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What’s Eating You? Hookworm and Cutaneous Larva Migrans
What’s Eating You? Hookworm and
Cutaneous Larva Migrans
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
cutaneous larval migrans on the palm.
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.
- Vos T, Abajobir AA, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211-1259.
- Bartsch SM, Hotez PJ, Asti L, et al. The global economic and health burden of human hookworm infection. PLoS Negl Trop Dis. 2016;10:E0004922.
- Seguel M, Gottdenker N. The diversity and impact of hookworm infections in wildlife. Int J Parasitol Parasites Wildl. 2017;6:177-194.
- Adams BJ, Peat SM, Dillman AR. Phylogeny and evolution. In: Entomopathogenic Nematodes: Systematics, Phylogeny and Bacterial Symbionts. Brill; 2010:693-733.
- Heukelbach J, Feldmeier H. Epidemiological and clinical characteristics of hookworm-related cutaneous larva migrans. Lancet Infect Dis. 2008;8:302-309.
- Haas W, Haberl B, Idris I, et al. Infective larvae of the human hookworms Necator americanus and Ancylostoma duodenale differ in their orientation behaviour when crawling on surfaces. Parasitol Res. 2005;95:25-29.
- Hotez P, Narasimhan S, Haggerty J, et al. Hyaluronidase from infective Ancylostoma hookworm larvae and its possible function as a virulence factor in tissue invasion and in cutaneous larva migrans. Infect Immun. 1992;60:1018-1023.
- Brooker S, Bethony J, Hotez PJ. Human hookworm infection in the 21st century. Adv Parasitol. 2004;58:197-288.
- Hoagland K, Schad G. Necator americanus and Ancylostoma duodenale: life history parameters and epidemiological implications of two sympatric hookworms of humans. Exp Parasitol. 1978;44:36-49.
- Clements ACA, Alene KA. Global distribution of human hookworm species and differences in their morbidity effects: a systematic review. Lancet Microbe. 2022;3:E72-E79.
- Loukas A, Hotez PJ, Diemert D, et al. Hookworm infection. Nat Rev Dis Primers. 2016;2:1-18.
- Gazzinelli A, Correa-Oliveira R, Yang GJ, et al. A research agenda for helminth diseases of humans: social ecology, environmental determinants, and health systems. PLoS Negl Trop Dis. 2012;6:E1603.
- Starr MC, Montgomery SP. Soil-transmitted helminthiasis in the United States: a systematic review—1940-2010. Am J Trop Med Hyg. 2011;85:680-684.
- Strunz EC, Addiss DG, Stocks ME, et al. Water, sanitation, hygiene, and soil-transmitted helminth infection: a systematic review and metaanalysis. PLoS Med. 2014;11:E1001620.
- Liotta JL, Youn H, Aksel S, et al. Prevalence of Ancylostoma braziliense in dogs from Alachua and Marion Counties, Florida, United States. J Parasitol. 2012;98:1039-1040.
- Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med. 2004;351:799-807.
- Prickett KA, Ferringer TC. What’s eating you? cutaneous larva migrans. Cutis. 2015;95:126-128.
- Feldmeier H, Schuster A. Mini review: hookworm-related cutaneous larva migrans. Eur J Clin Microbiol Infect Dis. 2012;31:915-918.
- Tan SK, Liu TT. Cutaneous larva migrans complicated by Löffler syndrome. Arch Dermatol. 2010;146:210-212.
- Eksomtramage T, Aiempanakit K. Bullous and pustular cutaneous larva migrans: two case reports and a literature review. IDCases. 2018;12:130-132.
- Utzinger J, Rinaldi L, Lohourignon LK, et al. FLOTAC: a new sensitive technique for the diagnosis of hookworm infections in humans. Trans R Soc Trop Med Hyg. 2008;102:84-90.
- Chidambaram M, Parija SC, Toi PC, et al. Evaluation of the utility of conventional polymerase chain reaction for detection and species differentiation in human hookworm infections. Trop Parasitol. 2017;7:111-116.
- Gaze S, McSorley HJ, Daveson J, et al. Characterising the mucosal and systemic immune responses to experimental human hookworm infection. PLoS Pathog. 2012;8:E1002520.
- Croese J, O’Neil J, Masson J, et al. A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut. 2006;55:136-137.
- Mpairwe H, Amoah AS. Parasites and allergy: observations from Africa. Parasite Immunol. 2019;41:E12589.
- Albonico M, Savioli L. Hookworm: a neglected resurgent infection. Editorial. BMJ. 2017;359:j4813.
- McKenna ML, McAtee S, Bryan PE, et al. Human intestinal parasite burden and poor sanitation in rural Alabama. Am J Trop Med Hyg. 2017;97:1623-1628.
- Traversa D. Pet roundworms and hookworms: a continuing need for global worming. Parasit Vectors. 2012;5:1-19.
- Geerts S, Gryseels B. Drug resistance in human helminths: current situation and lessons from livestock. Clin Microbiol Rev. 2000;13:207-222.
- Jimenez Castro PD, Howell SB, Schaefer JJ, et al. Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? Parasit Vectors. 2019;12:1-15.
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
cutaneous larval migrans on the palm.
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
cutaneous larval migrans on the palm.
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.
- Vos T, Abajobir AA, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211-1259.
- Bartsch SM, Hotez PJ, Asti L, et al. The global economic and health burden of human hookworm infection. PLoS Negl Trop Dis. 2016;10:E0004922.
- Seguel M, Gottdenker N. The diversity and impact of hookworm infections in wildlife. Int J Parasitol Parasites Wildl. 2017;6:177-194.
- Adams BJ, Peat SM, Dillman AR. Phylogeny and evolution. In: Entomopathogenic Nematodes: Systematics, Phylogeny and Bacterial Symbionts. Brill; 2010:693-733.
- Heukelbach J, Feldmeier H. Epidemiological and clinical characteristics of hookworm-related cutaneous larva migrans. Lancet Infect Dis. 2008;8:302-309.
- Haas W, Haberl B, Idris I, et al. Infective larvae of the human hookworms Necator americanus and Ancylostoma duodenale differ in their orientation behaviour when crawling on surfaces. Parasitol Res. 2005;95:25-29.
- Hotez P, Narasimhan S, Haggerty J, et al. Hyaluronidase from infective Ancylostoma hookworm larvae and its possible function as a virulence factor in tissue invasion and in cutaneous larva migrans. Infect Immun. 1992;60:1018-1023.
- Brooker S, Bethony J, Hotez PJ. Human hookworm infection in the 21st century. Adv Parasitol. 2004;58:197-288.
- Hoagland K, Schad G. Necator americanus and Ancylostoma duodenale: life history parameters and epidemiological implications of two sympatric hookworms of humans. Exp Parasitol. 1978;44:36-49.
- Clements ACA, Alene KA. Global distribution of human hookworm species and differences in their morbidity effects: a systematic review. Lancet Microbe. 2022;3:E72-E79.
- Loukas A, Hotez PJ, Diemert D, et al. Hookworm infection. Nat Rev Dis Primers. 2016;2:1-18.
- Gazzinelli A, Correa-Oliveira R, Yang GJ, et al. A research agenda for helminth diseases of humans: social ecology, environmental determinants, and health systems. PLoS Negl Trop Dis. 2012;6:E1603.
- Starr MC, Montgomery SP. Soil-transmitted helminthiasis in the United States: a systematic review—1940-2010. Am J Trop Med Hyg. 2011;85:680-684.
- Strunz EC, Addiss DG, Stocks ME, et al. Water, sanitation, hygiene, and soil-transmitted helminth infection: a systematic review and metaanalysis. PLoS Med. 2014;11:E1001620.
- Liotta JL, Youn H, Aksel S, et al. Prevalence of Ancylostoma braziliense in dogs from Alachua and Marion Counties, Florida, United States. J Parasitol. 2012;98:1039-1040.
- Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med. 2004;351:799-807.
- Prickett KA, Ferringer TC. What’s eating you? cutaneous larva migrans. Cutis. 2015;95:126-128.
- Feldmeier H, Schuster A. Mini review: hookworm-related cutaneous larva migrans. Eur J Clin Microbiol Infect Dis. 2012;31:915-918.
- Tan SK, Liu TT. Cutaneous larva migrans complicated by Löffler syndrome. Arch Dermatol. 2010;146:210-212.
- Eksomtramage T, Aiempanakit K. Bullous and pustular cutaneous larva migrans: two case reports and a literature review. IDCases. 2018;12:130-132.
- Utzinger J, Rinaldi L, Lohourignon LK, et al. FLOTAC: a new sensitive technique for the diagnosis of hookworm infections in humans. Trans R Soc Trop Med Hyg. 2008;102:84-90.
- Chidambaram M, Parija SC, Toi PC, et al. Evaluation of the utility of conventional polymerase chain reaction for detection and species differentiation in human hookworm infections. Trop Parasitol. 2017;7:111-116.
- Gaze S, McSorley HJ, Daveson J, et al. Characterising the mucosal and systemic immune responses to experimental human hookworm infection. PLoS Pathog. 2012;8:E1002520.
- Croese J, O’Neil J, Masson J, et al. A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut. 2006;55:136-137.
- Mpairwe H, Amoah AS. Parasites and allergy: observations from Africa. Parasite Immunol. 2019;41:E12589.
- Albonico M, Savioli L. Hookworm: a neglected resurgent infection. Editorial. BMJ. 2017;359:j4813.
- McKenna ML, McAtee S, Bryan PE, et al. Human intestinal parasite burden and poor sanitation in rural Alabama. Am J Trop Med Hyg. 2017;97:1623-1628.
- Traversa D. Pet roundworms and hookworms: a continuing need for global worming. Parasit Vectors. 2012;5:1-19.
- Geerts S, Gryseels B. Drug resistance in human helminths: current situation and lessons from livestock. Clin Microbiol Rev. 2000;13:207-222.
- Jimenez Castro PD, Howell SB, Schaefer JJ, et al. Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? Parasit Vectors. 2019;12:1-15.
- Vos T, Abajobir AA, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211-1259.
- Bartsch SM, Hotez PJ, Asti L, et al. The global economic and health burden of human hookworm infection. PLoS Negl Trop Dis. 2016;10:E0004922.
- Seguel M, Gottdenker N. The diversity and impact of hookworm infections in wildlife. Int J Parasitol Parasites Wildl. 2017;6:177-194.
- Adams BJ, Peat SM, Dillman AR. Phylogeny and evolution. In: Entomopathogenic Nematodes: Systematics, Phylogeny and Bacterial Symbionts. Brill; 2010:693-733.
- Heukelbach J, Feldmeier H. Epidemiological and clinical characteristics of hookworm-related cutaneous larva migrans. Lancet Infect Dis. 2008;8:302-309.
- Haas W, Haberl B, Idris I, et al. Infective larvae of the human hookworms Necator americanus and Ancylostoma duodenale differ in their orientation behaviour when crawling on surfaces. Parasitol Res. 2005;95:25-29.
- Hotez P, Narasimhan S, Haggerty J, et al. Hyaluronidase from infective Ancylostoma hookworm larvae and its possible function as a virulence factor in tissue invasion and in cutaneous larva migrans. Infect Immun. 1992;60:1018-1023.
- Brooker S, Bethony J, Hotez PJ. Human hookworm infection in the 21st century. Adv Parasitol. 2004;58:197-288.
- Hoagland K, Schad G. Necator americanus and Ancylostoma duodenale: life history parameters and epidemiological implications of two sympatric hookworms of humans. Exp Parasitol. 1978;44:36-49.
- Clements ACA, Alene KA. Global distribution of human hookworm species and differences in their morbidity effects: a systematic review. Lancet Microbe. 2022;3:E72-E79.
- Loukas A, Hotez PJ, Diemert D, et al. Hookworm infection. Nat Rev Dis Primers. 2016;2:1-18.
- Gazzinelli A, Correa-Oliveira R, Yang GJ, et al. A research agenda for helminth diseases of humans: social ecology, environmental determinants, and health systems. PLoS Negl Trop Dis. 2012;6:E1603.
- Starr MC, Montgomery SP. Soil-transmitted helminthiasis in the United States: a systematic review—1940-2010. Am J Trop Med Hyg. 2011;85:680-684.
- Strunz EC, Addiss DG, Stocks ME, et al. Water, sanitation, hygiene, and soil-transmitted helminth infection: a systematic review and metaanalysis. PLoS Med. 2014;11:E1001620.
- Liotta JL, Youn H, Aksel S, et al. Prevalence of Ancylostoma braziliense in dogs from Alachua and Marion Counties, Florida, United States. J Parasitol. 2012;98:1039-1040.
- Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med. 2004;351:799-807.
- Prickett KA, Ferringer TC. What’s eating you? cutaneous larva migrans. Cutis. 2015;95:126-128.
- Feldmeier H, Schuster A. Mini review: hookworm-related cutaneous larva migrans. Eur J Clin Microbiol Infect Dis. 2012;31:915-918.
- Tan SK, Liu TT. Cutaneous larva migrans complicated by Löffler syndrome. Arch Dermatol. 2010;146:210-212.
- Eksomtramage T, Aiempanakit K. Bullous and pustular cutaneous larva migrans: two case reports and a literature review. IDCases. 2018;12:130-132.
- Utzinger J, Rinaldi L, Lohourignon LK, et al. FLOTAC: a new sensitive technique for the diagnosis of hookworm infections in humans. Trans R Soc Trop Med Hyg. 2008;102:84-90.
- Chidambaram M, Parija SC, Toi PC, et al. Evaluation of the utility of conventional polymerase chain reaction for detection and species differentiation in human hookworm infections. Trop Parasitol. 2017;7:111-116.
- Gaze S, McSorley HJ, Daveson J, et al. Characterising the mucosal and systemic immune responses to experimental human hookworm infection. PLoS Pathog. 2012;8:E1002520.
- Croese J, O’Neil J, Masson J, et al. A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut. 2006;55:136-137.
- Mpairwe H, Amoah AS. Parasites and allergy: observations from Africa. Parasite Immunol. 2019;41:E12589.
- Albonico M, Savioli L. Hookworm: a neglected resurgent infection. Editorial. BMJ. 2017;359:j4813.
- McKenna ML, McAtee S, Bryan PE, et al. Human intestinal parasite burden and poor sanitation in rural Alabama. Am J Trop Med Hyg. 2017;97:1623-1628.
- Traversa D. Pet roundworms and hookworms: a continuing need for global worming. Parasit Vectors. 2012;5:1-19.
- Geerts S, Gryseels B. Drug resistance in human helminths: current situation and lessons from livestock. Clin Microbiol Rev. 2000;13:207-222.
- Jimenez Castro PD, Howell SB, Schaefer JJ, et al. Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? Parasit Vectors. 2019;12:1-15.
What’s Eating You? Hookworm and
Cutaneous Larva Migrans
What’s Eating You? Hookworm and
Cutaneous Larva Migrans
PRACTICE POINTS
- Anthropophilic hookworm infection should be considered with evidence of either transient ground itch or iron-deficient anemia in individuals who go barefoot, permitting ground-to-skin transmission.
- Zoonotic hookworm infection manifests as cutaneous larva migrans, an elevated serpiginous rash that, while usually self-resolving, can be intensely pruritic and should be treated accordingly.
- Considered a neglected tropical disease, hookworm infection still represents an enormous global disease burden. In addition to ongoing afflicted regions, hookworms are making a resurgence in developed nations, and drug-resistant strains have evolved.
