of butterflies and moths, caterpillar-associated skin reactions also have been conveniently denominated caterpillar dermatitis.¹ Henceforth in this article, both terms erucism and caterpillar dermatitis are used interchangeably.

Caterpillar Envenomation

Caterpillars cause the vast majority of adverse events from lepidopteran exposures.² Envenomation by caterpillars might stand as the world’s most common envenomation given the larvae proximity to humans.³ Although involvement of internal organs (eg, renal failure), cerebral hemorrhage, and joint lesions can occur, skin manifestations are more predominant with the majority of species. Initial localized pain, edema, and erythema usually are present at the site of direct contact and subsequently progress toward maculopapular to bullous lesions, erosions, petechiae, necrosis, and ulceration depending on the offending species.^1,4

Megalopyge opercularis

In the United States, more than 50 species of caterpillars have been identified as poisonous or venomous.⁵ Megalopyge opercularis (Figure 1), the larval form of the flannel moth, is an important cause of caterpillar-associated dermatitis in the southern United States.^6,7 Megalopyge opercularis also is commonly known as the puss caterpillar, opossum bug, wooly slug, el perrito, tree asp, or Italian asp.⁶ This lepidopteran insect is mainly found in the southeastern and southcentral United States, with noted particular abundance in Texas, Louisiana, and Florida.^6,8 The puss caterpillar has 2 generations per year; the first develops during the months of June to July, and the second develops from September to October, carrying seasonal health hazards.^6,8

Megalopyge opercularis is tapered at the ends and can measure 2.5 to 3.5×1 cm at maturity. It is covered by silky, long-streaked, wavy hairs that may appear single colored or as a mix of colors—from white to gray to brown—forming a mid-dorsal crest.⁶ Beneath this furry coat, rows of short sharp spines are hidden. Upon contact with the human skin, these spines will break and discharge venom.^1,6,8 Toxins contained within the hollow spines are thought to be produced by specialized basal cells, but there still is little knowledge about the dynamics and composition of the venom.¹

Clinical Manifestations

The severity of the reaction depends on the caterpillar’s size and the extent of contact.^1,4 Contact with M opercularis instantly presents with a throbbing or burning pain that may be followed by localized erythema and rash.^1,6 A characteristic gridlike pattern of erythematous macules develops, reflecting each site of puncture from the insect’s spines (Figure 2).^8,9 Skin lesions can progress from erythematous macules to hemorrhagic vesicles or pustules, usually self-resolving after a few days. The reaction also can present with radiating pain to regional lymph nodes and numbness of the affected area.^1,6,8 Moreover, some patients may report urticaria and pruritus.⁹

Envenomation by a puss caterpillar also can present with systemic manifestations including fever, headache, nausea, vomiting, shocklike symptoms, and seizures.^1,6,7 Anaphylactic reaction is rare but also can present.⁷ Uncommon cases have been reported with severe abdominal pain and muscle spasm mimicking acute appendicitis and latrodectism, respectively.^7,9

Diagnosis

The diagnosis of M opercularis envenomation is made clinically based on the morphology of the skin lesions and a history of probable exposure. Coexistent leukocytosis is likely, but laboratory testing is not warranted, as it is both nonspecific and insensitive.⁹

Management/Treatment

The most commonly reported immediate approaches to treatment involve attempts to remove the spines from the skin with tape (stripping), application of ice packs over the affected area, oral antihistamines, topical and intralesional anesthetics, regional nerve block, and oral analgesics.^6,9 There have been several cases detailing the successful use of parenteral calcium gluconate,^5,7 and diazepam has been used to treat severe muscle spasms. Anaphylactic reactions should be managed in a controlled monitored setting with subcutaneous epinephrine.⁷ Despite their common use, some data suggest that ice packs and mid- to high-potency topical steroids are ineffective.⁹

Incidence

From 2001 to 2005, a mean average of 94,552 annual cases of animal bites and stings were reported to poison control centers in the United States, of which 2094 were linked to caterpillars in this 5-year period.¹⁰ There were 3484 M opercularis caterpillar stings reported to the Texas Poison Center Network from 2000 to 2016.^5,6 Given their ability to sting throughout their life cycle, thousands of M opercularis caterpillar stings can occur each year.^1,6 Existing literature on M opercularis caterpillar stings mainly involves case reports with affections of the skin and oral mucosa, self-reported envenomation, and case studies.^5,6,8

Although multiple health concerns associated with caterpillar envenomation have been reported worldwide, the lack of official epidemiologic reports highly suggests that this problem remains underestimated. There also may be many unreported cases because certain reactions are mild or self-limited and can even go unnoticed.¹¹ Nonetheless, there is an evident rise of cases reported in the United States. According to the 2018 annual report of the American Association of Poison Control Centers, there were 2815 case mentions from caterpillar envenomation.¹²

In 1921 and 1952, some public schools in Texas were temporarily closed due to outbreaks of puss caterpillar–associated dermatitis.⁸ Similar outbreaks also have been reported in South Carolina, Virginia, and Oklahoma.⁹ Emerging data suggest that plant oil products and the pesticide cypermethrin may be helpful in controlling local infestations of the puss caterpillar.⁸

Epidemiology and Identification

Centruroides is a common genus of bark scorpions in the United States with at least 21 species considered to be medically important, including the closely related Centruroides exilicauda and Centruroides sculpturatus.¹ Scorpions can be recognized by a bulbous sac and pointed stinger at the end of a tail-like abdomen. They also have long lobsterlike pedipalps (pincers) for grasping their prey. Identifying characteristics for C exilicauda and C sculpturatus include a small, slender, yellow to light brown or tan body typically measuring 1.3 to 7.6 cm in length with a subaculear tooth or tubercle at the base of the stinger, a characteristic that is common to all Centruroides species (Figure).² Some variability in size has been shown, with smaller scorpions found in increased elevations and cooler temperatures.^1,3 Both C exilicauda and C sculpturatus are found in northern Mexico as well as the southwestern United States (eg, Arizona, New Mexico, Texas, California, Nevada).¹ They have a preference for residing in or around trees and often are found on the underside of bark, stones, or tables as well as inside shoes or small cracks and crevices. Scorpions typically sting in self-defense, and stings commonly occur when humans attempt to move tables, put on shoes, or walk barefoot in scorpion-infested areas. Most stings occur from the end of spring through the end summer, but many may go unreported.^1,4

The venom of the Centruroides genus includes peptides and proteins that play a fundamental role in toxic activity by impairing potassium, sodium, and calcium ion channels.^1,3 Toxins have been shown to be species specific, functioning either in capturing prey or deterring predators. Intraspecies variability in toxins has been demonstrated, which may complicate the production of adequate antivenin.³ Many have thought that C exilicauda Wood and C sculpturatus Ewing are the same species, and the names have been used synonymously in the past; however, genetic and biochemical studies of their venom components have shown that they are distinct species and that C sculpturatus is the more dangerous of the two.⁵ The median lethal dose 50% of C sculpturatus was found to be 22.7 μg in CD1 mice.⁶

Envenomation and Clinical Manifestations

Stings from C exilicauda and C sculpturatus have been shown to cause fatality in children more often than in adults.⁷ In the United States, Arizona has the highest frequency of serious symptoms of envenomation as well as the highest hospital and intensive care unit admission rates.⁶ Envenomation results in an immediate sharp burning pain followed by numbness.⁴ Wounds can produce some regional lymph node swelling, ecchymosis, paresthesia, and lymphangitis. More often than not, however, wounds have little to no inflammation and are characterized only by pain.⁴ The puncture wound is too small to be seen, and C exilicauda and C sculpturatus venom do not cause local tissue destruction, an important factor in distinguishing it from other scorpion envenomations.

More severe complications that may follow are caused by the neurotoxin released by Centruroides stings. The toxin components can increase the duration and amplitude of the neuronal action potential and enhance the release of neurotransmitters such as acetylcholine and norepinephrine.⁸ Stings can lead to cranial nerve dysfunction and somatic skeletal neuromuscular dysfunction as well as autonomic dysfunction, specifically salivation, fever, tongue and muscle fasciculations, opsoclonus, vomiting, bronchoconstriction, diaphoresis, nystagmus, blurred vision, slurred speech, hypertension, rhabdomyolysis, stridor, wheezing, aspiration, anaphylaxis, and tachycardia, leading to cardiac and respiratory compromise.^4,8 Some patients have experienced a decreased sense of smell or hearing and decreased fine motor movements.⁷ Although pancreatitis may occur with scorpion stings, it is not common for C exilicauda.⁹ Comorbidities such as cardiac disease and substance use disorders contribute to prolonged length of hospital stay and poor outcome.⁸

Treatment

Most Centruroides stings can be managed at home, but patients with more serious symptoms and children younger than 2 years should be taken to a hospital for treatment.⁷ If a patient reports only pain but shows no other signs of neurotoxicity, observation and pain relief with rest, ice, and elevation is appropriate management. Patients with severe manifestations have been treated with various combinations of lorazepam, glycopyrrolate, ipratropium bromide, and ondansetron, but the only treatment definitively shown to decrease time to symptom abatement is antivenin.⁷ It has been demonstrated that C exilicauda and C sculpturatus antivenin is relatively safe.⁷ Most patients, especially adults, do not die from C exilicauda and C sculpturatus stings; therefore, antivenin more commonly is symptom abating than it is lifesaving.¹⁰ In children, time to symptom resolution was decreased to fewer than 4 hours with antivenin, and there is a lower rate of inpatient admission when antivenin is administered.^4,10,11 There is a low incidence of anaphylactic reaction after antivenin, but there have been reported cases of self-limited serum sickness after antivenin use that generally can be managed with antihistamines and corticosteroids.^4,7

Epidemiology and Identification

Centruroides is a common genus of bark scorpions in the United States with at least 21 species considered to be medically important, including the closely related Centruroides exilicauda and Centruroides sculpturatus.¹ Scorpions can be recognized by a bulbous sac and pointed stinger at the end of a tail-like abdomen. They also have long lobsterlike pedipalps (pincers) for grasping their prey. Identifying characteristics for C exilicauda and C sculpturatus include a small, slender, yellow to light brown or tan body typically measuring 1.3 to 7.6 cm in length with a subaculear tooth or tubercle at the base of the stinger, a characteristic that is common to all Centruroides species (Figure).² Some variability in size has been shown, with smaller scorpions found in increased elevations and cooler temperatures.^1,3 Both C exilicauda and C sculpturatus are found in northern Mexico as well as the southwestern United States (eg, Arizona, New Mexico, Texas, California, Nevada).¹ They have a preference for residing in or around trees and often are found on the underside of bark, stones, or tables as well as inside shoes or small cracks and crevices. Scorpions typically sting in self-defense, and stings commonly occur when humans attempt to move tables, put on shoes, or walk barefoot in scorpion-infested areas. Most stings occur from the end of spring through the end summer, but many may go unreported.^1,4

The venom of the Centruroides genus includes peptides and proteins that play a fundamental role in toxic activity by impairing potassium, sodium, and calcium ion channels.^1,3 Toxins have been shown to be species specific, functioning either in capturing prey or deterring predators. Intraspecies variability in toxins has been demonstrated, which may complicate the production of adequate antivenin.³ Many have thought that C exilicauda Wood and C sculpturatus Ewing are the same species, and the names have been used synonymously in the past; however, genetic and biochemical studies of their venom components have shown that they are distinct species and that C sculpturatus is the more dangerous of the two.⁵ The median lethal dose 50% of C sculpturatus was found to be 22.7 μg in CD1 mice.⁶

Envenomation and Clinical Manifestations

Stings from C exilicauda and C sculpturatus have been shown to cause fatality in children more often than in adults.⁷ In the United States, Arizona has the highest frequency of serious symptoms of envenomation as well as the highest hospital and intensive care unit admission rates.⁶ Envenomation results in an immediate sharp burning pain followed by numbness.⁴ Wounds can produce some regional lymph node swelling, ecchymosis, paresthesia, and lymphangitis. More often than not, however, wounds have little to no inflammation and are characterized only by pain.⁴ The puncture wound is too small to be seen, and C exilicauda and C sculpturatus venom do not cause local tissue destruction, an important factor in distinguishing it from other scorpion envenomations.

More severe complications that may follow are caused by the neurotoxin released by Centruroides stings. The toxin components can increase the duration and amplitude of the neuronal action potential and enhance the release of neurotransmitters such as acetylcholine and norepinephrine.⁸ Stings can lead to cranial nerve dysfunction and somatic skeletal neuromuscular dysfunction as well as autonomic dysfunction, specifically salivation, fever, tongue and muscle fasciculations, opsoclonus, vomiting, bronchoconstriction, diaphoresis, nystagmus, blurred vision, slurred speech, hypertension, rhabdomyolysis, stridor, wheezing, aspiration, anaphylaxis, and tachycardia, leading to cardiac and respiratory compromise.^4,8 Some patients have experienced a decreased sense of smell or hearing and decreased fine motor movements.⁷ Although pancreatitis may occur with scorpion stings, it is not common for C exilicauda.⁹ Comorbidities such as cardiac disease and substance use disorders contribute to prolonged length of hospital stay and poor outcome.⁸

Treatment

Most Centruroides stings can be managed at home, but patients with more serious symptoms and children younger than 2 years should be taken to a hospital for treatment.⁷ If a patient reports only pain but shows no other signs of neurotoxicity, observation and pain relief with rest, ice, and elevation is appropriate management. Patients with severe manifestations have been treated with various combinations of lorazepam, glycopyrrolate, ipratropium bromide, and ondansetron, but the only treatment definitively shown to decrease time to symptom abatement is antivenin.⁷ It has been demonstrated that C exilicauda and C sculpturatus antivenin is relatively safe.⁷ Most patients, especially adults, do not die from C exilicauda and C sculpturatus stings; therefore, antivenin more commonly is symptom abating than it is lifesaving.¹⁰ In children, time to symptom resolution was decreased to fewer than 4 hours with antivenin, and there is a lower rate of inpatient admission when antivenin is administered.^4,10,11 There is a low incidence of anaphylactic reaction after antivenin, but there have been reported cases of self-limited serum sickness after antivenin use that generally can be managed with antihistamines and corticosteroids.^4,7

Epidemiology and Identification

Centruroides is a common genus of bark scorpions in the United States with at least 21 species considered to be medically important, including the closely related Centruroides exilicauda and Centruroides sculpturatus.¹ Scorpions can be recognized by a bulbous sac and pointed stinger at the end of a tail-like abdomen. They also have long lobsterlike pedipalps (pincers) for grasping their prey. Identifying characteristics for C exilicauda and C sculpturatus include a small, slender, yellow to light brown or tan body typically measuring 1.3 to 7.6 cm in length with a subaculear tooth or tubercle at the base of the stinger, a characteristic that is common to all Centruroides species (Figure).² Some variability in size has been shown, with smaller scorpions found in increased elevations and cooler temperatures.^1,3 Both C exilicauda and C sculpturatus are found in northern Mexico as well as the southwestern United States (eg, Arizona, New Mexico, Texas, California, Nevada).¹ They have a preference for residing in or around trees and often are found on the underside of bark, stones, or tables as well as inside shoes or small cracks and crevices. Scorpions typically sting in self-defense, and stings commonly occur when humans attempt to move tables, put on shoes, or walk barefoot in scorpion-infested areas. Most stings occur from the end of spring through the end summer, but many may go unreported.^1,4

The venom of the Centruroides genus includes peptides and proteins that play a fundamental role in toxic activity by impairing potassium, sodium, and calcium ion channels.^1,3 Toxins have been shown to be species specific, functioning either in capturing prey or deterring predators. Intraspecies variability in toxins has been demonstrated, which may complicate the production of adequate antivenin.³ Many have thought that C exilicauda Wood and C sculpturatus Ewing are the same species, and the names have been used synonymously in the past; however, genetic and biochemical studies of their venom components have shown that they are distinct species and that C sculpturatus is the more dangerous of the two.⁵ The median lethal dose 50% of C sculpturatus was found to be 22.7 μg in CD1 mice.⁶

Envenomation and Clinical Manifestations

Stings from C exilicauda and C sculpturatus have been shown to cause fatality in children more often than in adults.⁷ In the United States, Arizona has the highest frequency of serious symptoms of envenomation as well as the highest hospital and intensive care unit admission rates.⁶ Envenomation results in an immediate sharp burning pain followed by numbness.⁴ Wounds can produce some regional lymph node swelling, ecchymosis, paresthesia, and lymphangitis. More often than not, however, wounds have little to no inflammation and are characterized only by pain.⁴ The puncture wound is too small to be seen, and C exilicauda and C sculpturatus venom do not cause local tissue destruction, an important factor in distinguishing it from other scorpion envenomations.

More severe complications that may follow are caused by the neurotoxin released by Centruroides stings. The toxin components can increase the duration and amplitude of the neuronal action potential and enhance the release of neurotransmitters such as acetylcholine and norepinephrine.⁸ Stings can lead to cranial nerve dysfunction and somatic skeletal neuromuscular dysfunction as well as autonomic dysfunction, specifically salivation, fever, tongue and muscle fasciculations, opsoclonus, vomiting, bronchoconstriction, diaphoresis, nystagmus, blurred vision, slurred speech, hypertension, rhabdomyolysis, stridor, wheezing, aspiration, anaphylaxis, and tachycardia, leading to cardiac and respiratory compromise.^4,8 Some patients have experienced a decreased sense of smell or hearing and decreased fine motor movements.⁷ Although pancreatitis may occur with scorpion stings, it is not common for C exilicauda.⁹ Comorbidities such as cardiac disease and substance use disorders contribute to prolonged length of hospital stay and poor outcome.⁸

Treatment

Most Centruroides stings can be managed at home, but patients with more serious symptoms and children younger than 2 years should be taken to a hospital for treatment.⁷ If a patient reports only pain but shows no other signs of neurotoxicity, observation and pain relief with rest, ice, and elevation is appropriate management. Patients with severe manifestations have been treated with various combinations of lorazepam, glycopyrrolate, ipratropium bromide, and ondansetron, but the only treatment definitively shown to decrease time to symptom abatement is antivenin.⁷ It has been demonstrated that C exilicauda and C sculpturatus antivenin is relatively safe.⁷ Most patients, especially adults, do not die from C exilicauda and C sculpturatus stings; therefore, antivenin more commonly is symptom abating than it is lifesaving.¹⁰ In children, time to symptom resolution was decreased to fewer than 4 hours with antivenin, and there is a lower rate of inpatient admission when antivenin is administered.^4,10,11 There is a low incidence of anaphylactic reaction after antivenin, but there have been reported cases of self-limited serum sickness after antivenin use that generally can be managed with antihistamines and corticosteroids.^4,7

The Diagnosis: Candidal Intertrigo  

The biopsy confirmed a diagnosis of severe hyperkeratotic candidal intertrigo with no evidence of Hailey-Hailey disease. Hematoxylin and eosin- stained sections demonstrated irregular acanthosis and variable spongiosis. The stratum corneum was predominantly orthokeratotic with overlying psuedohyphae and yeast fungal elements (Figure 1). 

Hyperimmunoglobulinemia E syndrome (HIES), also known as hyper-IgE syndrome or Job syndrome, is a rare immunodeficiency disorder characterized by an eczematous dermatitis-like rash, recurrent skin and lung abscesses, eosinophilia, and elevated serum IgE. Facial asymmetry, prominent forehead, deep-set eyes, broad nose, and roughened facial skin with large pores are characteristic of the sporadic and autosomal-recessive forms. Other common findings include retained primary teeth, hyperextensible joints, and recurrent mucocutaneous candidiasis.¹ 

Although autosomal-dominant and autosomal-recessive inheritance patterns exist, sporadic mutations are the most common cause of HIES.² Several genes have been implicated depending on the inheritance pattern. The majority of autosomal-dominant cases are associated with inactivating STAT3 (signal transducer and activator of transcription 3) mutations, whereas the majority of autosomal-recessive cases are associated with inactivating DOCK8 (dedicator of cytokinesis 8) mutations.¹ Ultimately, all of these mutations lead to an impaired helper T cell (T_H17) response, which is crucial for clearing fungal and extracellular bacterial infections.³  

Skin eruptions typically are the first manifestation of HIES; they appear within the first week to month of life as papulopustular eruptions on the face and scalp and rapidly generalize to the rest of the body, favoring the shoulders, arms, chest, and buttocks. The pustules then coalesce into crusted plaques that resemble atopic dermatitis, frequently with superimposed Staphylococcus aureus infection. On microscopy, the pustules are folliculocentric and often contain eosinophils, whereas the plaques may contain intraepidermal collections of eosinophils.¹ 

Mucocutaneous candidiasis is seen in approximately 60% of HIES cases and is closely linked to STAT3 inactivating mutations.³ Histologically, there is marked acanthosis with neutrophil exocytosis and abundant yeast and pseudohyphal forms within the stratum corneum (Figure 2).⁴ Cutaneous candidal infections typically require both oral and topical antifungal agents to clear the infection.³ Most cases of mucocutaneous candidiasis are caused by Candida albicans; however, other known culprits include Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei.^5,6 Of note, species identification and antifungal susceptibility studies may be useful in refractory cases, especially with C glabrata, which is known to acquire resistance to azoles, such as fluconazole, with emerging resistance to echinocandins.⁶  

The differential diagnosis of this groin eruption included Hailey-Hailey disease; pemphigus vegetans, Hallopeau type; tinea cruris; and inverse psoriasis. Hailey-Hailey disease can be complicated by a superimposed candidal infection with similar clinical features, and biopsy may be required for definitive diagnosis. Hailey-Hailey disease typically presents with macerated fissured plaques that resemble macerated tissue paper with red fissures (Figure 3). Biopsy confirms full-thickness acantholysis resembling a dilapidated brick wall with minimal dyskeratosis.¹ Pemphigus vegetans is a localized variant of pemphigus vulgaris with a predilection for flexural surfaces. The lesions progress to vegetating erosive plaques.⁴ The Hallopeau type often is studded with pustules and typically remains more localized than the Neumann type. Direct immunofluorescence demonstrates intercellular deposition of IgG and C3, and routine sections characteristically show pseudoepitheliomatous hyperplasia with intraepidermal eosinophilic microabscesses.^1,4 Tinea cruris is characterized by erythematous annular lesions with raised scaly borders spreading down the inner thighs.⁷ The epidermis is variably spongiotic with parakeratosis, and neutrophils often present in a layered stratum corneum with basketweave keratin above a layer of more compact and eosinophilic keratin. Fungal stains, such as periodic acid-Schiff, will highlight the fungal hyphae within the stratum corneum. The inguinal folds are a typical location for inverse psoriasis, which generally appears as thin, sharply demarcated, shiny red plaques with less scale than plaque psoriasis.¹ Psoriasiform hyperplasia with a diminished granular layer and tortuous papillary dermal vessels would be expected histologically.¹ 

The Diagnosis: Candidal Intertrigo  

The biopsy confirmed a diagnosis of severe hyperkeratotic candidal intertrigo with no evidence of Hailey-Hailey disease. Hematoxylin and eosin- stained sections demonstrated irregular acanthosis and variable spongiosis. The stratum corneum was predominantly orthokeratotic with overlying psuedohyphae and yeast fungal elements (Figure 1). 

Hyperimmunoglobulinemia E syndrome (HIES), also known as hyper-IgE syndrome or Job syndrome, is a rare immunodeficiency disorder characterized by an eczematous dermatitis-like rash, recurrent skin and lung abscesses, eosinophilia, and elevated serum IgE. Facial asymmetry, prominent forehead, deep-set eyes, broad nose, and roughened facial skin with large pores are characteristic of the sporadic and autosomal-recessive forms. Other common findings include retained primary teeth, hyperextensible joints, and recurrent mucocutaneous candidiasis.¹ 

Although autosomal-dominant and autosomal-recessive inheritance patterns exist, sporadic mutations are the most common cause of HIES.² Several genes have been implicated depending on the inheritance pattern. The majority of autosomal-dominant cases are associated with inactivating STAT3 (signal transducer and activator of transcription 3) mutations, whereas the majority of autosomal-recessive cases are associated with inactivating DOCK8 (dedicator of cytokinesis 8) mutations.¹ Ultimately, all of these mutations lead to an impaired helper T cell (T_H17) response, which is crucial for clearing fungal and extracellular bacterial infections.³  

Skin eruptions typically are the first manifestation of HIES; they appear within the first week to month of life as papulopustular eruptions on the face and scalp and rapidly generalize to the rest of the body, favoring the shoulders, arms, chest, and buttocks. The pustules then coalesce into crusted plaques that resemble atopic dermatitis, frequently with superimposed Staphylococcus aureus infection. On microscopy, the pustules are folliculocentric and often contain eosinophils, whereas the plaques may contain intraepidermal collections of eosinophils.¹ 

Mucocutaneous candidiasis is seen in approximately 60% of HIES cases and is closely linked to STAT3 inactivating mutations.³ Histologically, there is marked acanthosis with neutrophil exocytosis and abundant yeast and pseudohyphal forms within the stratum corneum (Figure 2).⁴ Cutaneous candidal infections typically require both oral and topical antifungal agents to clear the infection.³ Most cases of mucocutaneous candidiasis are caused by Candida albicans; however, other known culprits include Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei.^5,6 Of note, species identification and antifungal susceptibility studies may be useful in refractory cases, especially with C glabrata, which is known to acquire resistance to azoles, such as fluconazole, with emerging resistance to echinocandins.⁶  

The differential diagnosis of this groin eruption included Hailey-Hailey disease; pemphigus vegetans, Hallopeau type; tinea cruris; and inverse psoriasis. Hailey-Hailey disease can be complicated by a superimposed candidal infection with similar clinical features, and biopsy may be required for definitive diagnosis. Hailey-Hailey disease typically presents with macerated fissured plaques that resemble macerated tissue paper with red fissures (Figure 3). Biopsy confirms full-thickness acantholysis resembling a dilapidated brick wall with minimal dyskeratosis.¹ Pemphigus vegetans is a localized variant of pemphigus vulgaris with a predilection for flexural surfaces. The lesions progress to vegetating erosive plaques.⁴ The Hallopeau type often is studded with pustules and typically remains more localized than the Neumann type. Direct immunofluorescence demonstrates intercellular deposition of IgG and C3, and routine sections characteristically show pseudoepitheliomatous hyperplasia with intraepidermal eosinophilic microabscesses.^1,4 Tinea cruris is characterized by erythematous annular lesions with raised scaly borders spreading down the inner thighs.⁷ The epidermis is variably spongiotic with parakeratosis, and neutrophils often present in a layered stratum corneum with basketweave keratin above a layer of more compact and eosinophilic keratin. Fungal stains, such as periodic acid-Schiff, will highlight the fungal hyphae within the stratum corneum. The inguinal folds are a typical location for inverse psoriasis, which generally appears as thin, sharply demarcated, shiny red plaques with less scale than plaque psoriasis.¹ Psoriasiform hyperplasia with a diminished granular layer and tortuous papillary dermal vessels would be expected histologically.¹ 

The Diagnosis: Candidal Intertrigo  

The biopsy confirmed a diagnosis of severe hyperkeratotic candidal intertrigo with no evidence of Hailey-Hailey disease. Hematoxylin and eosin- stained sections demonstrated irregular acanthosis and variable spongiosis. The stratum corneum was predominantly orthokeratotic with overlying psuedohyphae and yeast fungal elements (Figure 1). 

Hyperimmunoglobulinemia E syndrome (HIES), also known as hyper-IgE syndrome or Job syndrome, is a rare immunodeficiency disorder characterized by an eczematous dermatitis-like rash, recurrent skin and lung abscesses, eosinophilia, and elevated serum IgE. Facial asymmetry, prominent forehead, deep-set eyes, broad nose, and roughened facial skin with large pores are characteristic of the sporadic and autosomal-recessive forms. Other common findings include retained primary teeth, hyperextensible joints, and recurrent mucocutaneous candidiasis.¹ 

Although autosomal-dominant and autosomal-recessive inheritance patterns exist, sporadic mutations are the most common cause of HIES.² Several genes have been implicated depending on the inheritance pattern. The majority of autosomal-dominant cases are associated with inactivating STAT3 (signal transducer and activator of transcription 3) mutations, whereas the majority of autosomal-recessive cases are associated with inactivating DOCK8 (dedicator of cytokinesis 8) mutations.¹ Ultimately, all of these mutations lead to an impaired helper T cell (T_H17) response, which is crucial for clearing fungal and extracellular bacterial infections.³  

Skin eruptions typically are the first manifestation of HIES; they appear within the first week to month of life as papulopustular eruptions on the face and scalp and rapidly generalize to the rest of the body, favoring the shoulders, arms, chest, and buttocks. The pustules then coalesce into crusted plaques that resemble atopic dermatitis, frequently with superimposed Staphylococcus aureus infection. On microscopy, the pustules are folliculocentric and often contain eosinophils, whereas the plaques may contain intraepidermal collections of eosinophils.¹ 

Mucocutaneous candidiasis is seen in approximately 60% of HIES cases and is closely linked to STAT3 inactivating mutations.³ Histologically, there is marked acanthosis with neutrophil exocytosis and abundant yeast and pseudohyphal forms within the stratum corneum (Figure 2).⁴ Cutaneous candidal infections typically require both oral and topical antifungal agents to clear the infection.³ Most cases of mucocutaneous candidiasis are caused by Candida albicans; however, other known culprits include Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei.^5,6 Of note, species identification and antifungal susceptibility studies may be useful in refractory cases, especially with C glabrata, which is known to acquire resistance to azoles, such as fluconazole, with emerging resistance to echinocandins.⁶  

The differential diagnosis of this groin eruption included Hailey-Hailey disease; pemphigus vegetans, Hallopeau type; tinea cruris; and inverse psoriasis. Hailey-Hailey disease can be complicated by a superimposed candidal infection with similar clinical features, and biopsy may be required for definitive diagnosis. Hailey-Hailey disease typically presents with macerated fissured plaques that resemble macerated tissue paper with red fissures (Figure 3). Biopsy confirms full-thickness acantholysis resembling a dilapidated brick wall with minimal dyskeratosis.¹ Pemphigus vegetans is a localized variant of pemphigus vulgaris with a predilection for flexural surfaces. The lesions progress to vegetating erosive plaques.⁴ The Hallopeau type often is studded with pustules and typically remains more localized than the Neumann type. Direct immunofluorescence demonstrates intercellular deposition of IgG and C3, and routine sections characteristically show pseudoepitheliomatous hyperplasia with intraepidermal eosinophilic microabscesses.^1,4 Tinea cruris is characterized by erythematous annular lesions with raised scaly borders spreading down the inner thighs.⁷ The epidermis is variably spongiotic with parakeratosis, and neutrophils often present in a layered stratum corneum with basketweave keratin above a layer of more compact and eosinophilic keratin. Fungal stains, such as periodic acid-Schiff, will highlight the fungal hyphae within the stratum corneum. The inguinal folds are a typical location for inverse psoriasis, which generally appears as thin, sharply demarcated, shiny red plaques with less scale than plaque psoriasis.¹ Psoriasiform hyperplasia with a diminished granular layer and tortuous papillary dermal vessels would be expected histologically.¹ 

The expanding range of tick-borne diseases is a growing problem worldwide. Climate change plays a preeminent role in the expansion of tick species, especially for southern ticks in the United States such as Amblyomma species, which have introduced new pathogens to northern states.^1-5 In addition to well-known tick-borne diseases, Amblyomma ticks have been implicated in the spread of emerging severe and potentially fatal viral illnesses, including Bourbon virus and Heartland virus.⁶ The increasing range of Amblyomma ticks also exposes new populations to tick-induced meat allergy (alpha-gal) syndrome, whereby development of specific IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) following tick bites results in severe allergic responses to consumption of beef, pork, and lamb.⁷

Amblyomma ticks have now been identified close to the Canadian border in Michigan and New York, and predictions of continued climate change raise the possibility of northward range expansion into all provinces of Canada from Alberta to Newfoundland and Labrador during the coming decades.^8,9 Additional factors that contribute to the expanding range of many tick species include international travel, migratory patterns of birds, competition, and natural predators such as fire ants that feed on tick eggs and influence the feeding behavior of adults.¹⁰

Traditional methods of tick identification rely on gross morphology, including the presence of festoons, shape of the coxae where the legs attach, and markings on the hard overlying scutum. More recently, molecular identification has improved tick identification, leading to more accurate assessment of tick prevalence. These modern identification studies include analysis of 16S ribosomal DNA (rDNA), 12S rDNA, and ITS1 rDNA, and ITS2 rDNA genes.¹¹

The spread of tick vectors has huge public health implications, and better methods to control tick populations are needed.¹² New acaricides and growth regulators are being developed,¹³ and early spring applications of acaricides such as bifenthrin can suppress nymphs prior to the initiation of host-seeking activity.¹⁴ Controlled burns within tick habitats have proved helpful in reducing the risk for vector-borne disease.^15,16 Personal protection is best accomplished with the use of a repellent together with clothing impregnated with an acaricide such as permethrin.¹⁷ Efforts to slow climate change and continued surveillance for the spread of tick vectors is urgently needed.

The expanding range of tick-borne diseases is a growing problem worldwide. Climate change plays a preeminent role in the expansion of tick species, especially for southern ticks in the United States such as Amblyomma species, which have introduced new pathogens to northern states.^1-5 In addition to well-known tick-borne diseases, Amblyomma ticks have been implicated in the spread of emerging severe and potentially fatal viral illnesses, including Bourbon virus and Heartland virus.⁶ The increasing range of Amblyomma ticks also exposes new populations to tick-induced meat allergy (alpha-gal) syndrome, whereby development of specific IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) following tick bites results in severe allergic responses to consumption of beef, pork, and lamb.⁷

Amblyomma ticks have now been identified close to the Canadian border in Michigan and New York, and predictions of continued climate change raise the possibility of northward range expansion into all provinces of Canada from Alberta to Newfoundland and Labrador during the coming decades.^8,9 Additional factors that contribute to the expanding range of many tick species include international travel, migratory patterns of birds, competition, and natural predators such as fire ants that feed on tick eggs and influence the feeding behavior of adults.¹⁰

Traditional methods of tick identification rely on gross morphology, including the presence of festoons, shape of the coxae where the legs attach, and markings on the hard overlying scutum. More recently, molecular identification has improved tick identification, leading to more accurate assessment of tick prevalence. These modern identification studies include analysis of 16S ribosomal DNA (rDNA), 12S rDNA, and ITS1 rDNA, and ITS2 rDNA genes.¹¹

The spread of tick vectors has huge public health implications, and better methods to control tick populations are needed.¹² New acaricides and growth regulators are being developed,¹³ and early spring applications of acaricides such as bifenthrin can suppress nymphs prior to the initiation of host-seeking activity.¹⁴ Controlled burns within tick habitats have proved helpful in reducing the risk for vector-borne disease.^15,16 Personal protection is best accomplished with the use of a repellent together with clothing impregnated with an acaricide such as permethrin.¹⁷ Efforts to slow climate change and continued surveillance for the spread of tick vectors is urgently needed.

The expanding range of tick-borne diseases is a growing problem worldwide. Climate change plays a preeminent role in the expansion of tick species, especially for southern ticks in the United States such as Amblyomma species, which have introduced new pathogens to northern states.^1-5 In addition to well-known tick-borne diseases, Amblyomma ticks have been implicated in the spread of emerging severe and potentially fatal viral illnesses, including Bourbon virus and Heartland virus.⁶ The increasing range of Amblyomma ticks also exposes new populations to tick-induced meat allergy (alpha-gal) syndrome, whereby development of specific IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) following tick bites results in severe allergic responses to consumption of beef, pork, and lamb.⁷

Amblyomma ticks have now been identified close to the Canadian border in Michigan and New York, and predictions of continued climate change raise the possibility of northward range expansion into all provinces of Canada from Alberta to Newfoundland and Labrador during the coming decades.^8,9 Additional factors that contribute to the expanding range of many tick species include international travel, migratory patterns of birds, competition, and natural predators such as fire ants that feed on tick eggs and influence the feeding behavior of adults.¹⁰

Traditional methods of tick identification rely on gross morphology, including the presence of festoons, shape of the coxae where the legs attach, and markings on the hard overlying scutum. More recently, molecular identification has improved tick identification, leading to more accurate assessment of tick prevalence. These modern identification studies include analysis of 16S ribosomal DNA (rDNA), 12S rDNA, and ITS1 rDNA, and ITS2 rDNA genes.¹¹

The spread of tick vectors has huge public health implications, and better methods to control tick populations are needed.¹² New acaricides and growth regulators are being developed,¹³ and early spring applications of acaricides such as bifenthrin can suppress nymphs prior to the initiation of host-seeking activity.¹⁴ Controlled burns within tick habitats have proved helpful in reducing the risk for vector-borne disease.^15,16 Personal protection is best accomplished with the use of a repellent together with clothing impregnated with an acaricide such as permethrin.¹⁷ Efforts to slow climate change and continued surveillance for the spread of tick vectors is urgently needed.

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

Epidemiology and Transmission

Pediculus humanus corporis, commonly known as the human body louse, is one in a family of 3 ectoparasites of the same suborder that also encompasses pubic lice (Phthirus pubis) and head lice (Pediculus humanus capitis). Adults are approximately 2 mm in size, with the same life cycle as head lice (Figure 1). They require blood meals roughly 5 times per day and cannot survive longer than 2 days without feeding.¹ Although similar in structure to head lice, body lice differ behaviorally in that they do not reside on their human host’s body; instead, they infest the host’s clothing, localizing to seams (Figure 2), and migrate to the host for blood meals. In fact, based on this behavior, genetic analysis of early human body lice has been used to postulate when clothing was first used by humans as well as to determine early human migration patterns.^2,3

Although clinicians in developed countries may be less familiar with body lice compared to their counterparts, body lice nevertheless remain a global health concern in impoverished, densely populated areas, as well as in homeless populations due to poor hygiene. Transmission frequently occurs via physical contact with an affected individual and his/her personal items (eg, linens) via fomites.^4,5 Body louse infestation is more prevalent in homeless individuals who sleep outside vs in shelters; a history of pubic lice and lack of regular bathing have been reported as additional risk factors.⁶ Outbreaks have been noted in the wake of natural disasters, in the setting of political upheavals, and in refugee camps, as well as in individuals seeking political asylum.⁷ Unlike head and pubic lice, body lice can serve as vectors for infectious diseases including Rickettsia prowazekii (epidemic typhus), Borrelia recurrentis (louse-borne relapsing fever), Bartonella quintana (trench fever), and Yersinia pestis (plague).^5,8,9 Several Acinetobacter species were isolated from nearly one-third of collected body louse specimens in a French study.¹⁰ Additionally, serology for B quintana was found to be positive in up to 30% of cases in one United States urban homeless population.⁴

Clinical Manifestations

Patients often present with generalized pruritus, usually considerably more severe than with P humanus capitis, with lesions concentrated on the trunk.¹¹ In addition to often impetiginized, self-inflicted excoriations, feeding sites may present as erythematous macules (Figure 3), papules, or papular urticaria with a central hemorrhagic punctum. Extensive infestation also can manifest as the colloquial vagabond disease, characterized by postinflammatory hyperpigmentation and thickening of the involved skin. Remarkably, patients also may present with considerable iron-deficiency anemia secondary to high parasite load and large volume blood feeding. Multiple case reports have demonstrated associated morbidity.^12-14 The differential diagnosis for pediculosis may include scabies, lichen simplex chronicus, and eczematous dermatitis, though the clinician should prudently consider whether both scabies and pediculosis may be present, as coexistence is possible.^4,15

Diagnosis

Diagnosis can be reached by visualizing adult lice, nymphs, or viable nits on the body or more commonly within inner clothing seams; nits also fluoresce under Wood light.¹⁵ Although dermoscopy has proven useful for increased sensitivity and differentiation between viable and hatched nits, the insects also can be viewed with the unaided eye.¹⁶

Treatment: New Concerns and Strategies

The mainstay of treatment for body lice has long consisted of thorough washing and drying of all clothing and linens in a hot dryer. Treatment can be augmented with the addition of pharmacotherapy, plus antibiotics as warranted for louse-borne disease. Pharmacologic intervention often is used in cases of mass infestation and is similar to head lice.

Options for head lice include topical permethrin, malathion, lindane, spinosad, benzyl alcohol, and ivermectin. Pyrethroids, derived from the chrysanthemum, generally are considered safe for human use with a side-effect profile limited to irritation and allergy¹⁷; however, neurotoxicity and leukemia are clinical concerns, with an association more recently shown between large-volume use of pyrethroids and acute lymphoblastic leukemia.^18,19 Use of lindane is not recommended due to a greater potential for central nervous system neurotoxicity, manifested by seizures, with repeated large surface application. Malathion is problematic due to the risk for mucosal irritation, flammability of some formulations, and theoretical organophosphate poisoning, as its mechanism of action involves inhibition of acetylcholinesterase.¹⁵ However, in the context of head lice treatment, a randomized controlled trial reported no incidence of acetylcholinesterase inhibition.²⁰ Spinosad, manufactured from the soil bacterium Saccharopolyspora spinosa, functions similarly by interfering with the nicotinic acetylcholine receptor and also carries a risk for skin irritation.²¹ Among all the treatment options, we prefer benzyl alcohol, particularly in the context of resistance, as it is effective via a physical mechanism of action and lacks notable neurotoxic effects to the host. Use of benzyl alcohol is approved for patients as young as 6 months; it functions by asphyxiating the lice via paralysis of the respiratory spiracle with occlusion by inert ingredients. Itching, episodic numbness, and scalp or mucosal irritation are possible complications of treatment.²²

Treatment resistance of body lice has increased in recent years, warranting exploration of additional management strategies. Moreover, developing resistance to lindane and malathion has been reported.²³ Resistance to pyrethroids has been attributed to mutations in a voltage-gated sodium channel, one of which was universally present in the sampling of a single population.²⁴ A randomized controlled trial showed that off-label oral ivermectin 400 μg/kg was superior to malathion lotion 0.5% in difficult-to-treat cases of head lice²⁵; utility of oral ivermectin also has been reported in body lice.²⁶ In vitro studies also have shown promise for pursuing synergistic treatment of body lice with both ivermectin and antibiotics.²⁷

A novel primary prophylaxis approach for at-risk homeless individuals recently utilized permethrin-impregnated underwear. Although the intervention provided short-term infestation improvement, longer-term use did not show improvement from placebo and also increased prevalence of permethrin-resistant haplotypes.²

Epidemiology and Transmission

Pediculus humanus corporis, commonly known as the human body louse, is one in a family of 3 ectoparasites of the same suborder that also encompasses pubic lice (Phthirus pubis) and head lice (Pediculus humanus capitis). Adults are approximately 2 mm in size, with the same life cycle as head lice (Figure 1). They require blood meals roughly 5 times per day and cannot survive longer than 2 days without feeding.¹ Although similar in structure to head lice, body lice differ behaviorally in that they do not reside on their human host’s body; instead, they infest the host’s clothing, localizing to seams (Figure 2), and migrate to the host for blood meals. In fact, based on this behavior, genetic analysis of early human body lice has been used to postulate when clothing was first used by humans as well as to determine early human migration patterns.^2,3

Although clinicians in developed countries may be less familiar with body lice compared to their counterparts, body lice nevertheless remain a global health concern in impoverished, densely populated areas, as well as in homeless populations due to poor hygiene. Transmission frequently occurs via physical contact with an affected individual and his/her personal items (eg, linens) via fomites.^4,5 Body louse infestation is more prevalent in homeless individuals who sleep outside vs in shelters; a history of pubic lice and lack of regular bathing have been reported as additional risk factors.⁶ Outbreaks have been noted in the wake of natural disasters, in the setting of political upheavals, and in refugee camps, as well as in individuals seeking political asylum.⁷ Unlike head and pubic lice, body lice can serve as vectors for infectious diseases including Rickettsia prowazekii (epidemic typhus), Borrelia recurrentis (louse-borne relapsing fever), Bartonella quintana (trench fever), and Yersinia pestis (plague).^5,8,9 Several Acinetobacter species were isolated from nearly one-third of collected body louse specimens in a French study.¹⁰ Additionally, serology for B quintana was found to be positive in up to 30% of cases in one United States urban homeless population.⁴

Clinical Manifestations

Patients often present with generalized pruritus, usually considerably more severe than with P humanus capitis, with lesions concentrated on the trunk.¹¹ In addition to often impetiginized, self-inflicted excoriations, feeding sites may present as erythematous macules (Figure 3), papules, or papular urticaria with a central hemorrhagic punctum. Extensive infestation also can manifest as the colloquial vagabond disease, characterized by postinflammatory hyperpigmentation and thickening of the involved skin. Remarkably, patients also may present with considerable iron-deficiency anemia secondary to high parasite load and large volume blood feeding. Multiple case reports have demonstrated associated morbidity.^12-14 The differential diagnosis for pediculosis may include scabies, lichen simplex chronicus, and eczematous dermatitis, though the clinician should prudently consider whether both scabies and pediculosis may be present, as coexistence is possible.^4,15

Diagnosis

Diagnosis can be reached by visualizing adult lice, nymphs, or viable nits on the body or more commonly within inner clothing seams; nits also fluoresce under Wood light.¹⁵ Although dermoscopy has proven useful for increased sensitivity and differentiation between viable and hatched nits, the insects also can be viewed with the unaided eye.¹⁶

Treatment: New Concerns and Strategies

The mainstay of treatment for body lice has long consisted of thorough washing and drying of all clothing and linens in a hot dryer. Treatment can be augmented with the addition of pharmacotherapy, plus antibiotics as warranted for louse-borne disease. Pharmacologic intervention often is used in cases of mass infestation and is similar to head lice.

Options for head lice include topical permethrin, malathion, lindane, spinosad, benzyl alcohol, and ivermectin. Pyrethroids, derived from the chrysanthemum, generally are considered safe for human use with a side-effect profile limited to irritation and allergy¹⁷; however, neurotoxicity and leukemia are clinical concerns, with an association more recently shown between large-volume use of pyrethroids and acute lymphoblastic leukemia.^18,19 Use of lindane is not recommended due to a greater potential for central nervous system neurotoxicity, manifested by seizures, with repeated large surface application. Malathion is problematic due to the risk for mucosal irritation, flammability of some formulations, and theoretical organophosphate poisoning, as its mechanism of action involves inhibition of acetylcholinesterase.¹⁵ However, in the context of head lice treatment, a randomized controlled trial reported no incidence of acetylcholinesterase inhibition.²⁰ Spinosad, manufactured from the soil bacterium Saccharopolyspora spinosa, functions similarly by interfering with the nicotinic acetylcholine receptor and also carries a risk for skin irritation.²¹ Among all the treatment options, we prefer benzyl alcohol, particularly in the context of resistance, as it is effective via a physical mechanism of action and lacks notable neurotoxic effects to the host. Use of benzyl alcohol is approved for patients as young as 6 months; it functions by asphyxiating the lice via paralysis of the respiratory spiracle with occlusion by inert ingredients. Itching, episodic numbness, and scalp or mucosal irritation are possible complications of treatment.²²

Treatment resistance of body lice has increased in recent years, warranting exploration of additional management strategies. Moreover, developing resistance to lindane and malathion has been reported.²³ Resistance to pyrethroids has been attributed to mutations in a voltage-gated sodium channel, one of which was universally present in the sampling of a single population.²⁴ A randomized controlled trial showed that off-label oral ivermectin 400 μg/kg was superior to malathion lotion 0.5% in difficult-to-treat cases of head lice²⁵; utility of oral ivermectin also has been reported in body lice.²⁶ In vitro studies also have shown promise for pursuing synergistic treatment of body lice with both ivermectin and antibiotics.²⁷

A novel primary prophylaxis approach for at-risk homeless individuals recently utilized permethrin-impregnated underwear. Although the intervention provided short-term infestation improvement, longer-term use did not show improvement from placebo and also increased prevalence of permethrin-resistant haplotypes.²

Epidemiology and Transmission

Pediculus humanus corporis, commonly known as the human body louse, is one in a family of 3 ectoparasites of the same suborder that also encompasses pubic lice (Phthirus pubis) and head lice (Pediculus humanus capitis). Adults are approximately 2 mm in size, with the same life cycle as head lice (Figure 1). They require blood meals roughly 5 times per day and cannot survive longer than 2 days without feeding.¹ Although similar in structure to head lice, body lice differ behaviorally in that they do not reside on their human host’s body; instead, they infest the host’s clothing, localizing to seams (Figure 2), and migrate to the host for blood meals. In fact, based on this behavior, genetic analysis of early human body lice has been used to postulate when clothing was first used by humans as well as to determine early human migration patterns.^2,3

Although clinicians in developed countries may be less familiar with body lice compared to their counterparts, body lice nevertheless remain a global health concern in impoverished, densely populated areas, as well as in homeless populations due to poor hygiene. Transmission frequently occurs via physical contact with an affected individual and his/her personal items (eg, linens) via fomites.^4,5 Body louse infestation is more prevalent in homeless individuals who sleep outside vs in shelters; a history of pubic lice and lack of regular bathing have been reported as additional risk factors.⁶ Outbreaks have been noted in the wake of natural disasters, in the setting of political upheavals, and in refugee camps, as well as in individuals seeking political asylum.⁷ Unlike head and pubic lice, body lice can serve as vectors for infectious diseases including Rickettsia prowazekii (epidemic typhus), Borrelia recurrentis (louse-borne relapsing fever), Bartonella quintana (trench fever), and Yersinia pestis (plague).^5,8,9 Several Acinetobacter species were isolated from nearly one-third of collected body louse specimens in a French study.¹⁰ Additionally, serology for B quintana was found to be positive in up to 30% of cases in one United States urban homeless population.⁴

Clinical Manifestations

Patients often present with generalized pruritus, usually considerably more severe than with P humanus capitis, with lesions concentrated on the trunk.¹¹ In addition to often impetiginized, self-inflicted excoriations, feeding sites may present as erythematous macules (Figure 3), papules, or papular urticaria with a central hemorrhagic punctum. Extensive infestation also can manifest as the colloquial vagabond disease, characterized by postinflammatory hyperpigmentation and thickening of the involved skin. Remarkably, patients also may present with considerable iron-deficiency anemia secondary to high parasite load and large volume blood feeding. Multiple case reports have demonstrated associated morbidity.^12-14 The differential diagnosis for pediculosis may include scabies, lichen simplex chronicus, and eczematous dermatitis, though the clinician should prudently consider whether both scabies and pediculosis may be present, as coexistence is possible.^4,15

Diagnosis

Diagnosis can be reached by visualizing adult lice, nymphs, or viable nits on the body or more commonly within inner clothing seams; nits also fluoresce under Wood light.¹⁵ Although dermoscopy has proven useful for increased sensitivity and differentiation between viable and hatched nits, the insects also can be viewed with the unaided eye.¹⁶

Treatment: New Concerns and Strategies

The mainstay of treatment for body lice has long consisted of thorough washing and drying of all clothing and linens in a hot dryer. Treatment can be augmented with the addition of pharmacotherapy, plus antibiotics as warranted for louse-borne disease. Pharmacologic intervention often is used in cases of mass infestation and is similar to head lice.

Options for head lice include topical permethrin, malathion, lindane, spinosad, benzyl alcohol, and ivermectin. Pyrethroids, derived from the chrysanthemum, generally are considered safe for human use with a side-effect profile limited to irritation and allergy¹⁷; however, neurotoxicity and leukemia are clinical concerns, with an association more recently shown between large-volume use of pyrethroids and acute lymphoblastic leukemia.^18,19 Use of lindane is not recommended due to a greater potential for central nervous system neurotoxicity, manifested by seizures, with repeated large surface application. Malathion is problematic due to the risk for mucosal irritation, flammability of some formulations, and theoretical organophosphate poisoning, as its mechanism of action involves inhibition of acetylcholinesterase.¹⁵ However, in the context of head lice treatment, a randomized controlled trial reported no incidence of acetylcholinesterase inhibition.²⁰ Spinosad, manufactured from the soil bacterium Saccharopolyspora spinosa, functions similarly by interfering with the nicotinic acetylcholine receptor and also carries a risk for skin irritation.²¹ Among all the treatment options, we prefer benzyl alcohol, particularly in the context of resistance, as it is effective via a physical mechanism of action and lacks notable neurotoxic effects to the host. Use of benzyl alcohol is approved for patients as young as 6 months; it functions by asphyxiating the lice via paralysis of the respiratory spiracle with occlusion by inert ingredients. Itching, episodic numbness, and scalp or mucosal irritation are possible complications of treatment.²²

Treatment resistance of body lice has increased in recent years, warranting exploration of additional management strategies. Moreover, developing resistance to lindane and malathion has been reported.²³ Resistance to pyrethroids has been attributed to mutations in a voltage-gated sodium channel, one of which was universally present in the sampling of a single population.²⁴ A randomized controlled trial showed that off-label oral ivermectin 400 μg/kg was superior to malathion lotion 0.5% in difficult-to-treat cases of head lice²⁵; utility of oral ivermectin also has been reported in body lice.²⁶ In vitro studies also have shown promise for pursuing synergistic treatment of body lice with both ivermectin and antibiotics.²⁷

A novel primary prophylaxis approach for at-risk homeless individuals recently utilized permethrin-impregnated underwear. Although the intervention provided short-term infestation improvement, longer-term use did not show improvement from placebo and also increased prevalence of permethrin-resistant haplotypes.²