Environmental Dermatology

The scabies mite, originally known as Acarus scabiei,¹ now is considered an arthropod of the class Arachnida, order Astigmata, and family Sarcoptidae.² Scabies mites are able to adhere to the surface of human skin.³ The mites burrow and lay eggs in the top layer of the epidermis; most patients have 10 to 15 mites.³ The patient’s immune system incites an allergic reaction to the mite protein and feces in the skin, causing itching and rash.⁴

Scabies is common in indigenous populations and in low-income areas of developing countries.⁵ It is most prevalent in Africa, South America, Australia, and Southeast Asia, in part due to poverty, poor nutritional status, homelessness, and inadequate hygiene.² In 2009, the World Health Organization declared scabies a neglected skin disease²; however, in 2010, 1.5 million disability adjusted life-years were attributed to scabies,⁶ and it is estimated that 200 million people worldwide have scabies at any given time. Children and elderly individuals in resource-poor communities are the most at risk. In fact, 5% to 50% of children in low-income areas have scabies.⁴

The purpose of this article is to provide background on scabies and its effect on the human immune system. We also discuss manipulation of the immune response for the purposes of creating a potential scabies vaccine.

Life Cycle and Transmission

The life cycle of Sarcoptes scabiei consists of 4 stages. The first is the egg. As female scabies mites burrow under the skin, they lay 2 to 3 ovular eggs per day.³ The second stage is the larva. When the egg hatches, the larva has 3 pairs of legs and travels to the surface of the skin where it burrows into the stratum corneum, creating short, nearly invisible burrows called molting pouches. After 3 to 4 days, the larva molts into a nymph, which is the third stage. The nymph has 4 pairs of legs and will continue to grow before molting into an adult, which is the fourth stage. Both the larva and nymph may be found in hair follicles or molting pouches. The fourth stage is the adult, which is round and saclike and does not have eyes. Adult females are 0.30 mm to 0.45 mm long and 0.25 mm to 0.35 mm wide, which is half the size of adult males.³ On warm skin, the female mite can crawl at a rate of 2.5 cm per minute.⁷

Scabies mites mate via an active male penetrating the molting pouch of a female. This only occurs once but leaves the female fertile for the rest of her life. Once a female is pregnant, she leaves her molting pouch and travels along the surface of the skin looking for a place to make her permanent burrow.³ The most common sites for scabies burrows are the axillae, umbilicus, interdigital spaces, beltline, buttocks, flexor surfaces of the wrists, female nipples, and male penile shaft.⁵ Once she finds an acceptable location, the female scabies mite will create a serpentine burrow and lay her eggs. Once she burrows, she will stay there and continue to lay eggs for the rest of her life, lengthening the burrow as needed.³ Female mites lay their eggs in the superficial epidermis, and the eggs take approximately 2 to 3 weeks to hatch. Female mites die 30 to 60 days later.²

Scabies infestations typically spread via the transfer of pregnant adult females during skin-to-skin contact, but they also can spread via fomites.³ During all stages of their life cycle, scabies mites can secrete enzymes that allow them to penetrate the intact epidermis in less than 30 minutes; in fact, an otherwise healthy patient with scabies must have 15 to 20 minutes of close skin-to-skin contact with an infected individual for the disease to be transmitted.⁷ Because scabies mites can survive for more than 3 days outside the human body, it is thought that fomites also may be involved in transmission. Scabies mites also have been collected from clothing, bedding, and furniture, which further supports the idea that fomites are involved in disease transmission.⁷

Clinical Manifestation of Scabies

Scabies symptoms include severe pruritus as well as linear burrows and vesicles in the interdigital spaces on the hands, wrists, arms and legs, and lower abdomen. Infants and young children also can develop a rash on the palms, soles, ankles, and scalp. Men can develop inflammatory scabies nodules on the penis and scrotum, while women can develop these nodules on the nipple.⁴ Type I and type IV hypersensitivity reactions contribute to the rash and itching associated with scabies infestation via host allergic and inflammatory reactions to the mites and their byproducts. Patients with scabies typically are infested with fewer than 15 mites,⁶ but just a few can cause substantial pruritus and scratching, leading to hyperkeratosis.⁸

Additionally, when patients with scabies scratch the skin, they become vulnerable to bacterial infections.⁴ Scabies lesions can be coinfected with group A streptococci and Staphylococcus aureus,⁸ potentially leading to abscesses and septicemia. These secondary infections also can cause renal and cardiac complications; in fact, in tropical areas, scabies infections are considered a risk factor for kidney disease and rheumatic heart disease.⁴

The 2 main forms of scabies infestations are ordinary and crusted. The most common form is ordinary scabies, which typically manifests with fewer than 15 mites per patient; crusted scabies (CS) is the more rare and extreme form.⁶ Cases of CS present with thousands to millions of mites per patient, leading to more widespread and severe symptoms.⁴ Because of the large increase in the number of mites, CS is more contagious than ordinary scabies.⁶

Patients with CS typically present with hyperkeratotic skin disease, as evidenced by thick scaly crusts with large numbers of mites, which can lead to permanent skin disfiguration. Patients with CS also can develop deep fissuring of the crusts, within which other microbes can gain entry to the body and lead to secondary infection and possibly sepsis and death. Also, because of the increased number of mites as well as the crusted skin, patients with CS are contagious for longer. As it is more difficult to eradicate, reinfestation is common with CS.⁶

Patients with compromised immune systems are predisposed to CS. Specifically, patients with HIV or human T-lymphotropic virus 1 or those undergoing organ transplantation are thought to be the most at risk for CS.⁶ Crusted scabies also has been identified in large numbers in patients with Down syndrome and in Aboriginal Australians; however, the reasoning for this is poorly understood.⁶

Immune Response

The inflammatory reaction associated with scabies infestations occurs 4 to 6 weeks after initial exposure. It is hypothesized that scabies can alter parts of the host immune system, which contributes to the delayed onset of symptoms. Scabies mites also produce inactivated protease paralogues and serpins, which help to protect the mites from the host immune system by inhibiting the complement system.⁶

The complement system is part of the innate immune response and is the first line of defense against pathogens. Specifically with scabies infestations, C3 and C4 complement components have been found in skin lesions.⁶ C3a and C4a fragments cause local inflammation, while C3a and C5a activate mast cells to release histamine and tumor necrosis factor (TNF) α, further amplifying the inflammatory response; however, CS lesions show low C3 and C4, which can indicate immunodeficiency in patients with CS. It also can be due to the sheer number of mites in a CS infection causing the host immune system to be overloaded.⁶

Innate effector immune cells also are an important part of the innate immune response to scabies; for example, eosinophilia is seen in scabies infections. Specifically, in CS, eosinophils help modulate and sustain the T-helper (Th) 2 inflammatory response. One cytokine secreted by Th2 cells is IL-5, which is closely associated with the attraction, maturation, and survival of eosinophils.⁶ Eosinophils also can influence the Th1 inflammatory response in that they produce IL-12, interferon (IFN) γ, and several Toll-like receptors. Furthermore, eosinophilic expression of IL-2 can lead to expansion of regulatory T cells, while eosinophilic expression of IL-10 and transforming growth factor (TGF) Β also can suppress local inflammation by influencing regulatory T cells.⁶

Additionally, mast cells and basophils are important in the IgE-mediated allergic reaction as well as the host immune response to parasites. When activated, basophils and mast cells produce TNF-α, IL-6, Il-4, IL-5, and IL-13, which contribute to the Th2 inflammatory response; however, the role of mast cells and basophils in scabies infections still is poorly understood.⁶

Macrophages, neutrophils, and dendritic cells (DCs) contribute to phagocytosis, antigen presentation, and differentiation of T cells, which also contribute to the inflammatory and allergic reactions associated with parasitic infections.⁶ Macrophages have been found in low numbers in scabies infestation, possibly due to immune-modulating molecules secreted by scabies mites. Early in an infestation, the mites secrete immune-modulating molecules, which inhibit macrophage migration to the site of inflammation, allowing the mites to grow.⁶ Neutrophils and DCs also are involved in the host immune response to scabies. Neutrophils are the predominant inflammatory cell infiltrate in scabies lesions. The scabies protein SMSB4 inhibits neutrophil opsonization and phagocytosis, thus suppressing bacterial killing.⁶ Some of the first antigen-presenting cells encountered by the antigen are DCs. They are involved in preparing the antigens for presentation to effector T cells, which leads to T-cell differentiation and activation.⁶

Cytokines are another important factor in the innate immune response. The host immune response to ordinary scabies is Th1-cell mediated, during which CD4+ and CD8+ T cells secrete IFN-γ, TNF-α, and IL-2.⁶ Therefore, IFN- γ and TNF-α are elevated in the serum of patients with ordinary scabies. Conversely, the host immune response to CS is Th2-cell mediated. T-helper 2 cells are needed in IgE-mediated hypersensitivity reactions, and they secrete IL-4, IL-5, and IL-13. In the serum of patients with CS, IL-l4, IL-5, and IL-13 are elevated while IFN-γ is decreased.⁶ Additionally, IL-6, TGF-Β, IL-23, IL-1Β, or IL-18 can induce Th17 cells to generate and secrete IL-17, which enhances the inflammatory response by inducing further expression of TNF-α, IL-1Β, IL-6, keratinocytes, and fibroblasts. T-helper 17 and IL-17 also are involved in psoriasis and atopic dermatitis, as well as Leishmania major and Schistosoma japonicum.⁶

Regulatory T cells Tregs secrete TGF-Β and IL-10, which suppress pathologic inflammation, and IL-10 is substantially reduced in patients with CS compared to those with ordinary scabies and uninfected control patients. Additionally, IL-10 can inhibit the synthesis of TNF-γ and IFN-α. Reduced IL-10 expression can lead to proliferation of IL-17 secretion, resulting in a regulatory T cell/Th17 dysfunctional immune response.⁶

Immunoglobulins are antibodies that are involved in the host’s adaptive immune response. The first antibody to appear in response to an antigen is IgM, and IgM bound to scabies antigens is present in 74%⁶ of patients with ordinary scabies. Because IgM is the first antibody to appear in response to a scabies infection, detection of serum IgM may allow for earlier detection of scabies; however, IgM has a high cross-reactivity between scabies mites and dust mites, which can hinder scabies diagnosis via IgM detection.⁶

Both patients with ordinary scabies and CS also show an increased circulatory IgG concentration compared to control groups; patients with CS have higher concentrations. Increased IgG also can be in part due to concurrent bacterial infections.⁶ When IgG or IgM antibodies bind to a pathogen, they activate the complement cascade, which further enhances the activity of these antibodies.⁹

Additionally, IgA is important in mucosal immune function. In both patients with ordinary scabies and CS, there is increased IgA binding to recombinant scabies mite antigens.⁶ Sarcoptes scabiei proteases that are localized in the mite’s gut and scybala suggest their involvement in mite digestion and burrowing. The increased secretion of these proteases into the host skin may contribute to the increased IgA,⁹ and these increased IgA levels have been shown to be positively correlated with severity of scabies infection.⁶

Also essential in allergic and parasitic inflammation, IgE is observed at higher levels in secondary infections of scabies compared to primary infections.⁶ Additionally, T-cell infiltrates are implicated in adaptive immune response to scabies. CD4+ T cells are the most prevalent T cells in ordinary scabies skin lesions; however, CD4+ T cells are minimal and CD8+ T cells are elevated in CS skin lesions. The increased CD8+ T cells may cause apoptosis of keratinocytes, leading to epidermal hyperproliferation. The apoptotic keratinocytes can secrete cytokines, which can lead to tissue damage.⁶ These T cells also may be involved in the failure of the skin’s immune system to mount an effective response to the parasite infestation, leading to uncontrolled parasitic growth. Because patients with AIDS who are infected with scabies mites often develop CS, it is also thought that CD4+ T cells are essential in the immune response to scabies.⁶

Diagnosis and Current Treatment Options

Current diagnosis of scabies is based on mites, eggs, and fecal matter from the host’s skin. Dermoscopy and fluorescent dermoscopy can be helpful in identifying the mites, eggs, and feces on the patient’s skin. Scabies treatment sometimes may be based solely on symptoms without any positive tests.⁸

Acaricides are the current method of treatment for scabies infestations.⁵ Acaricides can be expensive and toxic to the environment and food sources,¹⁰ and some agents have been associated with neurotoxicity⁵ in children or the development of certain cancers.¹¹ Although topical acaricides are the standard form of treatment, oral ivermectin also can be used. Ivermectin is not associated with selective fetal toxicity, but there are limited safety data in pregnant women and in children weighing less than 15 kg (33 lb). Additionally, because symptoms typically are not present during an early infection, treating everyone in the household and those who had close contact with the patient can help prevent reinfection.⁴

Although these drugs have been shown to be effective at treating scabies, scabies mites are becoming increasingly resistant to acaricides.⁵ There are 4 main proposed mechanisms for why this occurs.¹² The first is through voltage-gated sodium channels, which are involved in the normal functioning of neurons and myocytes. Permethrin, a type of acaricide, binds to voltage-gated sodium channels when it is in an open or active state and prevents it from closing. This creates repetitive neuron firing and hyperactivity, which ultimately kills the scabies mite. Some mites have mutated to close this channel, which reduces the binding potential of permethrin. Glutathione S-transferase is another mechanism of resistance. It catalyzes a bond that tags drugs for elimination. Increased activity or expressivity of glutathione S-transferase by scabies mites can lead to drug resistance.¹² Adenosine triphosphate– binding cassette (ABC) transporters also may contribute to this resistance. The ABC transporters use adenosine triphosphate to facilitate the import or export of molecules. Scabies mites express a protein called the multidrug-resistant protein, which is an ABC transporter that is associated with drug resistance and is present in scabies mites.¹² Lastly, ligand-gated chloride channels have been implicated in scabies resistance to acaricides. Ligand-gated chloride channels also are important in normal functioning of neurons and myocytes. Some antiparasitic drugs act on these channels, leading to a continuous influx of chloride, but some scabies mites have mutated this pathway.¹²

Pesticides and the Risk for Cancer

Pesticides commonly are used to treat scabies; however, a link between pesticide exposure and leukemia and lymphoma has been seen through epidemiologic studies, and there also is increasing biological evidence to suggest this.¹¹ For example, the pesticide permethrin, which works by paralyzing the nervous system of insects,¹³ has been associated with an increased risk for leukemia and lymphoma in humans. Permethrin is a pyrethroid and, compared to control patients, children with leukemia had higher levels of pyrethroid metabolites in their blood.¹⁴ Numerical and structural chromosomal aberrations that give rise to gene fusions are the most common abnormalities seen in leukemia, and permethrin has been shown to induce DNA breaks, chromosome aberrations, and sister chromatid exchanges.¹⁴ Permethrin also has been associated with an increased risk for multiple myeloma.¹³

Furthermore, in utero exposure to pesticides has been associated with an increased risk for childhood leukemia.¹⁵ Pesticide exposure shortly before conception, during pregnancy, and after birth is associated with an increased risk for acute lymphocytic leukemia.¹⁶ In fact, the children of mothers who were exposed to pesticides 3 months before conception have been found to be at least twice as likely to be diagnosed with acute lymphocytic leukemia within the first year of life compared with children whose mothers were not exposed to pesticides.¹⁷ It is hypothesized that permethrin can cross the placenta and alter the hematopoietic precursor cells in the fetus, resulting in leukemogenesis.¹⁸ Pyrethroid metabolites also have been detected in umbilical cord blood samples and breast milk.¹⁵

In contrast to the research demonstrating a link between permethrin and cancer, other studies have found no association between permethrin¹⁹ and leukemia²⁰; non-Hodgkin lymphoma¹⁹; or cancers of the colon, rectum, pancreas, lungs, skin, female breast, prostate, and urinary bladder.²⁰ Because of conflicting research on the link between permethrin and cancer, more research is needed.,²⁰

Importance of a Scabies Vaccine

Because scabies mites are developing increasing treatment resistance, more radical approaches such as vaccines are becoming important. While a scabies vaccine is still aspirational, animals that have been infected for a second time with scabies demonstrate a milder response to the second infection compared to the first infection, which could mean there is a potential for disease prevention through a vaccine.²¹ While educating patients and physicians, reporting cases of infection, and improving drug supply and access can help decrease scabies infestations, these are costly and difficult to implement. Scabies already is most prevalent in low-income areas, so costly interventions are even less feasible. An effective, one-dose vaccine would cost less than these efforts and therefore could be implemented more easily.⁹

In older adults, scabies more often manifests atypically and is more likely to progress to CS. Aged care centers are prone to institutional outbreaks, even in developed countries, so a vaccine also would greatly help this population. Additionally, the number of children attending day care centers, which also are prone to scabies outbreaks, is increasing. When a child contracts scabies, all close contacts need to be treated, so a preventive vaccine can be useful.⁹

One potential candidate for a scabies vaccine is total mite extract. Studies show that rabbits immunized with a total mite extract induce antibodies to more antigens than rabbits naturally infested with scabies mites; however, the mites cannot be cultured in vitro, which makes obtaining a large amount of their total extract difficult. Therefore, recombinant vaccines also have been proposed, as they are more easily available.²² One recombinant vaccine candidate is recombinant S scabiei serpin (rSs-serpin). Immunization with rSs-serpin has strong immunogenicity and produced immune protection in rabbits.²²

Two other recombinant vaccine candidates are the rSs chitinaselike protein (CLP) 12 and the rSsCLP5. Chitinaselike proteins are very similar to chitinases; however, they are unable to degrade chitin. They are involved in immune reactions to infections, and CLPs from scabies mites have been shown to induce the host immune response.²² For example, in a particular rabbit study, rSsCLP5 demonstrated high immunoreactivity and immunogenicity. In fact, after exposure to S scabiei, 74.3% of rabbits who were vaccinated with rSsCLP5 had no detectable lesions.⁵ Also, after immunization with rSsCLP5 and rSsCLP12, there were increased levels of specific IgG and IgE antibodies produced and decreased numbers of infesting mites.²² Weight loss also is associated with severe scabies infection. Rabbits vaccinated with rSsCLP5 and exposed to the parasite gained weight, indicating protection via rSsCLP5. Even rabbits who did develop symptoms of scabies after immunization with rSsCLP5 and exposure to S scabiei showed less serious manifestations.⁵

A combination vaccine cocktail of rSs-serpin, rSsCLP12, and rSsCLP5 also has been proposed by Shen et al.²² Four test groups and a control group (n=12 per group) were included in a vaccine trial. Between 83.33% and 91.67% of rabbits vaccinated with this mixed recombinant cocktail vaccine had no detectable skin lesions from scabies. After immunization with the cocktail vaccine, the specific serum IgG and IgE antibodies also increased. For both IgG and IgE, increased levels were first detected at 1 week postimmunization and peaked at 2 weeks postimmunization.²² A multiepitope vaccine derived from these 3 recombinant proteins also was explored by Shen et al²²; fewer rabbits vaccinated with it had no detectable scabies skin lesions compared to those treated with the vaccine cocktail. Although the multiepitope vaccine yielded less immume protection, it was associated with a slower disease course and milder symptoms compared with no vaccination.²²

Two more proposed scabies recombinant vaccine candidates are derived from the antigens Ssag1 and Ssag2; however, rabbits vaccinated with Ssag1 or Ssag2 showed no immune protection or mite burden reduction.²² The lack of protection could be due to denaturation or degradation of the protective antigens. It also can be due to the low abundance of these antigens, meaning they may not be vital for the mite’s survival—survival—a potential avenue for future research. The antigens also could have lost their native structure and immunogenic properties during the purification and production process. Therefore, more research is needed to investigate how to purify these vaccines to keep the peptides more structurally similar to their native makeups.¹⁰ More research also is needed to better understand the antigen or antigens and their mechanisms that elicit a protective immune response.⁹

Final Thoughts

Scabies causes severe pruritus in mild cases but also can lead to severe disfigurement, sepsis, and even death. Scabies infestations are seen disproportionately more often in low-income and resource-poor communities, and the current treatment options are less accessible to these populations. Scabies infestations induce a complex immune response that involves multiple aspects of both the innate and adaptive immune systems and can be targeted to create a scabies vaccine. Development of a scabies vaccine is crucial considering the growing resistance to current standard treatments. Acaricides potentially are associated with an increased risk for malignancy, which further amplifies the need for a scabies vaccine. There currently are multiple promising scabies vaccine candidates; however, more research is needed to better understand the host’s immune response to scabies as well as how to more accurately and efficiently produce the vaccine. The development of a safe, effective, economical vaccine that can be mass distributed would be beneficial in the treatment of scabies, especially in resource-poor communities.

The scabies mite, originally known as Acarus scabiei,¹ now is considered an arthropod of the class Arachnida, order Astigmata, and family Sarcoptidae.² Scabies mites are able to adhere to the surface of human skin.³ The mites burrow and lay eggs in the top layer of the epidermis; most patients have 10 to 15 mites.³ The patient’s immune system incites an allergic reaction to the mite protein and feces in the skin, causing itching and rash.⁴

Scabies is common in indigenous populations and in low-income areas of developing countries.⁵ It is most prevalent in Africa, South America, Australia, and Southeast Asia, in part due to poverty, poor nutritional status, homelessness, and inadequate hygiene.² In 2009, the World Health Organization declared scabies a neglected skin disease²; however, in 2010, 1.5 million disability adjusted life-years were attributed to scabies,⁶ and it is estimated that 200 million people worldwide have scabies at any given time. Children and elderly individuals in resource-poor communities are the most at risk. In fact, 5% to 50% of children in low-income areas have scabies.⁴

The purpose of this article is to provide background on scabies and its effect on the human immune system. We also discuss manipulation of the immune response for the purposes of creating a potential scabies vaccine.

Life Cycle and Transmission

The life cycle of Sarcoptes scabiei consists of 4 stages. The first is the egg. As female scabies mites burrow under the skin, they lay 2 to 3 ovular eggs per day.³ The second stage is the larva. When the egg hatches, the larva has 3 pairs of legs and travels to the surface of the skin where it burrows into the stratum corneum, creating short, nearly invisible burrows called molting pouches. After 3 to 4 days, the larva molts into a nymph, which is the third stage. The nymph has 4 pairs of legs and will continue to grow before molting into an adult, which is the fourth stage. Both the larva and nymph may be found in hair follicles or molting pouches. The fourth stage is the adult, which is round and saclike and does not have eyes. Adult females are 0.30 mm to 0.45 mm long and 0.25 mm to 0.35 mm wide, which is half the size of adult males.³ On warm skin, the female mite can crawl at a rate of 2.5 cm per minute.⁷

Scabies mites mate via an active male penetrating the molting pouch of a female. This only occurs once but leaves the female fertile for the rest of her life. Once a female is pregnant, she leaves her molting pouch and travels along the surface of the skin looking for a place to make her permanent burrow.³ The most common sites for scabies burrows are the axillae, umbilicus, interdigital spaces, beltline, buttocks, flexor surfaces of the wrists, female nipples, and male penile shaft.⁵ Once she finds an acceptable location, the female scabies mite will create a serpentine burrow and lay her eggs. Once she burrows, she will stay there and continue to lay eggs for the rest of her life, lengthening the burrow as needed.³ Female mites lay their eggs in the superficial epidermis, and the eggs take approximately 2 to 3 weeks to hatch. Female mites die 30 to 60 days later.²

Scabies infestations typically spread via the transfer of pregnant adult females during skin-to-skin contact, but they also can spread via fomites.³ During all stages of their life cycle, scabies mites can secrete enzymes that allow them to penetrate the intact epidermis in less than 30 minutes; in fact, an otherwise healthy patient with scabies must have 15 to 20 minutes of close skin-to-skin contact with an infected individual for the disease to be transmitted.⁷ Because scabies mites can survive for more than 3 days outside the human body, it is thought that fomites also may be involved in transmission. Scabies mites also have been collected from clothing, bedding, and furniture, which further supports the idea that fomites are involved in disease transmission.⁷

Clinical Manifestation of Scabies

Scabies symptoms include severe pruritus as well as linear burrows and vesicles in the interdigital spaces on the hands, wrists, arms and legs, and lower abdomen. Infants and young children also can develop a rash on the palms, soles, ankles, and scalp. Men can develop inflammatory scabies nodules on the penis and scrotum, while women can develop these nodules on the nipple.⁴ Type I and type IV hypersensitivity reactions contribute to the rash and itching associated with scabies infestation via host allergic and inflammatory reactions to the mites and their byproducts. Patients with scabies typically are infested with fewer than 15 mites,⁶ but just a few can cause substantial pruritus and scratching, leading to hyperkeratosis.⁸

Additionally, when patients with scabies scratch the skin, they become vulnerable to bacterial infections.⁴ Scabies lesions can be coinfected with group A streptococci and Staphylococcus aureus,⁸ potentially leading to abscesses and septicemia. These secondary infections also can cause renal and cardiac complications; in fact, in tropical areas, scabies infections are considered a risk factor for kidney disease and rheumatic heart disease.⁴

The 2 main forms of scabies infestations are ordinary and crusted. The most common form is ordinary scabies, which typically manifests with fewer than 15 mites per patient; crusted scabies (CS) is the more rare and extreme form.⁶ Cases of CS present with thousands to millions of mites per patient, leading to more widespread and severe symptoms.⁴ Because of the large increase in the number of mites, CS is more contagious than ordinary scabies.⁶

Patients with CS typically present with hyperkeratotic skin disease, as evidenced by thick scaly crusts with large numbers of mites, which can lead to permanent skin disfiguration. Patients with CS also can develop deep fissuring of the crusts, within which other microbes can gain entry to the body and lead to secondary infection and possibly sepsis and death. Also, because of the increased number of mites as well as the crusted skin, patients with CS are contagious for longer. As it is more difficult to eradicate, reinfestation is common with CS.⁶

Patients with compromised immune systems are predisposed to CS. Specifically, patients with HIV or human T-lymphotropic virus 1 or those undergoing organ transplantation are thought to be the most at risk for CS.⁶ Crusted scabies also has been identified in large numbers in patients with Down syndrome and in Aboriginal Australians; however, the reasoning for this is poorly understood.⁶

Immune Response

The inflammatory reaction associated with scabies infestations occurs 4 to 6 weeks after initial exposure. It is hypothesized that scabies can alter parts of the host immune system, which contributes to the delayed onset of symptoms. Scabies mites also produce inactivated protease paralogues and serpins, which help to protect the mites from the host immune system by inhibiting the complement system.⁶

The complement system is part of the innate immune response and is the first line of defense against pathogens. Specifically with scabies infestations, C3 and C4 complement components have been found in skin lesions.⁶ C3a and C4a fragments cause local inflammation, while C3a and C5a activate mast cells to release histamine and tumor necrosis factor (TNF) α, further amplifying the inflammatory response; however, CS lesions show low C3 and C4, which can indicate immunodeficiency in patients with CS. It also can be due to the sheer number of mites in a CS infection causing the host immune system to be overloaded.⁶

Innate effector immune cells also are an important part of the innate immune response to scabies; for example, eosinophilia is seen in scabies infections. Specifically, in CS, eosinophils help modulate and sustain the T-helper (Th) 2 inflammatory response. One cytokine secreted by Th2 cells is IL-5, which is closely associated with the attraction, maturation, and survival of eosinophils.⁶ Eosinophils also can influence the Th1 inflammatory response in that they produce IL-12, interferon (IFN) γ, and several Toll-like receptors. Furthermore, eosinophilic expression of IL-2 can lead to expansion of regulatory T cells, while eosinophilic expression of IL-10 and transforming growth factor (TGF) Β also can suppress local inflammation by influencing regulatory T cells.⁶

Additionally, mast cells and basophils are important in the IgE-mediated allergic reaction as well as the host immune response to parasites. When activated, basophils and mast cells produce TNF-α, IL-6, Il-4, IL-5, and IL-13, which contribute to the Th2 inflammatory response; however, the role of mast cells and basophils in scabies infections still is poorly understood.⁶

Macrophages, neutrophils, and dendritic cells (DCs) contribute to phagocytosis, antigen presentation, and differentiation of T cells, which also contribute to the inflammatory and allergic reactions associated with parasitic infections.⁶ Macrophages have been found in low numbers in scabies infestation, possibly due to immune-modulating molecules secreted by scabies mites. Early in an infestation, the mites secrete immune-modulating molecules, which inhibit macrophage migration to the site of inflammation, allowing the mites to grow.⁶ Neutrophils and DCs also are involved in the host immune response to scabies. Neutrophils are the predominant inflammatory cell infiltrate in scabies lesions. The scabies protein SMSB4 inhibits neutrophil opsonization and phagocytosis, thus suppressing bacterial killing.⁶ Some of the first antigen-presenting cells encountered by the antigen are DCs. They are involved in preparing the antigens for presentation to effector T cells, which leads to T-cell differentiation and activation.⁶

Cytokines are another important factor in the innate immune response. The host immune response to ordinary scabies is Th1-cell mediated, during which CD4+ and CD8+ T cells secrete IFN-γ, TNF-α, and IL-2.⁶ Therefore, IFN- γ and TNF-α are elevated in the serum of patients with ordinary scabies. Conversely, the host immune response to CS is Th2-cell mediated. T-helper 2 cells are needed in IgE-mediated hypersensitivity reactions, and they secrete IL-4, IL-5, and IL-13. In the serum of patients with CS, IL-l4, IL-5, and IL-13 are elevated while IFN-γ is decreased.⁶ Additionally, IL-6, TGF-Β, IL-23, IL-1Β, or IL-18 can induce Th17 cells to generate and secrete IL-17, which enhances the inflammatory response by inducing further expression of TNF-α, IL-1Β, IL-6, keratinocytes, and fibroblasts. T-helper 17 and IL-17 also are involved in psoriasis and atopic dermatitis, as well as Leishmania major and Schistosoma japonicum.⁶

Regulatory T cells Tregs secrete TGF-Β and IL-10, which suppress pathologic inflammation, and IL-10 is substantially reduced in patients with CS compared to those with ordinary scabies and uninfected control patients. Additionally, IL-10 can inhibit the synthesis of TNF-γ and IFN-α. Reduced IL-10 expression can lead to proliferation of IL-17 secretion, resulting in a regulatory T cell/Th17 dysfunctional immune response.⁶

Immunoglobulins are antibodies that are involved in the host’s adaptive immune response. The first antibody to appear in response to an antigen is IgM, and IgM bound to scabies antigens is present in 74%⁶ of patients with ordinary scabies. Because IgM is the first antibody to appear in response to a scabies infection, detection of serum IgM may allow for earlier detection of scabies; however, IgM has a high cross-reactivity between scabies mites and dust mites, which can hinder scabies diagnosis via IgM detection.⁶

Both patients with ordinary scabies and CS also show an increased circulatory IgG concentration compared to control groups; patients with CS have higher concentrations. Increased IgG also can be in part due to concurrent bacterial infections.⁶ When IgG or IgM antibodies bind to a pathogen, they activate the complement cascade, which further enhances the activity of these antibodies.⁹

Additionally, IgA is important in mucosal immune function. In both patients with ordinary scabies and CS, there is increased IgA binding to recombinant scabies mite antigens.⁶ Sarcoptes scabiei proteases that are localized in the mite’s gut and scybala suggest their involvement in mite digestion and burrowing. The increased secretion of these proteases into the host skin may contribute to the increased IgA,⁹ and these increased IgA levels have been shown to be positively correlated with severity of scabies infection.⁶

Also essential in allergic and parasitic inflammation, IgE is observed at higher levels in secondary infections of scabies compared to primary infections.⁶ Additionally, T-cell infiltrates are implicated in adaptive immune response to scabies. CD4+ T cells are the most prevalent T cells in ordinary scabies skin lesions; however, CD4+ T cells are minimal and CD8+ T cells are elevated in CS skin lesions. The increased CD8+ T cells may cause apoptosis of keratinocytes, leading to epidermal hyperproliferation. The apoptotic keratinocytes can secrete cytokines, which can lead to tissue damage.⁶ These T cells also may be involved in the failure of the skin’s immune system to mount an effective response to the parasite infestation, leading to uncontrolled parasitic growth. Because patients with AIDS who are infected with scabies mites often develop CS, it is also thought that CD4+ T cells are essential in the immune response to scabies.⁶

Diagnosis and Current Treatment Options

Current diagnosis of scabies is based on mites, eggs, and fecal matter from the host’s skin. Dermoscopy and fluorescent dermoscopy can be helpful in identifying the mites, eggs, and feces on the patient’s skin. Scabies treatment sometimes may be based solely on symptoms without any positive tests.⁸

Acaricides are the current method of treatment for scabies infestations.⁵ Acaricides can be expensive and toxic to the environment and food sources,¹⁰ and some agents have been associated with neurotoxicity⁵ in children or the development of certain cancers.¹¹ Although topical acaricides are the standard form of treatment, oral ivermectin also can be used. Ivermectin is not associated with selective fetal toxicity, but there are limited safety data in pregnant women and in children weighing less than 15 kg (33 lb). Additionally, because symptoms typically are not present during an early infection, treating everyone in the household and those who had close contact with the patient can help prevent reinfection.⁴

Although these drugs have been shown to be effective at treating scabies, scabies mites are becoming increasingly resistant to acaricides.⁵ There are 4 main proposed mechanisms for why this occurs.¹² The first is through voltage-gated sodium channels, which are involved in the normal functioning of neurons and myocytes. Permethrin, a type of acaricide, binds to voltage-gated sodium channels when it is in an open or active state and prevents it from closing. This creates repetitive neuron firing and hyperactivity, which ultimately kills the scabies mite. Some mites have mutated to close this channel, which reduces the binding potential of permethrin. Glutathione S-transferase is another mechanism of resistance. It catalyzes a bond that tags drugs for elimination. Increased activity or expressivity of glutathione S-transferase by scabies mites can lead to drug resistance.¹² Adenosine triphosphate– binding cassette (ABC) transporters also may contribute to this resistance. The ABC transporters use adenosine triphosphate to facilitate the import or export of molecules. Scabies mites express a protein called the multidrug-resistant protein, which is an ABC transporter that is associated with drug resistance and is present in scabies mites.¹² Lastly, ligand-gated chloride channels have been implicated in scabies resistance to acaricides. Ligand-gated chloride channels also are important in normal functioning of neurons and myocytes. Some antiparasitic drugs act on these channels, leading to a continuous influx of chloride, but some scabies mites have mutated this pathway.¹²

Pesticides and the Risk for Cancer

Pesticides commonly are used to treat scabies; however, a link between pesticide exposure and leukemia and lymphoma has been seen through epidemiologic studies, and there also is increasing biological evidence to suggest this.¹¹ For example, the pesticide permethrin, which works by paralyzing the nervous system of insects,¹³ has been associated with an increased risk for leukemia and lymphoma in humans. Permethrin is a pyrethroid and, compared to control patients, children with leukemia had higher levels of pyrethroid metabolites in their blood.¹⁴ Numerical and structural chromosomal aberrations that give rise to gene fusions are the most common abnormalities seen in leukemia, and permethrin has been shown to induce DNA breaks, chromosome aberrations, and sister chromatid exchanges.¹⁴ Permethrin also has been associated with an increased risk for multiple myeloma.¹³

Furthermore, in utero exposure to pesticides has been associated with an increased risk for childhood leukemia.¹⁵ Pesticide exposure shortly before conception, during pregnancy, and after birth is associated with an increased risk for acute lymphocytic leukemia.¹⁶ In fact, the children of mothers who were exposed to pesticides 3 months before conception have been found to be at least twice as likely to be diagnosed with acute lymphocytic leukemia within the first year of life compared with children whose mothers were not exposed to pesticides.¹⁷ It is hypothesized that permethrin can cross the placenta and alter the hematopoietic precursor cells in the fetus, resulting in leukemogenesis.¹⁸ Pyrethroid metabolites also have been detected in umbilical cord blood samples and breast milk.¹⁵

In contrast to the research demonstrating a link between permethrin and cancer, other studies have found no association between permethrin¹⁹ and leukemia²⁰; non-Hodgkin lymphoma¹⁹; or cancers of the colon, rectum, pancreas, lungs, skin, female breast, prostate, and urinary bladder.²⁰ Because of conflicting research on the link between permethrin and cancer, more research is needed.,²⁰

Importance of a Scabies Vaccine

Because scabies mites are developing increasing treatment resistance, more radical approaches such as vaccines are becoming important. While a scabies vaccine is still aspirational, animals that have been infected for a second time with scabies demonstrate a milder response to the second infection compared to the first infection, which could mean there is a potential for disease prevention through a vaccine.²¹ While educating patients and physicians, reporting cases of infection, and improving drug supply and access can help decrease scabies infestations, these are costly and difficult to implement. Scabies already is most prevalent in low-income areas, so costly interventions are even less feasible. An effective, one-dose vaccine would cost less than these efforts and therefore could be implemented more easily.⁹

In older adults, scabies more often manifests atypically and is more likely to progress to CS. Aged care centers are prone to institutional outbreaks, even in developed countries, so a vaccine also would greatly help this population. Additionally, the number of children attending day care centers, which also are prone to scabies outbreaks, is increasing. When a child contracts scabies, all close contacts need to be treated, so a preventive vaccine can be useful.⁹

One potential candidate for a scabies vaccine is total mite extract. Studies show that rabbits immunized with a total mite extract induce antibodies to more antigens than rabbits naturally infested with scabies mites; however, the mites cannot be cultured in vitro, which makes obtaining a large amount of their total extract difficult. Therefore, recombinant vaccines also have been proposed, as they are more easily available.²² One recombinant vaccine candidate is recombinant S scabiei serpin (rSs-serpin). Immunization with rSs-serpin has strong immunogenicity and produced immune protection in rabbits.²²

Two other recombinant vaccine candidates are the rSs chitinaselike protein (CLP) 12 and the rSsCLP5. Chitinaselike proteins are very similar to chitinases; however, they are unable to degrade chitin. They are involved in immune reactions to infections, and CLPs from scabies mites have been shown to induce the host immune response.²² For example, in a particular rabbit study, rSsCLP5 demonstrated high immunoreactivity and immunogenicity. In fact, after exposure to S scabiei, 74.3% of rabbits who were vaccinated with rSsCLP5 had no detectable lesions.⁵ Also, after immunization with rSsCLP5 and rSsCLP12, there were increased levels of specific IgG and IgE antibodies produced and decreased numbers of infesting mites.²² Weight loss also is associated with severe scabies infection. Rabbits vaccinated with rSsCLP5 and exposed to the parasite gained weight, indicating protection via rSsCLP5. Even rabbits who did develop symptoms of scabies after immunization with rSsCLP5 and exposure to S scabiei showed less serious manifestations.⁵

A combination vaccine cocktail of rSs-serpin, rSsCLP12, and rSsCLP5 also has been proposed by Shen et al.²² Four test groups and a control group (n=12 per group) were included in a vaccine trial. Between 83.33% and 91.67% of rabbits vaccinated with this mixed recombinant cocktail vaccine had no detectable skin lesions from scabies. After immunization with the cocktail vaccine, the specific serum IgG and IgE antibodies also increased. For both IgG and IgE, increased levels were first detected at 1 week postimmunization and peaked at 2 weeks postimmunization.²² A multiepitope vaccine derived from these 3 recombinant proteins also was explored by Shen et al²²; fewer rabbits vaccinated with it had no detectable scabies skin lesions compared to those treated with the vaccine cocktail. Although the multiepitope vaccine yielded less immume protection, it was associated with a slower disease course and milder symptoms compared with no vaccination.²²

Two more proposed scabies recombinant vaccine candidates are derived from the antigens Ssag1 and Ssag2; however, rabbits vaccinated with Ssag1 or Ssag2 showed no immune protection or mite burden reduction.²² The lack of protection could be due to denaturation or degradation of the protective antigens. It also can be due to the low abundance of these antigens, meaning they may not be vital for the mite’s survival—survival—a potential avenue for future research. The antigens also could have lost their native structure and immunogenic properties during the purification and production process. Therefore, more research is needed to investigate how to purify these vaccines to keep the peptides more structurally similar to their native makeups.¹⁰ More research also is needed to better understand the antigen or antigens and their mechanisms that elicit a protective immune response.⁹

Final Thoughts

Scabies causes severe pruritus in mild cases but also can lead to severe disfigurement, sepsis, and even death. Scabies infestations are seen disproportionately more often in low-income and resource-poor communities, and the current treatment options are less accessible to these populations. Scabies infestations induce a complex immune response that involves multiple aspects of both the innate and adaptive immune systems and can be targeted to create a scabies vaccine. Development of a scabies vaccine is crucial considering the growing resistance to current standard treatments. Acaricides potentially are associated with an increased risk for malignancy, which further amplifies the need for a scabies vaccine. There currently are multiple promising scabies vaccine candidates; however, more research is needed to better understand the host’s immune response to scabies as well as how to more accurately and efficiently produce the vaccine. The development of a safe, effective, economical vaccine that can be mass distributed would be beneficial in the treatment of scabies, especially in resource-poor communities.

The scabies mite, originally known as Acarus scabiei,¹ now is considered an arthropod of the class Arachnida, order Astigmata, and family Sarcoptidae.² Scabies mites are able to adhere to the surface of human skin.³ The mites burrow and lay eggs in the top layer of the epidermis; most patients have 10 to 15 mites.³ The patient’s immune system incites an allergic reaction to the mite protein and feces in the skin, causing itching and rash.⁴

Scabies is common in indigenous populations and in low-income areas of developing countries.⁵ It is most prevalent in Africa, South America, Australia, and Southeast Asia, in part due to poverty, poor nutritional status, homelessness, and inadequate hygiene.² In 2009, the World Health Organization declared scabies a neglected skin disease²; however, in 2010, 1.5 million disability adjusted life-years were attributed to scabies,⁶ and it is estimated that 200 million people worldwide have scabies at any given time. Children and elderly individuals in resource-poor communities are the most at risk. In fact, 5% to 50% of children in low-income areas have scabies.⁴

The purpose of this article is to provide background on scabies and its effect on the human immune system. We also discuss manipulation of the immune response for the purposes of creating a potential scabies vaccine.

Life Cycle and Transmission

The life cycle of Sarcoptes scabiei consists of 4 stages. The first is the egg. As female scabies mites burrow under the skin, they lay 2 to 3 ovular eggs per day.³ The second stage is the larva. When the egg hatches, the larva has 3 pairs of legs and travels to the surface of the skin where it burrows into the stratum corneum, creating short, nearly invisible burrows called molting pouches. After 3 to 4 days, the larva molts into a nymph, which is the third stage. The nymph has 4 pairs of legs and will continue to grow before molting into an adult, which is the fourth stage. Both the larva and nymph may be found in hair follicles or molting pouches. The fourth stage is the adult, which is round and saclike and does not have eyes. Adult females are 0.30 mm to 0.45 mm long and 0.25 mm to 0.35 mm wide, which is half the size of adult males.³ On warm skin, the female mite can crawl at a rate of 2.5 cm per minute.⁷

Scabies mites mate via an active male penetrating the molting pouch of a female. This only occurs once but leaves the female fertile for the rest of her life. Once a female is pregnant, she leaves her molting pouch and travels along the surface of the skin looking for a place to make her permanent burrow.³ The most common sites for scabies burrows are the axillae, umbilicus, interdigital spaces, beltline, buttocks, flexor surfaces of the wrists, female nipples, and male penile shaft.⁵ Once she finds an acceptable location, the female scabies mite will create a serpentine burrow and lay her eggs. Once she burrows, she will stay there and continue to lay eggs for the rest of her life, lengthening the burrow as needed.³ Female mites lay their eggs in the superficial epidermis, and the eggs take approximately 2 to 3 weeks to hatch. Female mites die 30 to 60 days later.²

Scabies infestations typically spread via the transfer of pregnant adult females during skin-to-skin contact, but they also can spread via fomites.³ During all stages of their life cycle, scabies mites can secrete enzymes that allow them to penetrate the intact epidermis in less than 30 minutes; in fact, an otherwise healthy patient with scabies must have 15 to 20 minutes of close skin-to-skin contact with an infected individual for the disease to be transmitted.⁷ Because scabies mites can survive for more than 3 days outside the human body, it is thought that fomites also may be involved in transmission. Scabies mites also have been collected from clothing, bedding, and furniture, which further supports the idea that fomites are involved in disease transmission.⁷

Clinical Manifestation of Scabies

Scabies symptoms include severe pruritus as well as linear burrows and vesicles in the interdigital spaces on the hands, wrists, arms and legs, and lower abdomen. Infants and young children also can develop a rash on the palms, soles, ankles, and scalp. Men can develop inflammatory scabies nodules on the penis and scrotum, while women can develop these nodules on the nipple.⁴ Type I and type IV hypersensitivity reactions contribute to the rash and itching associated with scabies infestation via host allergic and inflammatory reactions to the mites and their byproducts. Patients with scabies typically are infested with fewer than 15 mites,⁶ but just a few can cause substantial pruritus and scratching, leading to hyperkeratosis.⁸

Additionally, when patients with scabies scratch the skin, they become vulnerable to bacterial infections.⁴ Scabies lesions can be coinfected with group A streptococci and Staphylococcus aureus,⁸ potentially leading to abscesses and septicemia. These secondary infections also can cause renal and cardiac complications; in fact, in tropical areas, scabies infections are considered a risk factor for kidney disease and rheumatic heart disease.⁴

The 2 main forms of scabies infestations are ordinary and crusted. The most common form is ordinary scabies, which typically manifests with fewer than 15 mites per patient; crusted scabies (CS) is the more rare and extreme form.⁶ Cases of CS present with thousands to millions of mites per patient, leading to more widespread and severe symptoms.⁴ Because of the large increase in the number of mites, CS is more contagious than ordinary scabies.⁶

Patients with CS typically present with hyperkeratotic skin disease, as evidenced by thick scaly crusts with large numbers of mites, which can lead to permanent skin disfiguration. Patients with CS also can develop deep fissuring of the crusts, within which other microbes can gain entry to the body and lead to secondary infection and possibly sepsis and death. Also, because of the increased number of mites as well as the crusted skin, patients with CS are contagious for longer. As it is more difficult to eradicate, reinfestation is common with CS.⁶

Patients with compromised immune systems are predisposed to CS. Specifically, patients with HIV or human T-lymphotropic virus 1 or those undergoing organ transplantation are thought to be the most at risk for CS.⁶ Crusted scabies also has been identified in large numbers in patients with Down syndrome and in Aboriginal Australians; however, the reasoning for this is poorly understood.⁶

Immune Response

The inflammatory reaction associated with scabies infestations occurs 4 to 6 weeks after initial exposure. It is hypothesized that scabies can alter parts of the host immune system, which contributes to the delayed onset of symptoms. Scabies mites also produce inactivated protease paralogues and serpins, which help to protect the mites from the host immune system by inhibiting the complement system.⁶

The complement system is part of the innate immune response and is the first line of defense against pathogens. Specifically with scabies infestations, C3 and C4 complement components have been found in skin lesions.⁶ C3a and C4a fragments cause local inflammation, while C3a and C5a activate mast cells to release histamine and tumor necrosis factor (TNF) α, further amplifying the inflammatory response; however, CS lesions show low C3 and C4, which can indicate immunodeficiency in patients with CS. It also can be due to the sheer number of mites in a CS infection causing the host immune system to be overloaded.⁶

Innate effector immune cells also are an important part of the innate immune response to scabies; for example, eosinophilia is seen in scabies infections. Specifically, in CS, eosinophils help modulate and sustain the T-helper (Th) 2 inflammatory response. One cytokine secreted by Th2 cells is IL-5, which is closely associated with the attraction, maturation, and survival of eosinophils.⁶ Eosinophils also can influence the Th1 inflammatory response in that they produce IL-12, interferon (IFN) γ, and several Toll-like receptors. Furthermore, eosinophilic expression of IL-2 can lead to expansion of regulatory T cells, while eosinophilic expression of IL-10 and transforming growth factor (TGF) Β also can suppress local inflammation by influencing regulatory T cells.⁶

Additionally, mast cells and basophils are important in the IgE-mediated allergic reaction as well as the host immune response to parasites. When activated, basophils and mast cells produce TNF-α, IL-6, Il-4, IL-5, and IL-13, which contribute to the Th2 inflammatory response; however, the role of mast cells and basophils in scabies infections still is poorly understood.⁶

Macrophages, neutrophils, and dendritic cells (DCs) contribute to phagocytosis, antigen presentation, and differentiation of T cells, which also contribute to the inflammatory and allergic reactions associated with parasitic infections.⁶ Macrophages have been found in low numbers in scabies infestation, possibly due to immune-modulating molecules secreted by scabies mites. Early in an infestation, the mites secrete immune-modulating molecules, which inhibit macrophage migration to the site of inflammation, allowing the mites to grow.⁶ Neutrophils and DCs also are involved in the host immune response to scabies. Neutrophils are the predominant inflammatory cell infiltrate in scabies lesions. The scabies protein SMSB4 inhibits neutrophil opsonization and phagocytosis, thus suppressing bacterial killing.⁶ Some of the first antigen-presenting cells encountered by the antigen are DCs. They are involved in preparing the antigens for presentation to effector T cells, which leads to T-cell differentiation and activation.⁶

Cytokines are another important factor in the innate immune response. The host immune response to ordinary scabies is Th1-cell mediated, during which CD4+ and CD8+ T cells secrete IFN-γ, TNF-α, and IL-2.⁶ Therefore, IFN- γ and TNF-α are elevated in the serum of patients with ordinary scabies. Conversely, the host immune response to CS is Th2-cell mediated. T-helper 2 cells are needed in IgE-mediated hypersensitivity reactions, and they secrete IL-4, IL-5, and IL-13. In the serum of patients with CS, IL-l4, IL-5, and IL-13 are elevated while IFN-γ is decreased.⁶ Additionally, IL-6, TGF-Β, IL-23, IL-1Β, or IL-18 can induce Th17 cells to generate and secrete IL-17, which enhances the inflammatory response by inducing further expression of TNF-α, IL-1Β, IL-6, keratinocytes, and fibroblasts. T-helper 17 and IL-17 also are involved in psoriasis and atopic dermatitis, as well as Leishmania major and Schistosoma japonicum.⁶

Regulatory T cells Tregs secrete TGF-Β and IL-10, which suppress pathologic inflammation, and IL-10 is substantially reduced in patients with CS compared to those with ordinary scabies and uninfected control patients. Additionally, IL-10 can inhibit the synthesis of TNF-γ and IFN-α. Reduced IL-10 expression can lead to proliferation of IL-17 secretion, resulting in a regulatory T cell/Th17 dysfunctional immune response.⁶

Immunoglobulins are antibodies that are involved in the host’s adaptive immune response. The first antibody to appear in response to an antigen is IgM, and IgM bound to scabies antigens is present in 74%⁶ of patients with ordinary scabies. Because IgM is the first antibody to appear in response to a scabies infection, detection of serum IgM may allow for earlier detection of scabies; however, IgM has a high cross-reactivity between scabies mites and dust mites, which can hinder scabies diagnosis via IgM detection.⁶

Both patients with ordinary scabies and CS also show an increased circulatory IgG concentration compared to control groups; patients with CS have higher concentrations. Increased IgG also can be in part due to concurrent bacterial infections.⁶ When IgG or IgM antibodies bind to a pathogen, they activate the complement cascade, which further enhances the activity of these antibodies.⁹

Additionally, IgA is important in mucosal immune function. In both patients with ordinary scabies and CS, there is increased IgA binding to recombinant scabies mite antigens.⁶ Sarcoptes scabiei proteases that are localized in the mite’s gut and scybala suggest their involvement in mite digestion and burrowing. The increased secretion of these proteases into the host skin may contribute to the increased IgA,⁹ and these increased IgA levels have been shown to be positively correlated with severity of scabies infection.⁶

Also essential in allergic and parasitic inflammation, IgE is observed at higher levels in secondary infections of scabies compared to primary infections.⁶ Additionally, T-cell infiltrates are implicated in adaptive immune response to scabies. CD4+ T cells are the most prevalent T cells in ordinary scabies skin lesions; however, CD4+ T cells are minimal and CD8+ T cells are elevated in CS skin lesions. The increased CD8+ T cells may cause apoptosis of keratinocytes, leading to epidermal hyperproliferation. The apoptotic keratinocytes can secrete cytokines, which can lead to tissue damage.⁶ These T cells also may be involved in the failure of the skin’s immune system to mount an effective response to the parasite infestation, leading to uncontrolled parasitic growth. Because patients with AIDS who are infected with scabies mites often develop CS, it is also thought that CD4+ T cells are essential in the immune response to scabies.⁶

Diagnosis and Current Treatment Options

Current diagnosis of scabies is based on mites, eggs, and fecal matter from the host’s skin. Dermoscopy and fluorescent dermoscopy can be helpful in identifying the mites, eggs, and feces on the patient’s skin. Scabies treatment sometimes may be based solely on symptoms without any positive tests.⁸

Acaricides are the current method of treatment for scabies infestations.⁵ Acaricides can be expensive and toxic to the environment and food sources,¹⁰ and some agents have been associated with neurotoxicity⁵ in children or the development of certain cancers.¹¹ Although topical acaricides are the standard form of treatment, oral ivermectin also can be used. Ivermectin is not associated with selective fetal toxicity, but there are limited safety data in pregnant women and in children weighing less than 15 kg (33 lb). Additionally, because symptoms typically are not present during an early infection, treating everyone in the household and those who had close contact with the patient can help prevent reinfection.⁴

Although these drugs have been shown to be effective at treating scabies, scabies mites are becoming increasingly resistant to acaricides.⁵ There are 4 main proposed mechanisms for why this occurs.¹² The first is through voltage-gated sodium channels, which are involved in the normal functioning of neurons and myocytes. Permethrin, a type of acaricide, binds to voltage-gated sodium channels when it is in an open or active state and prevents it from closing. This creates repetitive neuron firing and hyperactivity, which ultimately kills the scabies mite. Some mites have mutated to close this channel, which reduces the binding potential of permethrin. Glutathione S-transferase is another mechanism of resistance. It catalyzes a bond that tags drugs for elimination. Increased activity or expressivity of glutathione S-transferase by scabies mites can lead to drug resistance.¹² Adenosine triphosphate– binding cassette (ABC) transporters also may contribute to this resistance. The ABC transporters use adenosine triphosphate to facilitate the import or export of molecules. Scabies mites express a protein called the multidrug-resistant protein, which is an ABC transporter that is associated with drug resistance and is present in scabies mites.¹² Lastly, ligand-gated chloride channels have been implicated in scabies resistance to acaricides. Ligand-gated chloride channels also are important in normal functioning of neurons and myocytes. Some antiparasitic drugs act on these channels, leading to a continuous influx of chloride, but some scabies mites have mutated this pathway.¹²

Pesticides and the Risk for Cancer

Pesticides commonly are used to treat scabies; however, a link between pesticide exposure and leukemia and lymphoma has been seen through epidemiologic studies, and there also is increasing biological evidence to suggest this.¹¹ For example, the pesticide permethrin, which works by paralyzing the nervous system of insects,¹³ has been associated with an increased risk for leukemia and lymphoma in humans. Permethrin is a pyrethroid and, compared to control patients, children with leukemia had higher levels of pyrethroid metabolites in their blood.¹⁴ Numerical and structural chromosomal aberrations that give rise to gene fusions are the most common abnormalities seen in leukemia, and permethrin has been shown to induce DNA breaks, chromosome aberrations, and sister chromatid exchanges.¹⁴ Permethrin also has been associated with an increased risk for multiple myeloma.¹³

Furthermore, in utero exposure to pesticides has been associated with an increased risk for childhood leukemia.¹⁵ Pesticide exposure shortly before conception, during pregnancy, and after birth is associated with an increased risk for acute lymphocytic leukemia.¹⁶ In fact, the children of mothers who were exposed to pesticides 3 months before conception have been found to be at least twice as likely to be diagnosed with acute lymphocytic leukemia within the first year of life compared with children whose mothers were not exposed to pesticides.¹⁷ It is hypothesized that permethrin can cross the placenta and alter the hematopoietic precursor cells in the fetus, resulting in leukemogenesis.¹⁸ Pyrethroid metabolites also have been detected in umbilical cord blood samples and breast milk.¹⁵

In contrast to the research demonstrating a link between permethrin and cancer, other studies have found no association between permethrin¹⁹ and leukemia²⁰; non-Hodgkin lymphoma¹⁹; or cancers of the colon, rectum, pancreas, lungs, skin, female breast, prostate, and urinary bladder.²⁰ Because of conflicting research on the link between permethrin and cancer, more research is needed.,²⁰

Importance of a Scabies Vaccine

Because scabies mites are developing increasing treatment resistance, more radical approaches such as vaccines are becoming important. While a scabies vaccine is still aspirational, animals that have been infected for a second time with scabies demonstrate a milder response to the second infection compared to the first infection, which could mean there is a potential for disease prevention through a vaccine.²¹ While educating patients and physicians, reporting cases of infection, and improving drug supply and access can help decrease scabies infestations, these are costly and difficult to implement. Scabies already is most prevalent in low-income areas, so costly interventions are even less feasible. An effective, one-dose vaccine would cost less than these efforts and therefore could be implemented more easily.⁹

In older adults, scabies more often manifests atypically and is more likely to progress to CS. Aged care centers are prone to institutional outbreaks, even in developed countries, so a vaccine also would greatly help this population. Additionally, the number of children attending day care centers, which also are prone to scabies outbreaks, is increasing. When a child contracts scabies, all close contacts need to be treated, so a preventive vaccine can be useful.⁹

One potential candidate for a scabies vaccine is total mite extract. Studies show that rabbits immunized with a total mite extract induce antibodies to more antigens than rabbits naturally infested with scabies mites; however, the mites cannot be cultured in vitro, which makes obtaining a large amount of their total extract difficult. Therefore, recombinant vaccines also have been proposed, as they are more easily available.²² One recombinant vaccine candidate is recombinant S scabiei serpin (rSs-serpin). Immunization with rSs-serpin has strong immunogenicity and produced immune protection in rabbits.²²

Two other recombinant vaccine candidates are the rSs chitinaselike protein (CLP) 12 and the rSsCLP5. Chitinaselike proteins are very similar to chitinases; however, they are unable to degrade chitin. They are involved in immune reactions to infections, and CLPs from scabies mites have been shown to induce the host immune response.²² For example, in a particular rabbit study, rSsCLP5 demonstrated high immunoreactivity and immunogenicity. In fact, after exposure to S scabiei, 74.3% of rabbits who were vaccinated with rSsCLP5 had no detectable lesions.⁵ Also, after immunization with rSsCLP5 and rSsCLP12, there were increased levels of specific IgG and IgE antibodies produced and decreased numbers of infesting mites.²² Weight loss also is associated with severe scabies infection. Rabbits vaccinated with rSsCLP5 and exposed to the parasite gained weight, indicating protection via rSsCLP5. Even rabbits who did develop symptoms of scabies after immunization with rSsCLP5 and exposure to S scabiei showed less serious manifestations.⁵

A combination vaccine cocktail of rSs-serpin, rSsCLP12, and rSsCLP5 also has been proposed by Shen et al.²² Four test groups and a control group (n=12 per group) were included in a vaccine trial. Between 83.33% and 91.67% of rabbits vaccinated with this mixed recombinant cocktail vaccine had no detectable skin lesions from scabies. After immunization with the cocktail vaccine, the specific serum IgG and IgE antibodies also increased. For both IgG and IgE, increased levels were first detected at 1 week postimmunization and peaked at 2 weeks postimmunization.²² A multiepitope vaccine derived from these 3 recombinant proteins also was explored by Shen et al²²; fewer rabbits vaccinated with it had no detectable scabies skin lesions compared to those treated with the vaccine cocktail. Although the multiepitope vaccine yielded less immume protection, it was associated with a slower disease course and milder symptoms compared with no vaccination.²²

Two more proposed scabies recombinant vaccine candidates are derived from the antigens Ssag1 and Ssag2; however, rabbits vaccinated with Ssag1 or Ssag2 showed no immune protection or mite burden reduction.²² The lack of protection could be due to denaturation or degradation of the protective antigens. It also can be due to the low abundance of these antigens, meaning they may not be vital for the mite’s survival—survival—a potential avenue for future research. The antigens also could have lost their native structure and immunogenic properties during the purification and production process. Therefore, more research is needed to investigate how to purify these vaccines to keep the peptides more structurally similar to their native makeups.¹⁰ More research also is needed to better understand the antigen or antigens and their mechanisms that elicit a protective immune response.⁹

Final Thoughts

Scabies causes severe pruritus in mild cases but also can lead to severe disfigurement, sepsis, and even death. Scabies infestations are seen disproportionately more often in low-income and resource-poor communities, and the current treatment options are less accessible to these populations. Scabies infestations induce a complex immune response that involves multiple aspects of both the innate and adaptive immune systems and can be targeted to create a scabies vaccine. Development of a scabies vaccine is crucial considering the growing resistance to current standard treatments. Acaricides potentially are associated with an increased risk for malignancy, which further amplifies the need for a scabies vaccine. There currently are multiple promising scabies vaccine candidates; however, more research is needed to better understand the host’s immune response to scabies as well as how to more accurately and efficiently produce the vaccine. The development of a safe, effective, economical vaccine that can be mass distributed would be beneficial in the treatment of scabies, especially in resource-poor communities.

The yellow fly (Diachlorus ferrugatus) is a flying biting insect belonging to the order Diptera, family Tabanidae, which also includes deer flies (genus Chrysops) and horse flies (genus Tabanus).¹ They are different from stinging insects of the order Hymenoptera (bees, wasps, yellow jackets, and hornets). As the name suggests, the yellow fly has a distinct yellow appearance, and adult yellow flies have a body length of approximately 1 cm.^1,2 Distinguishing features of the yellow fly include prominently dark forelegs (the remaining legs are yellow), dark purple to black eyes with 2 fluorescent green lines, and a yellow abdomen with black hairs along the lateral regions and a broad central yellow stripe.^1-3 Their wings have longitudinal black veins with clear spaces in between and a conspicuous brown patch at the apex (Figure 1A). In comparison, horse flies are darker and larger (Figure 1B), and deer flies are similar in shape but have stripes on the abdomen and thorax and mottled wings with dark patches near the apex (Figure 1C).¹

The Tabanidae family comprises 4455 species belonging to 137 genera and is notorious for bites that result in localized pain, swelling, itching, and discomfort.⁴ While some Tabanidae species are mechanical or biologic vectors of pathogens (eg, Loa loa, equine infectious anemia virus, Trypanosoma species, cattle and sheep anthrax and tularemia), yellow flies do not appear to play a considerable role in disease transmission.^4,5 Nonetheless, their bites can cause discomfort and create a nuisance for individuals residing within their distribution areas as well as for agricultural livestock, contributing to lower weight gain and milk production.¹

Yellow flies are a commonly occurring species in the southeastern United States; their distribution spans several states, including New Jersey, Florida, and Texas.^1,2 In Florida, specifically, yellow flies exhibit a seasonal pattern, with peak activity typically occurring from April through June.^6-9 Activity levels are heightened around sunset as well as sunrise.^1,9 Tabanids can be found in forests, parks, and gardens—particularly those that contain waterways such as freshwater lakes and streams—and typically stay near shaded woodlands that are prone to flooding.⁹

Tabanids go through the life cycle stages of egg, larva, pupa, and adult; the life cycle typically spans 1 year, with the adults living 30 to 60 days.¹ Mating occurs soon after adults emerge from the pupal case in the soil.^1,10 Females then are attracted to large dark moving objects and will feed on blood to develop eggs.^2,10 Only female members of the Tabanidae family have modifications of the mouth parts that allow wounding of the skin (Figure 2). Their bites introduce saliva to the skin containing anticoagulants and other likely allergens. The tongue is used to lap between 20 to 600 microliters of blood.¹¹ Males feed primarily on pollen and nectar.¹⁰ Most tabanid bites result in transient wheal-and-flare reactions, but some can result in more severe allergic reactions such as in our reported case.¹⁰ Rarely, anaphylactic reactions have been documented.^10,12

Case Report

A 48-year-old man presented with swelling of the left hand following a yellow fly bite to the wrist 30 minutes prior while he worked outside at a ranch in central Florida (Figure 3). The patient was afebrile and reported no respiratory or gastrointestinal symptoms. The left hand and forearm were warm to the touch and appeared red and edematous (Figure 4). He was not tachycardic and did not appear to be in any distress. The patient reported that he had worked on the ranch for several years, and during that time had noted he was developing worsening localized reactions to yellow fly bites. He had visually identified the offending insect prior to the current presentation and had trapped some flies in previous incidents. Recently he had experienced rapid swelling at the bite sites but had never experienced respiratory difficulties or signs of systemic allergic reactions. He previously had used topical steroids when bites resulted in mild wheal-and-flare reactions, but he reported that these were no longer effective.

Management of the current bite reaction included oral prednisone tapered over 1 week from 40 mg to 10 mg daily as well as oral cetirizine 10 mg daily. Although bacterial cellulitis was considered in the differential diagnosis, no oral antibiotics were prescribed given the patient’s history of similar clinical presentations following yellow fly bites. His symptoms resolved within a few hours of his dose of prednisone. Incidentally, our patient has been able to control the progression of subsequent hypersensitivity reactions to yellow fly bites with a single 20-mg dose of prednisone administered at the onset of the bite.

Comment

In general, blood-feeding (hematophagous) insects rarely cause anaphylaxis and are more likely to cause cutaneous hypersensitivity reactions, possibly due to the small amount of antigen injected from a bite.^13,14 The immediate wheal-and-flare reaction is an IgE-mediated type 1 immune reaction compared to a less common type 4 T-cell mediated delayed hypersensitivity reaction.^14,15 There are many protein allergens in the saliva of biting insects that are not well characterized. Relevant allergens include a 69 kDa salivary gland protein as well as a Tab y 1 (anticoagulant), Tab y 2 (hyaluronidase), and Tab y 5 (antigen 5–related venom protein).^11,15-17 Some of these proteins have structural homology between insects of different orders and can cause cross-reactivity in patients who also are allergic to Hymenoptera stings (wasp-horsefly syndrome).^12,16

Our patient’s cutaneous reaction was localized and clinically manifested with rapidly progressive erythema and edema at the bite location. He did not exhibit signs of a systemic reaction such as angioedema, respiratory or gastrointestinal symptoms, tachycardia, or hypotension. Management of affected patients depends on the extent of the reaction and may include oral or parenteral antihistamines as well as oral steroids for more severe edema.¹¹ Anaphylactic reactions generally respond to subcutaneous epinephrine.¹⁵ It would be prudent for patients with a relevant anaphylactic history to carry an autoinjectable epinephrine pen in case of difficulty breathing or general malaise following a bite. Besides avoidance of insect bites, personal protection methods include wearing long-sleeved shirts and pants and using insect repellents containing diethyl toluamide (DEET), citronella, or geraniol.¹

At present, diagnosis of cutaneous reactions to yellow fly bites is best made based on the patient’s personal history.¹⁴ If the offending fly is trapped, it can be identified. As most patients cannot differentiate between insects, it may be helpful for dermatologists to know that a small amount of blood at the bite site is suggestive of a fly bite rather than a sting from a member of the order Hymenoptera. Currently, there are no consistently useful extracts for intradermal skin testing.¹¹ Although there are several commercially available serum-specific IgE tests for suspected horse fly reactions, their usefulness is doubtful without further information on sensitivity and specificity as well as the allergen utilized.^11,18,19 The use of allergen immunotherapy to induce hyposensitization in patients who experience cutaneous reactions is not standardized and poses some risks including severe allergic reactions requiring facilities for resuscitation, variability of response patterns, and supporting evidence is weak.¹¹

Final Thoughts

Cutaneous reactions to yellow fly bites rarely are described in the dermatology literature. The salivary proteins implicated in inducing an allergic response and cross-reactivity of D ferrugatus with other biting and stinging insects as well as the natural course of immune reactions over time need to be further characterized.

The yellow fly (Diachlorus ferrugatus) is a flying biting insect belonging to the order Diptera, family Tabanidae, which also includes deer flies (genus Chrysops) and horse flies (genus Tabanus).¹ They are different from stinging insects of the order Hymenoptera (bees, wasps, yellow jackets, and hornets). As the name suggests, the yellow fly has a distinct yellow appearance, and adult yellow flies have a body length of approximately 1 cm.^1,2 Distinguishing features of the yellow fly include prominently dark forelegs (the remaining legs are yellow), dark purple to black eyes with 2 fluorescent green lines, and a yellow abdomen with black hairs along the lateral regions and a broad central yellow stripe.^1-3 Their wings have longitudinal black veins with clear spaces in between and a conspicuous brown patch at the apex (Figure 1A). In comparison, horse flies are darker and larger (Figure 1B), and deer flies are similar in shape but have stripes on the abdomen and thorax and mottled wings with dark patches near the apex (Figure 1C).¹

The Tabanidae family comprises 4455 species belonging to 137 genera and is notorious for bites that result in localized pain, swelling, itching, and discomfort.⁴ While some Tabanidae species are mechanical or biologic vectors of pathogens (eg, Loa loa, equine infectious anemia virus, Trypanosoma species, cattle and sheep anthrax and tularemia), yellow flies do not appear to play a considerable role in disease transmission.^4,5 Nonetheless, their bites can cause discomfort and create a nuisance for individuals residing within their distribution areas as well as for agricultural livestock, contributing to lower weight gain and milk production.¹

Yellow flies are a commonly occurring species in the southeastern United States; their distribution spans several states, including New Jersey, Florida, and Texas.^1,2 In Florida, specifically, yellow flies exhibit a seasonal pattern, with peak activity typically occurring from April through June.^6-9 Activity levels are heightened around sunset as well as sunrise.^1,9 Tabanids can be found in forests, parks, and gardens—particularly those that contain waterways such as freshwater lakes and streams—and typically stay near shaded woodlands that are prone to flooding.⁹

Tabanids go through the life cycle stages of egg, larva, pupa, and adult; the life cycle typically spans 1 year, with the adults living 30 to 60 days.¹ Mating occurs soon after adults emerge from the pupal case in the soil.^1,10 Females then are attracted to large dark moving objects and will feed on blood to develop eggs.^2,10 Only female members of the Tabanidae family have modifications of the mouth parts that allow wounding of the skin (Figure 2). Their bites introduce saliva to the skin containing anticoagulants and other likely allergens. The tongue is used to lap between 20 to 600 microliters of blood.¹¹ Males feed primarily on pollen and nectar.¹⁰ Most tabanid bites result in transient wheal-and-flare reactions, but some can result in more severe allergic reactions such as in our reported case.¹⁰ Rarely, anaphylactic reactions have been documented.^10,12

Case Report

A 48-year-old man presented with swelling of the left hand following a yellow fly bite to the wrist 30 minutes prior while he worked outside at a ranch in central Florida (Figure 3). The patient was afebrile and reported no respiratory or gastrointestinal symptoms. The left hand and forearm were warm to the touch and appeared red and edematous (Figure 4). He was not tachycardic and did not appear to be in any distress. The patient reported that he had worked on the ranch for several years, and during that time had noted he was developing worsening localized reactions to yellow fly bites. He had visually identified the offending insect prior to the current presentation and had trapped some flies in previous incidents. Recently he had experienced rapid swelling at the bite sites but had never experienced respiratory difficulties or signs of systemic allergic reactions. He previously had used topical steroids when bites resulted in mild wheal-and-flare reactions, but he reported that these were no longer effective.

Management of the current bite reaction included oral prednisone tapered over 1 week from 40 mg to 10 mg daily as well as oral cetirizine 10 mg daily. Although bacterial cellulitis was considered in the differential diagnosis, no oral antibiotics were prescribed given the patient’s history of similar clinical presentations following yellow fly bites. His symptoms resolved within a few hours of his dose of prednisone. Incidentally, our patient has been able to control the progression of subsequent hypersensitivity reactions to yellow fly bites with a single 20-mg dose of prednisone administered at the onset of the bite.

Comment

In general, blood-feeding (hematophagous) insects rarely cause anaphylaxis and are more likely to cause cutaneous hypersensitivity reactions, possibly due to the small amount of antigen injected from a bite.^13,14 The immediate wheal-and-flare reaction is an IgE-mediated type 1 immune reaction compared to a less common type 4 T-cell mediated delayed hypersensitivity reaction.^14,15 There are many protein allergens in the saliva of biting insects that are not well characterized. Relevant allergens include a 69 kDa salivary gland protein as well as a Tab y 1 (anticoagulant), Tab y 2 (hyaluronidase), and Tab y 5 (antigen 5–related venom protein).^11,15-17 Some of these proteins have structural homology between insects of different orders and can cause cross-reactivity in patients who also are allergic to Hymenoptera stings (wasp-horsefly syndrome).^12,16

Our patient’s cutaneous reaction was localized and clinically manifested with rapidly progressive erythema and edema at the bite location. He did not exhibit signs of a systemic reaction such as angioedema, respiratory or gastrointestinal symptoms, tachycardia, or hypotension. Management of affected patients depends on the extent of the reaction and may include oral or parenteral antihistamines as well as oral steroids for more severe edema.¹¹ Anaphylactic reactions generally respond to subcutaneous epinephrine.¹⁵ It would be prudent for patients with a relevant anaphylactic history to carry an autoinjectable epinephrine pen in case of difficulty breathing or general malaise following a bite. Besides avoidance of insect bites, personal protection methods include wearing long-sleeved shirts and pants and using insect repellents containing diethyl toluamide (DEET), citronella, or geraniol.¹

At present, diagnosis of cutaneous reactions to yellow fly bites is best made based on the patient’s personal history.¹⁴ If the offending fly is trapped, it can be identified. As most patients cannot differentiate between insects, it may be helpful for dermatologists to know that a small amount of blood at the bite site is suggestive of a fly bite rather than a sting from a member of the order Hymenoptera. Currently, there are no consistently useful extracts for intradermal skin testing.¹¹ Although there are several commercially available serum-specific IgE tests for suspected horse fly reactions, their usefulness is doubtful without further information on sensitivity and specificity as well as the allergen utilized.^11,18,19 The use of allergen immunotherapy to induce hyposensitization in patients who experience cutaneous reactions is not standardized and poses some risks including severe allergic reactions requiring facilities for resuscitation, variability of response patterns, and supporting evidence is weak.¹¹

Final Thoughts

Cutaneous reactions to yellow fly bites rarely are described in the dermatology literature. The salivary proteins implicated in inducing an allergic response and cross-reactivity of D ferrugatus with other biting and stinging insects as well as the natural course of immune reactions over time need to be further characterized.

The yellow fly (Diachlorus ferrugatus) is a flying biting insect belonging to the order Diptera, family Tabanidae, which also includes deer flies (genus Chrysops) and horse flies (genus Tabanus).¹ They are different from stinging insects of the order Hymenoptera (bees, wasps, yellow jackets, and hornets). As the name suggests, the yellow fly has a distinct yellow appearance, and adult yellow flies have a body length of approximately 1 cm.^1,2 Distinguishing features of the yellow fly include prominently dark forelegs (the remaining legs are yellow), dark purple to black eyes with 2 fluorescent green lines, and a yellow abdomen with black hairs along the lateral regions and a broad central yellow stripe.^1-3 Their wings have longitudinal black veins with clear spaces in between and a conspicuous brown patch at the apex (Figure 1A). In comparison, horse flies are darker and larger (Figure 1B), and deer flies are similar in shape but have stripes on the abdomen and thorax and mottled wings with dark patches near the apex (Figure 1C).¹

The Tabanidae family comprises 4455 species belonging to 137 genera and is notorious for bites that result in localized pain, swelling, itching, and discomfort.⁴ While some Tabanidae species are mechanical or biologic vectors of pathogens (eg, Loa loa, equine infectious anemia virus, Trypanosoma species, cattle and sheep anthrax and tularemia), yellow flies do not appear to play a considerable role in disease transmission.^4,5 Nonetheless, their bites can cause discomfort and create a nuisance for individuals residing within their distribution areas as well as for agricultural livestock, contributing to lower weight gain and milk production.¹

Yellow flies are a commonly occurring species in the southeastern United States; their distribution spans several states, including New Jersey, Florida, and Texas.^1,2 In Florida, specifically, yellow flies exhibit a seasonal pattern, with peak activity typically occurring from April through June.^6-9 Activity levels are heightened around sunset as well as sunrise.^1,9 Tabanids can be found in forests, parks, and gardens—particularly those that contain waterways such as freshwater lakes and streams—and typically stay near shaded woodlands that are prone to flooding.⁹

Tabanids go through the life cycle stages of egg, larva, pupa, and adult; the life cycle typically spans 1 year, with the adults living 30 to 60 days.¹ Mating occurs soon after adults emerge from the pupal case in the soil.^1,10 Females then are attracted to large dark moving objects and will feed on blood to develop eggs.^2,10 Only female members of the Tabanidae family have modifications of the mouth parts that allow wounding of the skin (Figure 2). Their bites introduce saliva to the skin containing anticoagulants and other likely allergens. The tongue is used to lap between 20 to 600 microliters of blood.¹¹ Males feed primarily on pollen and nectar.¹⁰ Most tabanid bites result in transient wheal-and-flare reactions, but some can result in more severe allergic reactions such as in our reported case.¹⁰ Rarely, anaphylactic reactions have been documented.^10,12

Case Report

A 48-year-old man presented with swelling of the left hand following a yellow fly bite to the wrist 30 minutes prior while he worked outside at a ranch in central Florida (Figure 3). The patient was afebrile and reported no respiratory or gastrointestinal symptoms. The left hand and forearm were warm to the touch and appeared red and edematous (Figure 4). He was not tachycardic and did not appear to be in any distress. The patient reported that he had worked on the ranch for several years, and during that time had noted he was developing worsening localized reactions to yellow fly bites. He had visually identified the offending insect prior to the current presentation and had trapped some flies in previous incidents. Recently he had experienced rapid swelling at the bite sites but had never experienced respiratory difficulties or signs of systemic allergic reactions. He previously had used topical steroids when bites resulted in mild wheal-and-flare reactions, but he reported that these were no longer effective.

Management of the current bite reaction included oral prednisone tapered over 1 week from 40 mg to 10 mg daily as well as oral cetirizine 10 mg daily. Although bacterial cellulitis was considered in the differential diagnosis, no oral antibiotics were prescribed given the patient’s history of similar clinical presentations following yellow fly bites. His symptoms resolved within a few hours of his dose of prednisone. Incidentally, our patient has been able to control the progression of subsequent hypersensitivity reactions to yellow fly bites with a single 20-mg dose of prednisone administered at the onset of the bite.

Comment

In general, blood-feeding (hematophagous) insects rarely cause anaphylaxis and are more likely to cause cutaneous hypersensitivity reactions, possibly due to the small amount of antigen injected from a bite.^13,14 The immediate wheal-and-flare reaction is an IgE-mediated type 1 immune reaction compared to a less common type 4 T-cell mediated delayed hypersensitivity reaction.^14,15 There are many protein allergens in the saliva of biting insects that are not well characterized. Relevant allergens include a 69 kDa salivary gland protein as well as a Tab y 1 (anticoagulant), Tab y 2 (hyaluronidase), and Tab y 5 (antigen 5–related venom protein).^11,15-17 Some of these proteins have structural homology between insects of different orders and can cause cross-reactivity in patients who also are allergic to Hymenoptera stings (wasp-horsefly syndrome).^12,16

Our patient’s cutaneous reaction was localized and clinically manifested with rapidly progressive erythema and edema at the bite location. He did not exhibit signs of a systemic reaction such as angioedema, respiratory or gastrointestinal symptoms, tachycardia, or hypotension. Management of affected patients depends on the extent of the reaction and may include oral or parenteral antihistamines as well as oral steroids for more severe edema.¹¹ Anaphylactic reactions generally respond to subcutaneous epinephrine.¹⁵ It would be prudent for patients with a relevant anaphylactic history to carry an autoinjectable epinephrine pen in case of difficulty breathing or general malaise following a bite. Besides avoidance of insect bites, personal protection methods include wearing long-sleeved shirts and pants and using insect repellents containing diethyl toluamide (DEET), citronella, or geraniol.¹

At present, diagnosis of cutaneous reactions to yellow fly bites is best made based on the patient’s personal history.¹⁴ If the offending fly is trapped, it can be identified. As most patients cannot differentiate between insects, it may be helpful for dermatologists to know that a small amount of blood at the bite site is suggestive of a fly bite rather than a sting from a member of the order Hymenoptera. Currently, there are no consistently useful extracts for intradermal skin testing.¹¹ Although there are several commercially available serum-specific IgE tests for suspected horse fly reactions, their usefulness is doubtful without further information on sensitivity and specificity as well as the allergen utilized.^11,18,19 The use of allergen immunotherapy to induce hyposensitization in patients who experience cutaneous reactions is not standardized and poses some risks including severe allergic reactions requiring facilities for resuscitation, variability of response patterns, and supporting evidence is weak.¹¹

Final Thoughts

Cutaneous reactions to yellow fly bites rarely are described in the dermatology literature. The salivary proteins implicated in inducing an allergic response and cross-reactivity of D ferrugatus with other biting and stinging insects as well as the natural course of immune reactions over time need to be further characterized.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

Buruli ulcer (BU) is a potentially disabling necrotizing skin and soft tissue disease caused by Mycobacterium ulcerans infection.^1,2 Buruli ulcer is most common in hot and humid climates and has caused considerable morbidity in Western African countries (Côte d’Ivoire, Ghana, and Benin account for 73% of annual cases) and the temperate areas of Australia (283 reported cases in 2017).^1-4 In fact, the first recognizable cases of BU were described in 6 Australian individuals living in a riverine area in 1948, although the term Buruli ulcer is derived from the increased number of cases reported from Buruli county in Uganda near the Nile River.^1,3,4

From 2002 to 2017, 66,000 cases of BU were reported in 33 countries.¹ While the focal distribution has been demonstrated in the tropical areas of Sri Lanka, Malaysia, Papua New Guinea, Peru, and Mexico,⁴ nontropical nations such as Japan also are affected. Since 1981, 66 cases have been reported in Japan with M ulcerans subspecies—primarily Shinshuense, which has adapted to higher latitudes.¹ Herein, we provide an overview of the pathogenesis, clinical presentation, and treatment of BU and highlight aquatic insects and mosquitoes as possible vectors of transmission.

Pathogenesis

Mycobacterium ulcerans is a nontuberculous mycobacterium and ubiquitous acid-fast gram-positive bacillus that can be cultured using a Lowenstein-Jensen agar and has a doubling rate of 48 hours.^1,5 It produces the small 174-kb plasmid pMUM001-encoded compound mycolactone, a pathogenic toxin that causes immunosuppression, analgesia, and cytotoxic-associated tissue necrosis.^1,5-9

Mycolactone is a polyketide macrolide with a 12-membrane lactone with 2 attached acyl side chains.^1,7 Mycolactone is synthesized by the giant polyketide synthetases of M ulcerans. Mycolactone post-transcriptionally inhibits the development of lipopolysaccharide-dependent proinflammatory mediators—specifically by blocking protein translocation from the cytosol into the endoplasmic reticulum by targeting the SEC61 translocon.^1,6 The lack of translocation of 30% to 50% of proteins leads to cellular stress and apoptosis mediated by Bim/Bcl2. A single point mutation in the SEC61 translocon subunit alpha 1 gene (SEC61A1) is associated with resistance to the cytotoxic effects of mycolactone.¹

There are divergent hypotheses regarding the relationship of mycolactone to the Wiskott-Aldrich syndrome protein, with some researchers suggesting that mycolactone can attach to this protein, leading to cell detachment and death.⁷ However, others have proposed that mycolactone inhibits mTOR, activating the Wiskott-Aldrich syndrome protein and leading to subsequent extensive cytoskeleton remodeling.¹ Mycolactone also can cause hypoesthesia, either by activating type 2 angiotensin II receptors and creating downstream neuron hyperpolarization or by killing Schwann cells.¹

Transmission

Buruli ulcer caused by M ulcerans has a poorly understood transmission mechanism, and further studies are required to understand the underlying pathophysiology to decrease transmission rates and associated morbidity. Buruli ulcer is widely accepted to be transmitted to humans via predominantly water-rich environments; most cases occur around slow-moving and still bodies of water such as swamps, ponds, and marshes.¹ Mycobacterium ulcerans DNA has been found in fish, water insects, and snails.^1,4 It also has been present in samples from aquatic insects such as Hemiptera (water strider), Naucoridae (creeping water bugs and saucer bugs), and Belostomatidae (giant water bugs) in West Africa and also from Aulacodes feces and moss.¹

Variations in geographic climate may lead to different modes of transmission of BU. For example, mosquitoes have been studied as a potential vector for BU in the temperate climate of Australia.² However, more data are needed from other countries to support mosquitoes as possible vectors. Wallace et al¹⁰ performed a study that showed skin puncture from insect bites or other injuries increases the chance of transmitting M ulcerans in the environment to the skin.

Clinical Presentation

Buruli ulcer most often manifests in healthy children younger than 15 years.^1,8 Potential risk factors include residing near a contaminated water source, swimming in a river, and being bitten by an insect in a river during the rainy season. Lack of protective clothing and mosquito nets also have been proposed as considerable risk factors for BU.² Genetic polymorphism in the solute carrier family 11 member 1 gene (SLC11A1) may increase the risk for BU with M ulcerans transmission. It is essential to understand that infection with M ulcerans does not always lead to the development of BU.¹

Buruli ulcer often begins as a painless nodule or papule that patients may confuse with an insect bite. Within a couple of weeks, the induration will grow into ill-defined edematous plaques that gradually turn into necrotic skin, which will eventually slough off to create painless to mildly painful irregular skin ulceration (Figure).¹¹ The surrounding uninvolved skin often is edematous and pigmented. Unfortunately, deep ulcerations can lead to osteomyelitis with exposure of the underlying bone. A secondary bacterial infection may be involved if a foul smell accompanies the ulcer. The vast extension of the ulcer has been known to lead to amputations, contractures, or deformities.^1-5 The nodule progression to ulceration varies and can occur within 3 weeks to 1 year of the initial exposure.^1,8

The World Health Organization (WHO) classifies BU into 3 categories: category 1 includes ulcers less than 5 cm in diameter; category 2 involves ulcers that are 5 to 15 cm in diameter; and category 3 involves ulcers that are larger than 15 cm in diameter as well as those involving the breasts, genitals, eyes, bones, or joints.^4,8

Diagnosis

Cultures and microscopic examination of M ulcerans acid-fast bacilli can be used to confirm the diagnosis of BU. However, polymerase chain reaction (PCR) is the best confirmatory test, as the WHO reports that 70% of reported cases of BU are confirmed by PCR detection of DNA.^1,4 Unfortunately, many BU-endemic areas lack feasible access to perform confirmatory tests such as PCR. Antigen detection assays, loop-mediated isothermal amplification tests, and detection of mycolactone by thinlayer chromatography are being developed to create more rapid and sensitive testing for BU.¹²

The lack of diagnostic testing for BU means physicians must rely on clinical diagnosis.¹ However, the differential diagnosis is extensive and includes ulcers due to diabetes and arterial and venous insufficiency, cutaneous leishmaniasis, and Haemophilus ducreyi ulcers.⁵ Despite the broad differential, Eddyani et al¹² found that BU diagnosed clinically by physicians had a sensitivity of 92%.

Treatment

Surgery was the first-line treatment for BU before the introduction of antibiotics for this condition. Antibiotics have created better outcomes with increased cure rates and decreased amputation.⁴

Pharmacotherapy—In the early 2000s, the WHO recommended a treatment regimen of once-daily 10 mg/kg rifampin (oral) and 15 mg/kg streptomycin ( intramuscular) for 8 weeks. This treatment protocol is effective for lesions measuring less than 10 cm in diameter and has an average cure rate of 50%.⁵ Unfortunately, streptomycin is associated with ototoxicity and nephrotoxicity.^1,4 Clinicians should be aware that 1.9% to 26% of patients may have paradoxical worsening of BU early during antibiotic use due to increased host inflammatory response, but it subsides with continued treatment.^1,4

Researchers in Australia have begun testing and using rifampin plus oral clarithromycin, ciprofloxacin, or moxifloxacin for 3 months. A common combination is oncedaily 10 mg/kg rifampicin and 400 mg/kg moxifloxacin.¹ After multiple randomized controlled trials showed the efficacy of rifampicin in combination with clarithromycin, many physicians now recommend 10 mg/kg of rifampicin once daily and 7.5 mg/kg of clarithromycin twice daily.^1,5 When BU is severe, intravenous amikacin and oral rifampin can be used for 4 to 8 weeks.⁵

Wound Management and Surgical Considerations—Since BU can cause extensive widespread ulceration, daily wound care is recommended. Clinicians should note that patients often experience pain during wound dressing, as gauze impairs dermal regeneration and adheres to wounds. A second-line treatment to combat patients’ intolerance to gauze placement—especially for large BU lesions causing mobility issues—includes surgical debridement with wide margins and grafting 4 weeks after antibiotic therapy. This surgical procedure also can treat the releasing contractures that BU is known to cause.¹ Severe cases of BU also can be treated with physiotherapy to prevent further disability.⁵

If histologic analysis of the margins reveals the presence of acid-fast bacilli and granulomas, the probability of future recurrence is high. In those instances, antibiotic therapy is given for prevention. In Australia, the Consensus Council Conference has recommended the removal of not only necrotic tissue but also a small margin of normal tissue to prevent the spread leading to recurrence.^1,5,8

Prevention—Multiple prevention techniques have been suggested to combat BU. Long sleeves and pants should be worn outdoors along with insect repellents in BU-endemic areas. Comprehensive—but perhaps impractical—prevention measures include avoidance of swimming and aquatic activities such as boating and fishing in BU-endemic areas. In the event of a skin abrasion, the wound should be cleaned and covered promptly.

There is no vaccine currently available for BU. Bacillus Calmette—Guérin vaccination can provide minimal protection against disseminated BU but with a short-term response.⁵ Fortunately, M ulcerans–specific vaccines are being developed. Currently, tested vaccines target an enzyme called mycolyl transferase, which is essential for the stability of the mycobacterial cell wall and could have powerful implications in preventing these ulcers. These mycolyl transferase–directed vaccines need to be further explored in the plight against BU.^1,5,8

Final Thoughts

Buruli ulcer remains a considerable public health challenge in endemic regions, with substantial morbidity and potential long-term disability. Hence, continued research into its transmission mechanisms, treatment options, and preventive measures is crucial for reducing the impact of this disease on affected populations.

Buruli ulcer (BU) is a potentially disabling necrotizing skin and soft tissue disease caused by Mycobacterium ulcerans infection.^1,2 Buruli ulcer is most common in hot and humid climates and has caused considerable morbidity in Western African countries (Côte d’Ivoire, Ghana, and Benin account for 73% of annual cases) and the temperate areas of Australia (283 reported cases in 2017).^1-4 In fact, the first recognizable cases of BU were described in 6 Australian individuals living in a riverine area in 1948, although the term Buruli ulcer is derived from the increased number of cases reported from Buruli county in Uganda near the Nile River.^1,3,4

From 2002 to 2017, 66,000 cases of BU were reported in 33 countries.¹ While the focal distribution has been demonstrated in the tropical areas of Sri Lanka, Malaysia, Papua New Guinea, Peru, and Mexico,⁴ nontropical nations such as Japan also are affected. Since 1981, 66 cases have been reported in Japan with M ulcerans subspecies—primarily Shinshuense, which has adapted to higher latitudes.¹ Herein, we provide an overview of the pathogenesis, clinical presentation, and treatment of BU and highlight aquatic insects and mosquitoes as possible vectors of transmission.

Pathogenesis

Mycobacterium ulcerans is a nontuberculous mycobacterium and ubiquitous acid-fast gram-positive bacillus that can be cultured using a Lowenstein-Jensen agar and has a doubling rate of 48 hours.^1,5 It produces the small 174-kb plasmid pMUM001-encoded compound mycolactone, a pathogenic toxin that causes immunosuppression, analgesia, and cytotoxic-associated tissue necrosis.^1,5-9

Mycolactone is a polyketide macrolide with a 12-membrane lactone with 2 attached acyl side chains.^1,7 Mycolactone is synthesized by the giant polyketide synthetases of M ulcerans. Mycolactone post-transcriptionally inhibits the development of lipopolysaccharide-dependent proinflammatory mediators—specifically by blocking protein translocation from the cytosol into the endoplasmic reticulum by targeting the SEC61 translocon.^1,6 The lack of translocation of 30% to 50% of proteins leads to cellular stress and apoptosis mediated by Bim/Bcl2. A single point mutation in the SEC61 translocon subunit alpha 1 gene (SEC61A1) is associated with resistance to the cytotoxic effects of mycolactone.¹

There are divergent hypotheses regarding the relationship of mycolactone to the Wiskott-Aldrich syndrome protein, with some researchers suggesting that mycolactone can attach to this protein, leading to cell detachment and death.⁷ However, others have proposed that mycolactone inhibits mTOR, activating the Wiskott-Aldrich syndrome protein and leading to subsequent extensive cytoskeleton remodeling.¹ Mycolactone also can cause hypoesthesia, either by activating type 2 angiotensin II receptors and creating downstream neuron hyperpolarization or by killing Schwann cells.¹

Transmission

Buruli ulcer caused by M ulcerans has a poorly understood transmission mechanism, and further studies are required to understand the underlying pathophysiology to decrease transmission rates and associated morbidity. Buruli ulcer is widely accepted to be transmitted to humans via predominantly water-rich environments; most cases occur around slow-moving and still bodies of water such as swamps, ponds, and marshes.¹ Mycobacterium ulcerans DNA has been found in fish, water insects, and snails.^1,4 It also has been present in samples from aquatic insects such as Hemiptera (water strider), Naucoridae (creeping water bugs and saucer bugs), and Belostomatidae (giant water bugs) in West Africa and also from Aulacodes feces and moss.¹

Variations in geographic climate may lead to different modes of transmission of BU. For example, mosquitoes have been studied as a potential vector for BU in the temperate climate of Australia.² However, more data are needed from other countries to support mosquitoes as possible vectors. Wallace et al¹⁰ performed a study that showed skin puncture from insect bites or other injuries increases the chance of transmitting M ulcerans in the environment to the skin.

Clinical Presentation

Buruli ulcer most often manifests in healthy children younger than 15 years.^1,8 Potential risk factors include residing near a contaminated water source, swimming in a river, and being bitten by an insect in a river during the rainy season. Lack of protective clothing and mosquito nets also have been proposed as considerable risk factors for BU.² Genetic polymorphism in the solute carrier family 11 member 1 gene (SLC11A1) may increase the risk for BU with M ulcerans transmission. It is essential to understand that infection with M ulcerans does not always lead to the development of BU.¹

Buruli ulcer often begins as a painless nodule or papule that patients may confuse with an insect bite. Within a couple of weeks, the induration will grow into ill-defined edematous plaques that gradually turn into necrotic skin, which will eventually slough off to create painless to mildly painful irregular skin ulceration (Figure).¹¹ The surrounding uninvolved skin often is edematous and pigmented. Unfortunately, deep ulcerations can lead to osteomyelitis with exposure of the underlying bone. A secondary bacterial infection may be involved if a foul smell accompanies the ulcer. The vast extension of the ulcer has been known to lead to amputations, contractures, or deformities.^1-5 The nodule progression to ulceration varies and can occur within 3 weeks to 1 year of the initial exposure.^1,8

The World Health Organization (WHO) classifies BU into 3 categories: category 1 includes ulcers less than 5 cm in diameter; category 2 involves ulcers that are 5 to 15 cm in diameter; and category 3 involves ulcers that are larger than 15 cm in diameter as well as those involving the breasts, genitals, eyes, bones, or joints.^4,8

Diagnosis

Cultures and microscopic examination of M ulcerans acid-fast bacilli can be used to confirm the diagnosis of BU. However, polymerase chain reaction (PCR) is the best confirmatory test, as the WHO reports that 70% of reported cases of BU are confirmed by PCR detection of DNA.^1,4 Unfortunately, many BU-endemic areas lack feasible access to perform confirmatory tests such as PCR. Antigen detection assays, loop-mediated isothermal amplification tests, and detection of mycolactone by thinlayer chromatography are being developed to create more rapid and sensitive testing for BU.¹²

The lack of diagnostic testing for BU means physicians must rely on clinical diagnosis.¹ However, the differential diagnosis is extensive and includes ulcers due to diabetes and arterial and venous insufficiency, cutaneous leishmaniasis, and Haemophilus ducreyi ulcers.⁵ Despite the broad differential, Eddyani et al¹² found that BU diagnosed clinically by physicians had a sensitivity of 92%.

Treatment

Surgery was the first-line treatment for BU before the introduction of antibiotics for this condition. Antibiotics have created better outcomes with increased cure rates and decreased amputation.⁴

Pharmacotherapy—In the early 2000s, the WHO recommended a treatment regimen of once-daily 10 mg/kg rifampin (oral) and 15 mg/kg streptomycin ( intramuscular) for 8 weeks. This treatment protocol is effective for lesions measuring less than 10 cm in diameter and has an average cure rate of 50%.⁵ Unfortunately, streptomycin is associated with ototoxicity and nephrotoxicity.^1,4 Clinicians should be aware that 1.9% to 26% of patients may have paradoxical worsening of BU early during antibiotic use due to increased host inflammatory response, but it subsides with continued treatment.^1,4

Researchers in Australia have begun testing and using rifampin plus oral clarithromycin, ciprofloxacin, or moxifloxacin for 3 months. A common combination is oncedaily 10 mg/kg rifampicin and 400 mg/kg moxifloxacin.¹ After multiple randomized controlled trials showed the efficacy of rifampicin in combination with clarithromycin, many physicians now recommend 10 mg/kg of rifampicin once daily and 7.5 mg/kg of clarithromycin twice daily.^1,5 When BU is severe, intravenous amikacin and oral rifampin can be used for 4 to 8 weeks.⁵

Wound Management and Surgical Considerations—Since BU can cause extensive widespread ulceration, daily wound care is recommended. Clinicians should note that patients often experience pain during wound dressing, as gauze impairs dermal regeneration and adheres to wounds. A second-line treatment to combat patients’ intolerance to gauze placement—especially for large BU lesions causing mobility issues—includes surgical debridement with wide margins and grafting 4 weeks after antibiotic therapy. This surgical procedure also can treat the releasing contractures that BU is known to cause.¹ Severe cases of BU also can be treated with physiotherapy to prevent further disability.⁵

If histologic analysis of the margins reveals the presence of acid-fast bacilli and granulomas, the probability of future recurrence is high. In those instances, antibiotic therapy is given for prevention. In Australia, the Consensus Council Conference has recommended the removal of not only necrotic tissue but also a small margin of normal tissue to prevent the spread leading to recurrence.^1,5,8

Prevention—Multiple prevention techniques have been suggested to combat BU. Long sleeves and pants should be worn outdoors along with insect repellents in BU-endemic areas. Comprehensive—but perhaps impractical—prevention measures include avoidance of swimming and aquatic activities such as boating and fishing in BU-endemic areas. In the event of a skin abrasion, the wound should be cleaned and covered promptly.

There is no vaccine currently available for BU. Bacillus Calmette—Guérin vaccination can provide minimal protection against disseminated BU but with a short-term response.⁵ Fortunately, M ulcerans–specific vaccines are being developed. Currently, tested vaccines target an enzyme called mycolyl transferase, which is essential for the stability of the mycobacterial cell wall and could have powerful implications in preventing these ulcers. These mycolyl transferase–directed vaccines need to be further explored in the plight against BU.^1,5,8

Final Thoughts

Buruli ulcer remains a considerable public health challenge in endemic regions, with substantial morbidity and potential long-term disability. Hence, continued research into its transmission mechanisms, treatment options, and preventive measures is crucial for reducing the impact of this disease on affected populations.

Buruli ulcer (BU) is a potentially disabling necrotizing skin and soft tissue disease caused by Mycobacterium ulcerans infection.^1,2 Buruli ulcer is most common in hot and humid climates and has caused considerable morbidity in Western African countries (Côte d’Ivoire, Ghana, and Benin account for 73% of annual cases) and the temperate areas of Australia (283 reported cases in 2017).^1-4 In fact, the first recognizable cases of BU were described in 6 Australian individuals living in a riverine area in 1948, although the term Buruli ulcer is derived from the increased number of cases reported from Buruli county in Uganda near the Nile River.^1,3,4

From 2002 to 2017, 66,000 cases of BU were reported in 33 countries.¹ While the focal distribution has been demonstrated in the tropical areas of Sri Lanka, Malaysia, Papua New Guinea, Peru, and Mexico,⁴ nontropical nations such as Japan also are affected. Since 1981, 66 cases have been reported in Japan with M ulcerans subspecies—primarily Shinshuense, which has adapted to higher latitudes.¹ Herein, we provide an overview of the pathogenesis, clinical presentation, and treatment of BU and highlight aquatic insects and mosquitoes as possible vectors of transmission.

Pathogenesis

Mycobacterium ulcerans is a nontuberculous mycobacterium and ubiquitous acid-fast gram-positive bacillus that can be cultured using a Lowenstein-Jensen agar and has a doubling rate of 48 hours.^1,5 It produces the small 174-kb plasmid pMUM001-encoded compound mycolactone, a pathogenic toxin that causes immunosuppression, analgesia, and cytotoxic-associated tissue necrosis.^1,5-9

Mycolactone is a polyketide macrolide with a 12-membrane lactone with 2 attached acyl side chains.^1,7 Mycolactone is synthesized by the giant polyketide synthetases of M ulcerans. Mycolactone post-transcriptionally inhibits the development of lipopolysaccharide-dependent proinflammatory mediators—specifically by blocking protein translocation from the cytosol into the endoplasmic reticulum by targeting the SEC61 translocon.^1,6 The lack of translocation of 30% to 50% of proteins leads to cellular stress and apoptosis mediated by Bim/Bcl2. A single point mutation in the SEC61 translocon subunit alpha 1 gene (SEC61A1) is associated with resistance to the cytotoxic effects of mycolactone.¹

There are divergent hypotheses regarding the relationship of mycolactone to the Wiskott-Aldrich syndrome protein, with some researchers suggesting that mycolactone can attach to this protein, leading to cell detachment and death.⁷ However, others have proposed that mycolactone inhibits mTOR, activating the Wiskott-Aldrich syndrome protein and leading to subsequent extensive cytoskeleton remodeling.¹ Mycolactone also can cause hypoesthesia, either by activating type 2 angiotensin II receptors and creating downstream neuron hyperpolarization or by killing Schwann cells.¹

Transmission

Buruli ulcer caused by M ulcerans has a poorly understood transmission mechanism, and further studies are required to understand the underlying pathophysiology to decrease transmission rates and associated morbidity. Buruli ulcer is widely accepted to be transmitted to humans via predominantly water-rich environments; most cases occur around slow-moving and still bodies of water such as swamps, ponds, and marshes.¹ Mycobacterium ulcerans DNA has been found in fish, water insects, and snails.^1,4 It also has been present in samples from aquatic insects such as Hemiptera (water strider), Naucoridae (creeping water bugs and saucer bugs), and Belostomatidae (giant water bugs) in West Africa and also from Aulacodes feces and moss.¹

Variations in geographic climate may lead to different modes of transmission of BU. For example, mosquitoes have been studied as a potential vector for BU in the temperate climate of Australia.² However, more data are needed from other countries to support mosquitoes as possible vectors. Wallace et al¹⁰ performed a study that showed skin puncture from insect bites or other injuries increases the chance of transmitting M ulcerans in the environment to the skin.

Clinical Presentation

Buruli ulcer most often manifests in healthy children younger than 15 years.^1,8 Potential risk factors include residing near a contaminated water source, swimming in a river, and being bitten by an insect in a river during the rainy season. Lack of protective clothing and mosquito nets also have been proposed as considerable risk factors for BU.² Genetic polymorphism in the solute carrier family 11 member 1 gene (SLC11A1) may increase the risk for BU with M ulcerans transmission. It is essential to understand that infection with M ulcerans does not always lead to the development of BU.¹

Buruli ulcer often begins as a painless nodule or papule that patients may confuse with an insect bite. Within a couple of weeks, the induration will grow into ill-defined edematous plaques that gradually turn into necrotic skin, which will eventually slough off to create painless to mildly painful irregular skin ulceration (Figure).¹¹ The surrounding uninvolved skin often is edematous and pigmented. Unfortunately, deep ulcerations can lead to osteomyelitis with exposure of the underlying bone. A secondary bacterial infection may be involved if a foul smell accompanies the ulcer. The vast extension of the ulcer has been known to lead to amputations, contractures, or deformities.^1-5 The nodule progression to ulceration varies and can occur within 3 weeks to 1 year of the initial exposure.^1,8

The World Health Organization (WHO) classifies BU into 3 categories: category 1 includes ulcers less than 5 cm in diameter; category 2 involves ulcers that are 5 to 15 cm in diameter; and category 3 involves ulcers that are larger than 15 cm in diameter as well as those involving the breasts, genitals, eyes, bones, or joints.^4,8

Diagnosis

Cultures and microscopic examination of M ulcerans acid-fast bacilli can be used to confirm the diagnosis of BU. However, polymerase chain reaction (PCR) is the best confirmatory test, as the WHO reports that 70% of reported cases of BU are confirmed by PCR detection of DNA.^1,4 Unfortunately, many BU-endemic areas lack feasible access to perform confirmatory tests such as PCR. Antigen detection assays, loop-mediated isothermal amplification tests, and detection of mycolactone by thinlayer chromatography are being developed to create more rapid and sensitive testing for BU.¹²

The lack of diagnostic testing for BU means physicians must rely on clinical diagnosis.¹ However, the differential diagnosis is extensive and includes ulcers due to diabetes and arterial and venous insufficiency, cutaneous leishmaniasis, and Haemophilus ducreyi ulcers.⁵ Despite the broad differential, Eddyani et al¹² found that BU diagnosed clinically by physicians had a sensitivity of 92%.

Treatment

Surgery was the first-line treatment for BU before the introduction of antibiotics for this condition. Antibiotics have created better outcomes with increased cure rates and decreased amputation.⁴

Pharmacotherapy—In the early 2000s, the WHO recommended a treatment regimen of once-daily 10 mg/kg rifampin (oral) and 15 mg/kg streptomycin ( intramuscular) for 8 weeks. This treatment protocol is effective for lesions measuring less than 10 cm in diameter and has an average cure rate of 50%.⁵ Unfortunately, streptomycin is associated with ototoxicity and nephrotoxicity.^1,4 Clinicians should be aware that 1.9% to 26% of patients may have paradoxical worsening of BU early during antibiotic use due to increased host inflammatory response, but it subsides with continued treatment.^1,4

Researchers in Australia have begun testing and using rifampin plus oral clarithromycin, ciprofloxacin, or moxifloxacin for 3 months. A common combination is oncedaily 10 mg/kg rifampicin and 400 mg/kg moxifloxacin.¹ After multiple randomized controlled trials showed the efficacy of rifampicin in combination with clarithromycin, many physicians now recommend 10 mg/kg of rifampicin once daily and 7.5 mg/kg of clarithromycin twice daily.^1,5 When BU is severe, intravenous amikacin and oral rifampin can be used for 4 to 8 weeks.⁵

Wound Management and Surgical Considerations—Since BU can cause extensive widespread ulceration, daily wound care is recommended. Clinicians should note that patients often experience pain during wound dressing, as gauze impairs dermal regeneration and adheres to wounds. A second-line treatment to combat patients’ intolerance to gauze placement—especially for large BU lesions causing mobility issues—includes surgical debridement with wide margins and grafting 4 weeks after antibiotic therapy. This surgical procedure also can treat the releasing contractures that BU is known to cause.¹ Severe cases of BU also can be treated with physiotherapy to prevent further disability.⁵

If histologic analysis of the margins reveals the presence of acid-fast bacilli and granulomas, the probability of future recurrence is high. In those instances, antibiotic therapy is given for prevention. In Australia, the Consensus Council Conference has recommended the removal of not only necrotic tissue but also a small margin of normal tissue to prevent the spread leading to recurrence.^1,5,8

Prevention—Multiple prevention techniques have been suggested to combat BU. Long sleeves and pants should be worn outdoors along with insect repellents in BU-endemic areas. Comprehensive—but perhaps impractical—prevention measures include avoidance of swimming and aquatic activities such as boating and fishing in BU-endemic areas. In the event of a skin abrasion, the wound should be cleaned and covered promptly.

There is no vaccine currently available for BU. Bacillus Calmette—Guérin vaccination can provide minimal protection against disseminated BU but with a short-term response.⁵ Fortunately, M ulcerans–specific vaccines are being developed. Currently, tested vaccines target an enzyme called mycolyl transferase, which is essential for the stability of the mycobacterial cell wall and could have powerful implications in preventing these ulcers. These mycolyl transferase–directed vaccines need to be further explored in the plight against BU.^1,5,8

Final Thoughts

Buruli ulcer remains a considerable public health challenge in endemic regions, with substantial morbidity and potential long-term disability. Hence, continued research into its transmission mechanisms, treatment options, and preventive measures is crucial for reducing the impact of this disease on affected populations.

It is estimated that the prevalence of human hookworm infection is approximately 450 million individuals worldwide, representing a substantial global disease burden.¹ The annual global public health burden ranges from approximately 2 million to 4 million disability-adjusted life-years and $10 billion to $140 billion in hookwormrelated costs.² In this article, we discuss the lifecycle, transmission, and disease burden of cutaneous larva migrans (CLM) as well as prevention and treatment strategies.

Background

The Ancylostomatidae nematode family comprises at least 68 known species of hookworm that infect more than 110 different species of mammals.³ Many of these parasites are able to infect more than 1 primary host species, but from a disease perspective they can be classified as either anthropophilic, with humans as the intended host, or zoonotic, with humans as an incidental host. It is important to make this distinction because, though the lifecycles and biology of hookworm species generally are similar, the manifestations of incidental human infection from zoonotic hookworms are different from those of anthropophilic hookworms. Of the anthropophilic species, Necator americanus and Ancylostoma duodenale predominate. In the instance of zoonotic hookworm, dog-infecting A caninum and cat- and doginfecting A braziliense and Uncinaria stenocephala are common causes of incidental human disease.³

The life cycle of Ancylostomatidae organisms is astounding. Through millions of years of co-evolution with mammals,⁴ these parasitic worms have developed perhaps one of the most circuitous paths to propagate themselves in the natural world. Hookworms start their arduous journey as eggs deposited in soil, sand, and ground vegetation from the feces of infected animals.⁵ Approximately 1 day after the eggs are deposited, they hatch and begin the larval stage, during which they become infective 1 to 5 weeks later. At this point, the larvae become sensitive to their environment, responding to rising temperatures, increasing carbon dioxide levels, and vibrations in the soil—all of which suggest the presence of a potential host and contribute to a concordant increase in undulatory movement of the larvae.^5,6 Here, the most vulnerable tissues include the uncovered soles, palms, and buttocks of host mammals that come into contact with contaminated soil. In an undulating fashion and guided by temperature cues, the larvae locate the skin of the host and utilize a mixture of enzymes including hyaluronidases, metalloprotease, and other proteases to penetrate the epidermis.⁷ Anthropophilic hookworms such as N americanus and A duodenale will enter the circulatory system; from there, the hookworms migrate through the right-sided cardiopulmonary circuit and eventually ascend into the pulmonary vasculature.⁸ They then penetrate the lung capillary beds and parenchyma to reach the alveoli, ascend the respiratory tree, and, with the help of the mucociliary escalator, reach the esophagus, where they are swallowed by the host. In the gastrointestinal tract, adult hookworms consume host blood, mate, and lay eggs over a period of approximately 1 to 3 years if left untreated.⁹ Eggs are laid into the lower gastrointestinal tract, and the journey begins again in feces contacting ground or soil.

Geographic Distribution

Hookworms are found in almost all regions of the world, with species-specific distributions that highlight tropical and subtropical regions. Necator americanus and A duodenale are the most common hookworm species, with the former found predominantly in Southeast Asia and Latin America and the latter in Asia-Pacific regions.¹⁰ The highest prevalence of hookworms is in Southeast Asia followed by Sub-Saharan Africa, and the unique climate and soil composition of a region help determine the best environments for specific species of hookworm to thrive.¹¹ In addition, socioeconomics and social determinants of health play a big role in the spread of hookworms, as hygiene practices (eg, wearing clean shoes and clothing, bathing), infrastructure (eg, clean water and streets), and anthelmintic campaigns help reduce transmission.¹² Soil-transmitted helminths were once endemic to the southeastern United States, with some reports of approximately 40% of individuals infected in the south in the early 1900s.¹³ Anthelmintic campaigns such as water, sanitation, and hygiene programs as well as deworming of humans and livestock have proven effective in reducing the prevalence of helminth disease in industrialized nations.^13,14 However, zoonotic infections remain a problem in these regions, and in some parts of the United States more than 40% of sampled cats and dogs harbored species such as A braziliense.¹⁵

Clinical Manifestation

Initial hookworm infection often goes unnoticed because symptoms can range in severity, but it is characterized by transient ground itch—a local pruritic, erythematous, and papular eruption that develops in response to epidermal penetration.¹⁶ Because the larvae must traverse the host from skin to target organs for reproduction over several weeks, iron-deficiency anemia will manifest much later than signs of the initial penetration. In the case of incidental infection from zoonotic Ancylostomatidae organisms, the misguided larvae result in CLM, an often intensely pruritic skin condition that will self-resolve in 2 to 8 weeks with eventual death of the larvae.⁵

Diagnosis and Pathology of Disease

Zoonotic Hookworm—The major presenting sign of zoonotic hookworm infection is CLM. The diagnosis of CLM usually is made clinically, as the larvae themselves are 0.5 mm thick to 10 mm long (Figure 1) and usually extend several centimeters beyond the dermal lesion, with dermoscopy having limited utility.¹⁷ Patients may begin to experience itching as little as 1 hour after hookworm penetration of the skin.¹⁸ Once in contact with the skin, the hookworms’ hyaluronidases and proteases are capable of breaking through the epidermis, but zoonotic hookworms typically are unable to penetrate the basal layer of the human epidermis and remain entombed between the stratum granulosum and stratum corneum. With the exception of rare cases of direct or indirect pulmonary involvement resulting in Löffler syndrome,¹⁹ the larvae will die within weeks to months, and symptoms will subsequently resolve.

Although the infection generally is self-limiting, the dermatologic manifestations of CLM can be severe and warrant intervention. The lesions start as small reddish papules at the site of penetration (Figure 2), then the hallmark elevated, migrating, serpiginous, urticarial rash develops (Figure 3). Cutaneous larva migrans generally manifests unilaterally and is both erythematous and intensely pruritic. As the larvae migrate, they leave behind 1- to 5-cm tunneled creeping eruptions in their wake. The lesions, which can manifest with pain or be painless, may develop eczematous, bullous, follicular, or impetiginized appearances.²⁰ Atypical manifestations include folliculitis and urticarial plaques.¹⁷

Anthropophilic Hookworm—The lifecycles of N americanus and A duodenale are completed in human infection. Dermatologic manifestations are transient with the development of ground itch at the site of epidermal penetration. The hookworms employ collagenases that allow penetration of the basal layer of the skin, and eosinophilia develops as the parasites travel from the skin to the small intestine. Once attached to the gastrointestinal lumen, blood meals and proteolytic enzymes result in iron-deficiency anemia in the host and may lead to weakness, fatigue, and low birth weights in pregnant patients. With prolonged infection or heavy parasitic burden, patients can develop hypoproteinemia, anasarca, and yellowing of the skin known as chlorosis.¹¹ A clinical diagnosis can be made by examining patient stool samples for eggs, and definitive characterization can be made using molecular tools such as polymerase chain reaction.^21,22

Common to hookworm infections is the immune reaction, which promotes inflammation with localized eosinophilia and mastocytosis.¹¹ In a clinical biopsy specimen of gut—usually obtained through esophagogastroduodenoscopy— T-helper (Th) 2–type immune (IL-4, IL-5, IL-9 and IL-13), regulatory Th10 (IL-10 and transcription growth factor β), and some evidence of Th1 (interferon gamma and IL-2) cytokines are present, but little evidence of Th17-type immune response was found.²³ It is believed that in zoonotic infections, antiparasitic IgE from basophils are somewhat successful at trapping the helminths in the epidermis, but in the anthropophilic species, IgE and Th2 responses are ineffective at clearing the parasite from the gut, and the defeated immune system transitions to a host-tolerance approach of limiting infection.¹¹ It is now believed that this natural armistice can be manipulated into a potential therapy against autoimmune and inflammatory conditions. Intentional infection with zoonotic whipworm or hookworm has been proposed as a mechanism of switching Th1 and Th2 responses to host-tolerant mechanisms in conditions such as Crohn disease and celiac disease,²⁴ and it has even been hypothesized that prior hookworm infection may reduce the chance of developing allergic conditions such as eczema.²⁵

Treatment and Prevention

The World Health Organization and Centers for Disease Control and Prevention recommend a single oral dose of 400 mg albendazole for adults or 10 to 15 mg/kg in children for CLM. A single dose of ivermectin at 12 mg in adults or 150 μg/kg in children can be used as an alternative where albendazole is not available.¹¹ Topical applications of thiabendazole 10% to 15% under occlusion or 3 times daily for 15 days without occlusion also can manage CLM, and pruritus can be treated with topical corticosteroids for symptomatic relief. Oral albendazole 400 mg twice daily or mebendazole 100 mg twice daily for 3 days or a single 500-mg dose, as well as 11 mg/kg (up to a maximum of 1 g) oral pyrantel pamoate once daily for 3 days can be used to treat intestinal hookworm infection, though it should be avoided in pregnancy. Iron deficiency should be managed with supplementation.¹¹

Prevention of hookworm infection is focused around 2 broad public health efforts: mass drug administration programs and the water, sanitation, and hygiene program. In mass drug administration, treatments such as benzimidazoles are given in mass to communities affected by endemic hookworm as a single dose to reduce the burden of disease. Together, these strategies effectively eliminated hookworms in many developed nations, but areas of resurgence are beginning to surface worldwide. With changes in climate, emerging drug resistance, and socioeconomic disparities, particularly affecting the southeast, a resurgence of hookworm has occurred in the United States.²⁶ One recent study demonstrated that almost one-third (19/55) of children sampled in an impoverished area of rural Alabama had hookworm eggs in their stool.²⁷ Furthermore, pets serve not only as zoonotic reservoirs for CLM recurrence but also as vehicles for the evolution of drug-resistant strains, leading some to call for a ban of animals from beaches and playgrounds as well as tightly controlled veterinary programs.^5,28 Ubiquitous benzimidazole use in livestock has led to bendazole-resistant strains, and it is likely that with continued and poorly adherent drug use, more zoonotic and anthropophilic drug-resistant strains of hookworm will emerge.^29,30

Conclusion

The burden of hookworm infection and CLM is substantial in parts of the United States. Dermatologists play a critical role in the recognition and management of hookworm infection for both treatment of affected patients and the subsequent prevention of its spread. As drug-resistant strains evolve, clinicians, public health officials, and scientists need to continue to work together to prevent and treat hookworm infection.

It is estimated that the prevalence of human hookworm infection is approximately 450 million individuals worldwide, representing a substantial global disease burden.¹ The annual global public health burden ranges from approximately 2 million to 4 million disability-adjusted life-years and $10 billion to $140 billion in hookwormrelated costs.² In this article, we discuss the lifecycle, transmission, and disease burden of cutaneous larva migrans (CLM) as well as prevention and treatment strategies.

Background

The Ancylostomatidae nematode family comprises at least 68 known species of hookworm that infect more than 110 different species of mammals.³ Many of these parasites are able to infect more than 1 primary host species, but from a disease perspective they can be classified as either anthropophilic, with humans as the intended host, or zoonotic, with humans as an incidental host. It is important to make this distinction because, though the lifecycles and biology of hookworm species generally are similar, the manifestations of incidental human infection from zoonotic hookworms are different from those of anthropophilic hookworms. Of the anthropophilic species, Necator americanus and Ancylostoma duodenale predominate. In the instance of zoonotic hookworm, dog-infecting A caninum and cat- and doginfecting A braziliense and Uncinaria stenocephala are common causes of incidental human disease.³

The life cycle of Ancylostomatidae organisms is astounding. Through millions of years of co-evolution with mammals,⁴ these parasitic worms have developed perhaps one of the most circuitous paths to propagate themselves in the natural world. Hookworms start their arduous journey as eggs deposited in soil, sand, and ground vegetation from the feces of infected animals.⁵ Approximately 1 day after the eggs are deposited, they hatch and begin the larval stage, during which they become infective 1 to 5 weeks later. At this point, the larvae become sensitive to their environment, responding to rising temperatures, increasing carbon dioxide levels, and vibrations in the soil—all of which suggest the presence of a potential host and contribute to a concordant increase in undulatory movement of the larvae.^5,6 Here, the most vulnerable tissues include the uncovered soles, palms, and buttocks of host mammals that come into contact with contaminated soil. In an undulating fashion and guided by temperature cues, the larvae locate the skin of the host and utilize a mixture of enzymes including hyaluronidases, metalloprotease, and other proteases to penetrate the epidermis.⁷ Anthropophilic hookworms such as N americanus and A duodenale will enter the circulatory system; from there, the hookworms migrate through the right-sided cardiopulmonary circuit and eventually ascend into the pulmonary vasculature.⁸ They then penetrate the lung capillary beds and parenchyma to reach the alveoli, ascend the respiratory tree, and, with the help of the mucociliary escalator, reach the esophagus, where they are swallowed by the host. In the gastrointestinal tract, adult hookworms consume host blood, mate, and lay eggs over a period of approximately 1 to 3 years if left untreated.⁹ Eggs are laid into the lower gastrointestinal tract, and the journey begins again in feces contacting ground or soil.

Geographic Distribution

Hookworms are found in almost all regions of the world, with species-specific distributions that highlight tropical and subtropical regions. Necator americanus and A duodenale are the most common hookworm species, with the former found predominantly in Southeast Asia and Latin America and the latter in Asia-Pacific regions.¹⁰ The highest prevalence of hookworms is in Southeast Asia followed by Sub-Saharan Africa, and the unique climate and soil composition of a region help determine the best environments for specific species of hookworm to thrive.¹¹ In addition, socioeconomics and social determinants of health play a big role in the spread of hookworms, as hygiene practices (eg, wearing clean shoes and clothing, bathing), infrastructure (eg, clean water and streets), and anthelmintic campaigns help reduce transmission.¹² Soil-transmitted helminths were once endemic to the southeastern United States, with some reports of approximately 40% of individuals infected in the south in the early 1900s.¹³ Anthelmintic campaigns such as water, sanitation, and hygiene programs as well as deworming of humans and livestock have proven effective in reducing the prevalence of helminth disease in industrialized nations.^13,14 However, zoonotic infections remain a problem in these regions, and in some parts of the United States more than 40% of sampled cats and dogs harbored species such as A braziliense.¹⁵

Clinical Manifestation

Initial hookworm infection often goes unnoticed because symptoms can range in severity, but it is characterized by transient ground itch—a local pruritic, erythematous, and papular eruption that develops in response to epidermal penetration.¹⁶ Because the larvae must traverse the host from skin to target organs for reproduction over several weeks, iron-deficiency anemia will manifest much later than signs of the initial penetration. In the case of incidental infection from zoonotic Ancylostomatidae organisms, the misguided larvae result in CLM, an often intensely pruritic skin condition that will self-resolve in 2 to 8 weeks with eventual death of the larvae.⁵

Diagnosis and Pathology of Disease

Zoonotic Hookworm—The major presenting sign of zoonotic hookworm infection is CLM. The diagnosis of CLM usually is made clinically, as the larvae themselves are 0.5 mm thick to 10 mm long (Figure 1) and usually extend several centimeters beyond the dermal lesion, with dermoscopy having limited utility.¹⁷ Patients may begin to experience itching as little as 1 hour after hookworm penetration of the skin.¹⁸ Once in contact with the skin, the hookworms’ hyaluronidases and proteases are capable of breaking through the epidermis, but zoonotic hookworms typically are unable to penetrate the basal layer of the human epidermis and remain entombed between the stratum granulosum and stratum corneum. With the exception of rare cases of direct or indirect pulmonary involvement resulting in Löffler syndrome,¹⁹ the larvae will die within weeks to months, and symptoms will subsequently resolve.

Although the infection generally is self-limiting, the dermatologic manifestations of CLM can be severe and warrant intervention. The lesions start as small reddish papules at the site of penetration (Figure 2), then the hallmark elevated, migrating, serpiginous, urticarial rash develops (Figure 3). Cutaneous larva migrans generally manifests unilaterally and is both erythematous and intensely pruritic. As the larvae migrate, they leave behind 1- to 5-cm tunneled creeping eruptions in their wake. The lesions, which can manifest with pain or be painless, may develop eczematous, bullous, follicular, or impetiginized appearances.²⁰ Atypical manifestations include folliculitis and urticarial plaques.¹⁷

Anthropophilic Hookworm—The lifecycles of N americanus and A duodenale are completed in human infection. Dermatologic manifestations are transient with the development of ground itch at the site of epidermal penetration. The hookworms employ collagenases that allow penetration of the basal layer of the skin, and eosinophilia develops as the parasites travel from the skin to the small intestine. Once attached to the gastrointestinal lumen, blood meals and proteolytic enzymes result in iron-deficiency anemia in the host and may lead to weakness, fatigue, and low birth weights in pregnant patients. With prolonged infection or heavy parasitic burden, patients can develop hypoproteinemia, anasarca, and yellowing of the skin known as chlorosis.¹¹ A clinical diagnosis can be made by examining patient stool samples for eggs, and definitive characterization can be made using molecular tools such as polymerase chain reaction.^21,22

Common to hookworm infections is the immune reaction, which promotes inflammation with localized eosinophilia and mastocytosis.¹¹ In a clinical biopsy specimen of gut—usually obtained through esophagogastroduodenoscopy— T-helper (Th) 2–type immune (IL-4, IL-5, IL-9 and IL-13), regulatory Th10 (IL-10 and transcription growth factor β), and some evidence of Th1 (interferon gamma and IL-2) cytokines are present, but little evidence of Th17-type immune response was found.²³ It is believed that in zoonotic infections, antiparasitic IgE from basophils are somewhat successful at trapping the helminths in the epidermis, but in the anthropophilic species, IgE and Th2 responses are ineffective at clearing the parasite from the gut, and the defeated immune system transitions to a host-tolerance approach of limiting infection.¹¹ It is now believed that this natural armistice can be manipulated into a potential therapy against autoimmune and inflammatory conditions. Intentional infection with zoonotic whipworm or hookworm has been proposed as a mechanism of switching Th1 and Th2 responses to host-tolerant mechanisms in conditions such as Crohn disease and celiac disease,²⁴ and it has even been hypothesized that prior hookworm infection may reduce the chance of developing allergic conditions such as eczema.²⁵

Treatment and Prevention

The World Health Organization and Centers for Disease Control and Prevention recommend a single oral dose of 400 mg albendazole for adults or 10 to 15 mg/kg in children for CLM. A single dose of ivermectin at 12 mg in adults or 150 μg/kg in children can be used as an alternative where albendazole is not available.¹¹ Topical applications of thiabendazole 10% to 15% under occlusion or 3 times daily for 15 days without occlusion also can manage CLM, and pruritus can be treated with topical corticosteroids for symptomatic relief. Oral albendazole 400 mg twice daily or mebendazole 100 mg twice daily for 3 days or a single 500-mg dose, as well as 11 mg/kg (up to a maximum of 1 g) oral pyrantel pamoate once daily for 3 days can be used to treat intestinal hookworm infection, though it should be avoided in pregnancy. Iron deficiency should be managed with supplementation.¹¹

Prevention of hookworm infection is focused around 2 broad public health efforts: mass drug administration programs and the water, sanitation, and hygiene program. In mass drug administration, treatments such as benzimidazoles are given in mass to communities affected by endemic hookworm as a single dose to reduce the burden of disease. Together, these strategies effectively eliminated hookworms in many developed nations, but areas of resurgence are beginning to surface worldwide. With changes in climate, emerging drug resistance, and socioeconomic disparities, particularly affecting the southeast, a resurgence of hookworm has occurred in the United States.²⁶ One recent study demonstrated that almost one-third (19/55) of children sampled in an impoverished area of rural Alabama had hookworm eggs in their stool.²⁷ Furthermore, pets serve not only as zoonotic reservoirs for CLM recurrence but also as vehicles for the evolution of drug-resistant strains, leading some to call for a ban of animals from beaches and playgrounds as well as tightly controlled veterinary programs.^5,28 Ubiquitous benzimidazole use in livestock has led to bendazole-resistant strains, and it is likely that with continued and poorly adherent drug use, more zoonotic and anthropophilic drug-resistant strains of hookworm will emerge.^29,30

Conclusion

The burden of hookworm infection and CLM is substantial in parts of the United States. Dermatologists play a critical role in the recognition and management of hookworm infection for both treatment of affected patients and the subsequent prevention of its spread. As drug-resistant strains evolve, clinicians, public health officials, and scientists need to continue to work together to prevent and treat hookworm infection.

It is estimated that the prevalence of human hookworm infection is approximately 450 million individuals worldwide, representing a substantial global disease burden.¹ The annual global public health burden ranges from approximately 2 million to 4 million disability-adjusted life-years and $10 billion to $140 billion in hookwormrelated costs.² In this article, we discuss the lifecycle, transmission, and disease burden of cutaneous larva migrans (CLM) as well as prevention and treatment strategies.

Background

The Ancylostomatidae nematode family comprises at least 68 known species of hookworm that infect more than 110 different species of mammals.³ Many of these parasites are able to infect more than 1 primary host species, but from a disease perspective they can be classified as either anthropophilic, with humans as the intended host, or zoonotic, with humans as an incidental host. It is important to make this distinction because, though the lifecycles and biology of hookworm species generally are similar, the manifestations of incidental human infection from zoonotic hookworms are different from those of anthropophilic hookworms. Of the anthropophilic species, Necator americanus and Ancylostoma duodenale predominate. In the instance of zoonotic hookworm, dog-infecting A caninum and cat- and doginfecting A braziliense and Uncinaria stenocephala are common causes of incidental human disease.³

The life cycle of Ancylostomatidae organisms is astounding. Through millions of years of co-evolution with mammals,⁴ these parasitic worms have developed perhaps one of the most circuitous paths to propagate themselves in the natural world. Hookworms start their arduous journey as eggs deposited in soil, sand, and ground vegetation from the feces of infected animals.⁵ Approximately 1 day after the eggs are deposited, they hatch and begin the larval stage, during which they become infective 1 to 5 weeks later. At this point, the larvae become sensitive to their environment, responding to rising temperatures, increasing carbon dioxide levels, and vibrations in the soil—all of which suggest the presence of a potential host and contribute to a concordant increase in undulatory movement of the larvae.^5,6 Here, the most vulnerable tissues include the uncovered soles, palms, and buttocks of host mammals that come into contact with contaminated soil. In an undulating fashion and guided by temperature cues, the larvae locate the skin of the host and utilize a mixture of enzymes including hyaluronidases, metalloprotease, and other proteases to penetrate the epidermis.⁷ Anthropophilic hookworms such as N americanus and A duodenale will enter the circulatory system; from there, the hookworms migrate through the right-sided cardiopulmonary circuit and eventually ascend into the pulmonary vasculature.⁸ They then penetrate the lung capillary beds and parenchyma to reach the alveoli, ascend the respiratory tree, and, with the help of the mucociliary escalator, reach the esophagus, where they are swallowed by the host. In the gastrointestinal tract, adult hookworms consume host blood, mate, and lay eggs over a period of approximately 1 to 3 years if left untreated.⁹ Eggs are laid into the lower gastrointestinal tract, and the journey begins again in feces contacting ground or soil.

Geographic Distribution

Hookworms are found in almost all regions of the world, with species-specific distributions that highlight tropical and subtropical regions. Necator americanus and A duodenale are the most common hookworm species, with the former found predominantly in Southeast Asia and Latin America and the latter in Asia-Pacific regions.¹⁰ The highest prevalence of hookworms is in Southeast Asia followed by Sub-Saharan Africa, and the unique climate and soil composition of a region help determine the best environments for specific species of hookworm to thrive.¹¹ In addition, socioeconomics and social determinants of health play a big role in the spread of hookworms, as hygiene practices (eg, wearing clean shoes and clothing, bathing), infrastructure (eg, clean water and streets), and anthelmintic campaigns help reduce transmission.¹² Soil-transmitted helminths were once endemic to the southeastern United States, with some reports of approximately 40% of individuals infected in the south in the early 1900s.¹³ Anthelmintic campaigns such as water, sanitation, and hygiene programs as well as deworming of humans and livestock have proven effective in reducing the prevalence of helminth disease in industrialized nations.^13,14 However, zoonotic infections remain a problem in these regions, and in some parts of the United States more than 40% of sampled cats and dogs harbored species such as A braziliense.¹⁵

Clinical Manifestation

Initial hookworm infection often goes unnoticed because symptoms can range in severity, but it is characterized by transient ground itch—a local pruritic, erythematous, and papular eruption that develops in response to epidermal penetration.¹⁶ Because the larvae must traverse the host from skin to target organs for reproduction over several weeks, iron-deficiency anemia will manifest much later than signs of the initial penetration. In the case of incidental infection from zoonotic Ancylostomatidae organisms, the misguided larvae result in CLM, an often intensely pruritic skin condition that will self-resolve in 2 to 8 weeks with eventual death of the larvae.⁵

Diagnosis and Pathology of Disease

Zoonotic Hookworm—The major presenting sign of zoonotic hookworm infection is CLM. The diagnosis of CLM usually is made clinically, as the larvae themselves are 0.5 mm thick to 10 mm long (Figure 1) and usually extend several centimeters beyond the dermal lesion, with dermoscopy having limited utility.¹⁷ Patients may begin to experience itching as little as 1 hour after hookworm penetration of the skin.¹⁸ Once in contact with the skin, the hookworms’ hyaluronidases and proteases are capable of breaking through the epidermis, but zoonotic hookworms typically are unable to penetrate the basal layer of the human epidermis and remain entombed between the stratum granulosum and stratum corneum. With the exception of rare cases of direct or indirect pulmonary involvement resulting in Löffler syndrome,¹⁹ the larvae will die within weeks to months, and symptoms will subsequently resolve.

Although the infection generally is self-limiting, the dermatologic manifestations of CLM can be severe and warrant intervention. The lesions start as small reddish papules at the site of penetration (Figure 2), then the hallmark elevated, migrating, serpiginous, urticarial rash develops (Figure 3). Cutaneous larva migrans generally manifests unilaterally and is both erythematous and intensely pruritic. As the larvae migrate, they leave behind 1- to 5-cm tunneled creeping eruptions in their wake. The lesions, which can manifest with pain or be painless, may develop eczematous, bullous, follicular, or impetiginized appearances.²⁰ Atypical manifestations include folliculitis and urticarial plaques.¹⁷

Anthropophilic Hookworm—The lifecycles of N americanus and A duodenale are completed in human infection. Dermatologic manifestations are transient with the development of ground itch at the site of epidermal penetration. The hookworms employ collagenases that allow penetration of the basal layer of the skin, and eosinophilia develops as the parasites travel from the skin to the small intestine. Once attached to the gastrointestinal lumen, blood meals and proteolytic enzymes result in iron-deficiency anemia in the host and may lead to weakness, fatigue, and low birth weights in pregnant patients. With prolonged infection or heavy parasitic burden, patients can develop hypoproteinemia, anasarca, and yellowing of the skin known as chlorosis.¹¹ A clinical diagnosis can be made by examining patient stool samples for eggs, and definitive characterization can be made using molecular tools such as polymerase chain reaction.^21,22

Common to hookworm infections is the immune reaction, which promotes inflammation with localized eosinophilia and mastocytosis.¹¹ In a clinical biopsy specimen of gut—usually obtained through esophagogastroduodenoscopy— T-helper (Th) 2–type immune (IL-4, IL-5, IL-9 and IL-13), regulatory Th10 (IL-10 and transcription growth factor β), and some evidence of Th1 (interferon gamma and IL-2) cytokines are present, but little evidence of Th17-type immune response was found.²³ It is believed that in zoonotic infections, antiparasitic IgE from basophils are somewhat successful at trapping the helminths in the epidermis, but in the anthropophilic species, IgE and Th2 responses are ineffective at clearing the parasite from the gut, and the defeated immune system transitions to a host-tolerance approach of limiting infection.¹¹ It is now believed that this natural armistice can be manipulated into a potential therapy against autoimmune and inflammatory conditions. Intentional infection with zoonotic whipworm or hookworm has been proposed as a mechanism of switching Th1 and Th2 responses to host-tolerant mechanisms in conditions such as Crohn disease and celiac disease,²⁴ and it has even been hypothesized that prior hookworm infection may reduce the chance of developing allergic conditions such as eczema.²⁵

Treatment and Prevention

The World Health Organization and Centers for Disease Control and Prevention recommend a single oral dose of 400 mg albendazole for adults or 10 to 15 mg/kg in children for CLM. A single dose of ivermectin at 12 mg in adults or 150 μg/kg in children can be used as an alternative where albendazole is not available.¹¹ Topical applications of thiabendazole 10% to 15% under occlusion or 3 times daily for 15 days without occlusion also can manage CLM, and pruritus can be treated with topical corticosteroids for symptomatic relief. Oral albendazole 400 mg twice daily or mebendazole 100 mg twice daily for 3 days or a single 500-mg dose, as well as 11 mg/kg (up to a maximum of 1 g) oral pyrantel pamoate once daily for 3 days can be used to treat intestinal hookworm infection, though it should be avoided in pregnancy. Iron deficiency should be managed with supplementation.¹¹

Prevention of hookworm infection is focused around 2 broad public health efforts: mass drug administration programs and the water, sanitation, and hygiene program. In mass drug administration, treatments such as benzimidazoles are given in mass to communities affected by endemic hookworm as a single dose to reduce the burden of disease. Together, these strategies effectively eliminated hookworms in many developed nations, but areas of resurgence are beginning to surface worldwide. With changes in climate, emerging drug resistance, and socioeconomic disparities, particularly affecting the southeast, a resurgence of hookworm has occurred in the United States.²⁶ One recent study demonstrated that almost one-third (19/55) of children sampled in an impoverished area of rural Alabama had hookworm eggs in their stool.²⁷ Furthermore, pets serve not only as zoonotic reservoirs for CLM recurrence but also as vehicles for the evolution of drug-resistant strains, leading some to call for a ban of animals from beaches and playgrounds as well as tightly controlled veterinary programs.^5,28 Ubiquitous benzimidazole use in livestock has led to bendazole-resistant strains, and it is likely that with continued and poorly adherent drug use, more zoonotic and anthropophilic drug-resistant strains of hookworm will emerge.^29,30

Conclusion

The burden of hookworm infection and CLM is substantial in parts of the United States. Dermatologists play a critical role in the recognition and management of hookworm infection for both treatment of affected patients and the subsequent prevention of its spread. As drug-resistant strains evolve, clinicians, public health officials, and scientists need to continue to work together to prevent and treat hookworm infection.