A Systematic Overview of Zoonotic Helminth Infections in North America

Blaine A. Mathison, BS, M(ASCP); Bobbi S. Pritt, MD, MS, DTM&H

Disclosures

Lab Med. 2018;49(4):e61-e93. 

In This Article

Nematodes

Nematodes (roundworms) constitute one of the largest animal taxa. Many species have evolved to be parasitic in humans and nonhuman animals. Most parasitic nematodes of humans are dioecious (ie, having separate male and female individuals) and have 5 developmental stages after the egg: 4 larval stages (L1 through L4) and adult (L5) (a notable exception to the dioecious life cycle is Strongyloides stercoralis, which only has parasitic females that reproduce parthenogenetically in the human host). For most parasitic nematodes, the infectious stage is the L3 larva (commonly referred to as a filariform larva).

Externally, many nematodes have a similar morphology, being long and slender and lacking true segmentation. However, nematodes vary considerably in the form of their internal organs and organ systems; the form and arrangement of internal structures are taxonomically and diagnostically important. Some of the important internal diagnostic structures include the form of the musculature, lateral nerve chords, intestine, and reproductive structures.[5]

There are many laboratory methods for diagnosing nematode infections, depending on the species and stage involved. For those nematodes that colonize the human intestinal tract, diagnosis is typically made by finding eggs or larvae in O&P examinations of stool or adult worms in stool specimens. Filarial nematodes are usually diagnosed by finding microfilariae (early L1 larvae) in blood or skin snips, or adults in biopsy specimens. For many zoonotic species for which humans are not part of the natural life cycle, or for those nematodes that colonize nonintestinal sites, diagnosis is often achieved by examining sections of worms in biopsy specimens. Serologic tests and NAATs, such as polymerase chain reaction (PCR), are available for other nematode infections.

Trichuroid Nematodes

The trichuroid (capillarid) nematodes (order Trichocephalida) are a specialized group of nematodes whose members are all parasites of vertebrates in the adult stage. Morphologically, they are distinguished by having a specialized glandular structure called a stichosome (which is made up of individual cells called stichocytes) that encases the esophagus, as well as a cellular hypodermis with specialized gland cells and modified regions of the cuticle forming bacillary bands (Figure 4B).[5] The most familiar members of this group are Trichuris trichiura (the human whipworm) and Trichinella spp; however, 2 other genera can cause zoonotic infections in the human host: Capillaria and Anatrichosoma.

Capillaria hepatica (hepatic capillariasis).General considerations: Capillaria hepatica is a cosmopolitan parasite of rodents. The entire life cycle, including maturation, mating, and oviposition, takes place in the liver of the host. Eggs are not shed in the feces of the host and are only liberated into the environment by death and decomposition of the host, or after being spuriously passed by a predator after predation of the rodent host. Eggs embryonate in the environment (or while being passed by a predator), and infection occurs from the ingestion of embryonated eggs containing infectious larvae. Humans infection also occurs from ingestion of embryonated eggs, usually in food or on fomites (objects or materials likely to carry infection) contaminated with soil containing such eggs, and also causes hepatic disease.[10]

Clinical manifestations and pathologic features; Although hepatic capillariasis can be a serious, life-threatening condition, clinical manifestations are usually nonspecific. The worms and their eggs cause focal chronic inflammation in the liver, resulting in granuloma formation made up of macrophages, eosinophils, and multinucleate giant cells and, eventually, the encapsulation or calcification of dead worms and their eggs. Septal fibrosis usually follows. Although infection with a single worm may be asymptomatic, patients with a heavy worm burden may experience severe, even fatal, disease. When present, clinical manifestations are similar to those in patients with visceral larva migrans, including fever, hepatomegaly, and hypereosinophilia.[8,11]

Laboratory Diagnosis: Diagnosis of hepatic capillariasis is made almost exclusively by the finding of adult worms or eggs in histopathologic sections of liver biopsy specimens (Figure 4A). Eggs are 51–67 μm long by 30–35 μm wide and have a thick, striated shell and bipolar prominences.[1] Because the entire life cycle takes places within the liver, eggs are not shed in the feces of the host. If eggs of C. hepatica are observed in O&P examinations of stool, they probably represent spurious passage after the consumption of infected animal liver, and further specimens should be collected to rule out true infection.[11] When observed in stool, C. hepatica eggs must also be differentiated from the similar-appearing eggs of T. trichiura; this differentiation is easily accomplished by recognition of the striated shell that is not a feature of T. trichiura eggs.[1]

Anatrichosoma species (anatrichosomiasis).General considerations: Anatrichosoma is a genus of nematodes that parasitize the oral mucosa of various mammals. Anatrichosoma buccalis, a parasite of the Virginia opossum, is the only species currently known to be from North America. Until recently, the few documented cases of human anatrichosomiasis were from incidental findings in biopsy specimens of skin and soft tissue. However, 2 recent cases[12,13] document Anatrichosoma in the oral cavity of patients from the Midwest with travel to Mexico. It was not possible in either of those cases to confirm the identity of the worm to the species level. However, the geographic distribution and clinical presentation suggest A. buccalis as the causal agent.

The life cycle of Anatrichosoma species is not fully understood. Embryonated eggs are shed directly into the environment in the respiratory secretions of, or swallowed and passed in the feces of, the definitive host, yet laboratory experiments have failed to infect new hosts by feeding them embryonated eggs. Several related nematodes require an insect intermediate host; that might be required for Anatrichosoma species too. The 2 patients from the second case report[13] participated in "snail facials" in Mexico, in which live snails were allowed to crawl on their faces. This detail could suggest the possible role of terrestrial mollusks as an intermediate host.

Clinical manifestations and pathologic features: The 2 case individuals who presented with oral lesions had ulcers and track-like lesions on the soft palate, tongue, inner lip, buccal mucosa, and palatal gingiva.[13] The microscopic pathologic response is undescribed in the literature, to our knowledge, for oral anatrichosomiasis.

Laboratory Diagnosis: Anatrichosomiasis has been diagnosed by the finding of adult worms in biopsy specimens. Adult worms possess typical trichuroid features, such as stichocytes and bacillary bands.

Trichinella species (trichinellosis, trichinosis). General considerations: Trichinella species are parasites of carnivorous and omnivorous mammals, birds, and reptiles. Approximately 8 species or strains have been implicated in human disease, 5 of which are endemic to North America: T. spiralis, T. pseudospiralis, T. nativa, T. murrelli, and strain Trichinella T6. Trichinella species have an unusual life cycle in which a host serves as a definitive host, then an intermediate host, and, if not consumed, a dead-end host. Perpetuation of the life cycle is dependent on continuous cycles of predation or scavenging.

There are 2 natural cycles; in the domestic cycle, Trichinella worms typically cycle between domestic pigs and anthropophilic rodents, whereas in the sylvatic cycle, the worms cycle between various wild carnivores or omnivores, including rodents, wild pigs, and bears. Because of improved animal husbandry practices in the United States, infection caused by eating domestic pigs is rare, except in cases of home-raised swine. Most cases acquired in the United States are observed in hunters; sources of infection include wild boars and pigs, bears, walruses, and mountain lions. Trichinella nativa and Trichinella T6, which are usually acquired from bear meat, are freeze-resistant, so freezing game meat does not eliminate the chances of infection.[14]

Infection is initiated when infective L1 larvae are ingested in infected meat or meat products. The larvae are liberated in the stomach and upper small intestine and invade the small intestinal mucosa, where they molt 4 times and develop into adult worms. Adults mate, and after approximately 1 week, gravid females release larvae that migrate to striated muscle, where they become dormant until the muscle is consumed by a predator or human. All North American species except T. pseudospiralis form encapsulated cysts that contain a single, coiled larva. Larvae remain viable and infectious for years; however, if the host is not eventually consumed, the worms will die and calcify in the tissues.[14]

Clinical manifestations and pathologic features: Although mild cases are often asymptomatic, there are 3 clinical phases of trichinellosis: enteric, invasive, and encystment. The enteric phase occurs while adult worms are mating in the small intestine. Symptoms vary based on species/strain and worm burden; in contrast, the enteric phase is usually accompanied by nausea, vomiting, abdominal pain, and alternating bouts of diarrhea and constipation. Adult worms elicit chronic inflammation and edema, characterized by lymphocytes, polymorphonuclear leukocytes (PMNs), and eosinophils.[5,6,8]

The invasive phase is initiated when larvae are migrating from the intestinal tract to the striated muscle. During the peak of the migration, larvae will elicit high fever, myalgia, facial and palpebral edema, and elevated eosinophilia. Site-specific manifestations may occur if larvae migrate through specific organs or organ systems. Larvae migrating through the central nervous system (CNS) may cause dizziness, meningitis, and psychosis, whereas larvae migrating through the eye can cause conjunctivitis. Colonization of the heart can cause cardiac arrhythmia or myocarditis and may result in death.[5,6,8]

The encystment phase is initiated as larvae are settling in striated muscle. Manifestations may include muscle pain and weakness, tenderness, dyspnea, and peripheral or facial edema. Pathologically, encapsulated species are surrounded by a hyaline membrane with an infiltrate made up primarily of eosinophils.[5,6,8]

Trichinellosis is treated with mebendazole or albendazole.[15]

Laboratory Diagnosis: Diagnosis of trichinellosis is not always easy and should be based on 3 criteria: clinical manifestations, positive laboratory test results, and epidemiologic data. The primary method for laboratory diagnosis is serologic testing by enzyme-linked immuosorbent assay (ELISA).[14,16] Larvae may be observed in muscle biopsy specimens. Also, the presence of a coiled encapsulated larva in striated muscle (Figure 4B) is pathognomonic for trichinellosis; however, the sensitivity of microscopic analysis is lower than with serologic testing. Larvae in muscle biopsy specimens usually exhibit typical trichuroid features, such as stichocytes and bacillary bands.[5,6,8]

Ascarid Nematodes

Members of the order Ascaridida are nematodes that are characterized in the adult stage (and often the L3 and L4 larval stages) as having 3 fleshy anterior projections commonly referred to as "lips" (Figure 1A, inset). Many species are parasitic in humans and nonhuman animals. Medically important genera include Ascaris, Toxocara, Baylisascaris, Lagaochilascaris, and the anisakids Anisakis, Pseudoterranova, and Contracaecum. Human infection with Lagaochilascaris is endemic to South America and is not covered further herein.

Ascaris lumbricoides (ascariasis).General considerations: Ascaris lumbricoides is the largest intestinal nematode in the human host and one of the most commonly encountered nematodes in the diagnostic laboratory. Nearly worldwide in distribution, it remains more common in warmer and humid climates. For many years, it was generally considered that there were 2 species of Ascaris that can infect humans: A. lumbricoides, which was believed to be primarily a human parasite, and A. suum, which was believed to be primarily a pig parasite. However, the biology, morphology, host range, and molecular data suggest that the 2 species are conspecific, and A. suum is now generally considered to be synonymous with A. lumbricoides.[17,18]Ascaris lumbricoides has been a burden on humans since antiquity; we include it in this zoonotic treatise because many clusters and cases acquired in the United States have been associated with pigs.[19,20]

Ascaris lumbricoides has a complex 1-host life cycle. Adults reside and mate in the small intestine of the host; adults sometime migrate to ectopic sites, including the liver, gall bladder, pancreas, abdominal cavity, and umbilicus, or may be coughed up or emerge from the nose or tear ducts. Females shed fertilized and unfertilized eggs into the environment via the feces of the host; the unfertilized eggs are a dead-end stage in the environment. Fertilized eggs are shed unembryonated, and over a period of 2–4 weeks (depending on environmental conditions), the embryo develops into an infective L3 larva. Infectious eggs can remain viable in soil for years, depending on conditions. Infection occurs when fully embryonated eggs are ingested in food, water, or fomites contaminated with soil containing the eggs. Eggs hatch in the upper small intestine, and the L3 larvae penetrate the intestinal mucosa and enter circulation, where they are carried to the lungs. After approximately 2 weeks, the larvae penetrate the alveolar walls, ascend the bronchial tree to the epiglottis, and are swallowed. After reaching the small intestine, they mature into adults. Adults can live for 1 to 2 years and then, after death, are passed in the stool of the host.[1,2]

Clinical manifestations and pathologic features: Because A. lumbricoides is relatively well adapted to the human host, light infections are usually asymptomatic. During the initial larval migration in the lungs, patients may exhibit an asthma-like condition called Loeffler syndrome or Ascaris pneumonitis. Pathologically, Loeffler syndrome is characterized by a pulmonary infiltration of eosinophils, macrophages, and epithelial cells; Charcot-Leyden crystals may also be present. This condition appears to worsen with subsequent infections.[5,6,8]

Intestinal colonization usually does not elicit a strong inflammatory response. There may be a shortening of the villous border and increased mononuclear cells in the lamina propria. Heavy worm burdens can cause generalized gastrointestinal symptoms and, in severe cases, intestinal obstruction. This may cause some worms to perforate the intestinal wall and migrate to the abdominal cavity, biliary and pancreatic ducts, and the appendix, resulting in peritonitis, liver and pancreatic abscesses, or other localized inflammatory reactions.[5,6,8] Albendazole, mebendazole, and ivermectin have been used to successfully treat ascariasis.15

Laboratory Diagnosis: Ascariasis is usually diagnosed by detecting eggs in routine O&P examinations of stool or by finding adult worms passed in stool specimens. Ascaris lumbricoides has relatively high fecundity, and there is usually not a problem detecting eggs in fecal concentrates. There are 4 morphotypes of eggs, so laboratory scientists should be familiar with all of them: eggs may be fertile or infertile, and both of those may be mamillated (having an outer bumpy proteinaceous layer) or decorticated (smooth, lacking the outer layer). Fertilized eggs (Figures 3A, 3B) of A. lumbricoides are 55–75 μm long by 35–50 μm wide and have a thick shell; the embryo is in the 1-celled stage when passed in feces. Infertile eggs (Figures 3C, 3D) are larger, measuring 85–95 μm long by 43–47 μm wide, and have a thin shell and disorganized internal contents. Mature adult A. lumbricoides (Figure 1A) usually are not difficult to diagnose due to their large size and characteristic ascarid-type "lips," although younger adults may be smaller and need to be distinguished from anisakid nematodes as described later in this article.[1] Ectopic ascariasis may be diagnosed by the finding of adult, often dead and degrading, worms in biopsy or endoscopy specimens. L3 larvae are also detected, in rare instances, in lung biopsy, sputum, and bronchoalveolar lavage specimens during their migratory phase.

Baylisascaris procyonis (baylisascariasis, visceral larval migrans, ocular larval migrans). General considerations: Baylisascaris procyonis is an ascarid parasite of raccoons and other members of the family Procyonidae from Canada to South America. Dogs, however, can also serve as definitive hosts for this parasite, enhancing the risk for disease in humans. In the natural cycle, raccoons acquire the parasite by 1 of 2 means. In the first, juvenile raccoons ingest fully embryonated eggs that have contaminated the fur of the mother or from soil contact in contaminated dens or raccoon latrines (communal defecation sites used by raccoons). The embryonated eggs hatch in the small intestine and colonize the intestinal mucosa. The worms molt 2 more times to become adults and then mate in the small intestine. Unembryonated eggs are shed by female worms approximately 50–75 days after infection. The second route of infection for the raccoon is by ingesting infective L3 larvae in paratenic hosts, such as mice, squirrels, rabbits, and chickens.

Humans become infected after the incidental ingestion of fully embryonated eggs in contaminated environmental sources, such as soil, wood chips, fireplace wood, and sandboxes. People who keep pet raccoons and children who have pica are at increased risk. The embryonation period for B. procyonis eggs is approximately 2–4 weeks in optimal environmental conditions, so exposure to fresh raccoon feces (for example, feces deposited overnight on a porch or deck) is not an immediate risk source, whereas exposure to feces in well-established latrines may present a substantial risk. Eggs hatch in the small intestine of the human host, and L3 larvae migrate to various body sites (liver, heart, lung, brain, eyes), resulting in a visceral larval migrans (VLM) or ocular larval migrans (OLM), similar to toxocariasis (see further information later in this article). Larvae will continue to grow, but not to develop further, in the human host; as such, humans are a dead-end host for B. procyonis.[21]

Clinical manifestations and pathologic features: Case individuals with a low worm burden may be asymptomatic. As larvae wander and grow, they cause severe physical damage to the affected tissue, especially the eyes and brain. Baylisascaris procyonis seems to have a predilection for the CNS and eyes, and in severe cases, infection can result in severe neurologic damage, permanent blindness, or death. Baylisascarisprocyonis tends to live longer in the human host than Toxocara species, so there is more time for increased physical damage to surrounding tissues. Its larger size relative to Toxocara may also contribute to increased tissue damage. When worms eventually die, they elicit delayed-type and intermediate-type hypersensitivity reactions and, eventually, eosinophilic granulomas.[5,6,8]

The drug regimen of choice for treatment of baylisascariasis is albendazole in combination with high-dose corticosteroids. Albendazole initiated early (as many as 3 days after exposure) might prevent clinical disease and is recommended for children with known exposure history. Mebendazole, levamisole, or ivermectin could be used if albendazole is not available. Ocular infection has been treated using laser photocoagulation therapy to destroy intraretinal larvae.[15]

Laboratory Diagnosis: The primary diagnostic method for baylisascariasis is serologic testing by immunoblot, especially in conjunction with a thorough epidemiologic investigation.[22] L3 larvae may also be detected in histological preparations of biopsy or autopsy specimens (Figure 4C). Because B. procyonis does not develop to adult stage in the human host, O&P examinations of stool are not appropriate for diagnosis.

Toxocara canis, T. cati (toxocariasis, visceral larval migrans, ocular larval migrans).General considerations: Toxocara species are ascarid nematode parasites of various carnivores. The 2 species usually implicated in human disease are T. canis and T. cati, which use dogs and cats, respectively, as their primary definitive hosts (although both species can be shared between both hosts). In the natural cycle, dogs acquire T. canis by 1 of 4 means: direct, paratenic, transmammary, and transplacental. Puppies and younger dogs are more susceptible to direct infection, which is similar to that of A. lumbricoides and involves the ingestion of embryonated eggs that hatch in the small intestine, larval migration through the lungs, and eventual colonization of the small intestine by adult worms. The paratenic cycle involves the ingestion of infective L3 larvae in paratenic hosts, such as rodents and rabbits, or the ingestion of embryonated eggs in earthworms or other soil-dwelling invertebrates. In older dogs, patent infection can occur, but more commonly, larvae liberated from ingested eggs enclose themselves in cysts in the body. These larvae are reactivated in pregnant dogs, and puppies can be infected by transmammary or transplacental routes. Toxocara cati has a similar life cycle in cats.[23]

Humans become infected with Toxocara species by ingestion of fully embryonated eggs in contaminated environmental sources or L3 larvae in paratenic hosts. As with other ascarids, the embryonation period is usually 2 to 4 weeks, so fresh dog or cat feces are not a risk of infection, although the soil in the areas where dogs and cats defecate can present risks. Toxocariasis is a nationally notifiable disease in the United States and is classified by the CDC as a neglected parasitic infection (NIP) in the United States; approximately 13.9% of the United States population is seropositive for antibodies to Toxocara, suggesting that a greater percentage of the population is at risk of exposure.[24]

Clinical manifestations and pathologic features: Toxocara species cause VLM or OLM similar to Baylisascaris procyonis (as mentioned earlier herein), but the liver is the most common organ affected. The lungs, brain, and eyes also can be infected. Patients may be asymptomatic or present with hypereosinophilia, hepatomegaly, fever, cough, pulmonary infiltrates, or endophthalmitis or papillitis with secondary glaucoma. The severity of symptoms is related to worm load and organ or organ system involved. Pathologically, VLM or OLM caused by Toxocara species is similar to that caused by B. procyonis; dead and dying worms elicit delayed-type or intermediate-type hypersensitivity reactions and eventual eosinophilic granuloma formation.[5,6,8]

VLM caused by Toxocara species can be treated with albendazole or mebendazole. For OLM, those drugs may help for active infection, and inflammation may be controlled using corticosteroids. Surgical procedures may be required to prevent further damage due to chronic inflammation.[15]

Laboratory Diagnosis: Toxocariasis is diagnosed primarily by serologic testing, which can be performed on serum, cerebrospinal fluid (CSF), and vitreous fluid.[25] As with baylisascariasis, larvae may be observed in histological preparations of biopsy or autopsy specimens. Also, because Toxocara spp also do not develop to adults in the human host, O&P examination of stool is not an appropriate test.

Anisakis species, Pseudoterranova species, and Contracaecum species (anisakiasis).General considerations: Anisakis, Pseudoterranova, and Contracaecum species (often collectively referred to as anisakids or codworms) are parasites that reside in the stomach or intestines of fish-eating birds and marine mammals. Gravid female worms shed fully embryonated eggs containing infectious L3 larvae. Eggs hatch in marine water, and the L3 larvae are ingested by a microscopic crustacean intermediate host. The infected crustaceans are eaten by fish or mollusks (squid), and the larvae become encapsulated in the host tissue and do not develop further. Because parasite development does not progress in the fish or molluscan hosts, they are considered paratenic hosts. Infected smaller fish are often eaten by larger fish, which also become infected and serve as paratenic hosts. The definitive host becomes infected after eating infected fish or squid. Encapsulated larvae are liberated and attach to the gastric or intestinal mucosa of the definitive host, where they develop into sexually mature male and female worms.[26,27]

Humans become infected after eating undercooked seafood harboring infective L3 larvae. Because anisakid nematodes have very low host specificity for the paratenic hosts, most commercial fish and squid may serve as sources of infection, including but not limited to salmon, cod, grouper, flounder, red snapper, tuna, mackerel, herring, shad, and various squid. Anisakid nematodes will not develop to adults in the human host.[26,27]

Clinical manifestations and pathologic features: The 4 main clinical presentations of anisakiasis are gastric, intestinal, ectopic, and acute allergic reactions. Most of the time, after being ingested, anisakid nematodes will leave the human body by expulsion of live worms out the nose or mouth (which, although unpleasant, is the best clinical outcome because removal is curative). However, sometimes, these nematodes will attempt to invade the gastric or intestinal mucosa. Gastric symptoms are acute, usually within hours after ingestion, and may include fever and epigastric pain, clinically mimicking an ulcer or angina-like chest pain. Abdominal manifestations usually take longer—as long as 1 week after consumption, and may include nausea, abdominal pain, fever, and diarrhea with blood or mucus. Eosinophilia and leukocytosis may develop.[27] If worms successfully penetrate the gastric or intestinal mucosa, they may migrate to ectopic sites, including the peritoneum, mesenteries, omental nodules, mesocolic lymph nodes, spleen, pancreas, or perimetrium.[28] Histologically, worms in tissues are usually surrounded by inflammatory cells such as eosinophils.[5,6,8]

Finally, acute and chronic allergic reactions may occur after eating seafood containing anisakid nematodes. Acute reactions may or may not be accompanied by gastric or intestinal symptoms, and the worms need not be alive. Clinical manifestations can range from urticaria or angioedema to anaphylactic shock. The severity of reactions may increase with continued exposure; thus, affected individuals should avoid ingesting potentially infected seafood. Fish handlers and food preparers may develop dermatitis or conjunctivitis from handling infected fish.[27]

Laboratory Diagnosis: Anisakiasis may be diagnosed by gross morphology of intact worms, histopathology, or serology, depending on the clinical presentation and specimen types. Most of the time, diagnosis is made by the examination of intact larvae that are expelled live or removed via endoscopy and submitted to the diagnostic laboratory. Larval anisakids (Figure 1B) grossly resemble young specimens of Ascaris and possess the typical ascarid-type "lips." Two features that may separate anisakids from young Ascaris are the presence of a boring tooth at the mouthparts and a terminal mucron (Figure 1B, inset), which is present in all species of Pseudoterranova but only some Anisakis species (and not any Contracaecum species). The larvae of all anisakid nematodes are superficially similar to one another externally; identification to the genus or species level is not required for patient management but may be performed for educational or epidemiologic purposes.[27] Anisakids in biopsy specimens are usually found incidentally when specimens are collected for other suspect etiologies (eg, tumors). The morphologic features of anisakid larvae in tissues are similar to, but should be differentiated from, those of ectopic Ascaris.[5,6,8]

Serologic diagnosis is made by observing positive skin-prick test results in conjunction with compatible clinical manifestations and an epidemiologic history of recent consumption of seafood. Positive skin-prick test results should be confirmed by specific immunoglobulin (Ig)E antibodies using additional assays, such as radioimmunoassay, and a lack of reaction to host fish proteins.[29] Because anisakid nematodes cannot develop to adults in a human host, O&P examination of stool is not an appropriate test.

Filarial Nematodes

Filarial nematodes (order: Spirurida, family: Onchocercidae) are highly specialized parasites that have a vertebrate definitive host and an arthropod vector intermediate host. The infectious stage for the vector, and the diagnostic stage for many human-adapted species, is a microfilaria, which is an early L1 larva. Adult worms tend to be very long and thread-like, often with marked sexual dimorphism regarding their size.[1] Some of the most debilitating parasitic diseases in the world are caused by filarial nematodes, including lymphatic filariasis caused by Wuchereria bancrofti and Brugia species and river blindness caused by Onchocerca volvulus. There are several zoonotic agents of disease in North America, including members of the genera Dirofilaria, Onchocerca, Molinema, and Brugia.

Dirofilaria immitis (pulmonary dirofilariasis).General considerations: Dirofilaria immitis is a cosmopolitan parasite of dogs and wild canids and is commonly referred to as dog heartworm. Heartworm is the most clinically important disease of dogs in the United States. Once considered restricted to the southern United States, it now occurs in every state in the continental United States, Canada, and Alaska.[30] In 2015, at least 115,000 dogs were infected in the United States.[31] In addition to dogs, many other mammals can serve as natural definitive hosts, including seals, wild and domestic cats, horses, bears, muskrats, and nutria. Adult worms reside in the right ventricle of the heart and pulmonary artery of the canine host, resulting in blood flow obstruction and congestive heart failure. Gravid females shed microfilariae into the bloodstream, where they circulate in peripheral blood and get picked up by a mosquito vector with its blood meal. In the vector host, the worms mature to infective L3 larvae, and these are inoculated into the bite wound of a new host when the mosquito takes another blood meal.[30] The larvae undergo early development in subcutaneous tissues of the canine host for approximately 3 months before migrating to the heart.

Humans also become infected after being fed on by an infected mosquito. A wide range of species of mosquitoes can serve as vectors, increasing the chances of canine and human infection. In humans, the L3 larvae do not undergo partial maturation in the subcutaneous tissues but instead travel through the bloodstream to the right ventricle and pulmonary artery, where they are usually destroyed by the host immune system.[30] Occasionally, dead larvae will embolize into the distal pulmonary vasculature, causing an infarct, which eventually undergoes healing via fibrosis, forming a well-defined circular lesion (ie, coin lesion) on chest imaging studies.[6] In most cases, D. immitis will not develop to an adult in the human host.[32]

Clinical manifestations and pathologic features: Patients with pulmonary dirofilariasis may be asymptomatic or may present with generalized respiratory symptoms, such as chest pain, cough, fever, hemoptysis, and malaise associated with the embolus of the dead larva into the lungs. Pathologically, dead and degenerating worms are usually observed within the lumen of a vessel surrounded by a sharply demarcated area of infarct in varying stages of organization. The necrotic area is surrounded by a narrow rim of granulomatous inflammation consisting of plasma cells, lymphocytes, and giant cells.[5,6,8]

Laboratory Diagnosis: Diagnosis of pulmonary dirofilariasis is made almost exclusively by the observation of coin lesions on radiography in conjunction with clinical symptoms.[6] If the coin lesion is biopsied (usually to evaluate for neoplasia, tuberculosis, or other infection), then the degrading and calcified worms may be observed in the histopathologic sections. The presence of a large degenerating nematode (100–350 μm in diameter) in a pulmonary infarct allows for presumptive diagnosis of Dirofilaria immitis, but many of the characteristic morphologic features are sometimes obscured. Because the larvae live short lives and rarely mature to adulthood, microfilariae are not produced, and therefore, examination of peripheral blood is not warranted.

Dirofilaria species, Non-immitis (Cutaneous Dirofilariasis, Ocular Dirofilariasis).General considerations: In addition to D. immitis, several other species of Dirofilaria can cause human infection. In North America, these include D. tenuis, a raccoon parasite in the eastern and southeastern United States; D. striata, a parasite of bobcats and other wild felids in North and South America; D. ursi, a parasite of bears in northern North America; and D. subdermata, a porcupine parasite in the northern United States and Canada. Mosquitoes are the vectors for all of these except D. ursi, which is transmitted by black flies. All of these species reside in subcutaneous tissues of their natural hosts and release microfilariae into peripheral blood.[32] Humans also become infected after being fed on by an appropriate infected vector. Humans may serve as definitive hosts, but because worm burdens are low, females are rarely gravid in the human host.

Clinical manifestations and pathologic features: Most cases of non-immitis dirofilariasis present with skin nodules that may be painful or painless, and stationary or migratory. The most common sites of these nodules are the face, neck, breast, and scalp. Adult Dirofilaria have also been recovered from the conjunctiva.

By histopathology, skin nodules are usually seen to contain a single, coiled worm with a surrounding abscess composed of neutrophils and eosinophils. Older lesions will contain a dead, calcified worm surrounded by a granuloma composed of epithelioid cells, macrophages, eosinophils, giant cells, and lymphocytes. Parasite morphology may be obscured in older infections but is usually sufficient for making an accurate diagnosis.[5,6,8]

Laboratory Diagnosis: Cutaneous dirofilariasis is diagnosed most frequently by the observation of worms in histopathologic sections of subcutaneous nodules (Figure 4D). Dirofilaria species have several well-described morphologic features that should make a definitive diagnosis possible, including features of the cuticle, hypodermis, musculature, and lateral chords.[5,6,8] Ocular dirofilariasis is usually diagnosed by the gross morphology of adult worms removed from the conjunctiva. Few worms are recovered this way, and the presence of a long, thread-like worm in the eye of a patient who has not travelled internationally should first suggest Dirofilaria species (Figure 1C). Microscopic examination of the worm would reveal thin longitudinal ridges running lengthwise down the body of the worm.

Although Dirofilaria can develop to an adult in the human host, mating rarely takes place due to low worm burdens. As such, microscopic examination of peripheral blood for microfilariae is not appropriate for diagnosing dirofilariasis.

Onchocerca lupi and Onchocerca species (Zoonotic Onchocerciasis).General Considerations: Human onchocerciasis is usually attributed to infection with Onchocerca volvulus, found in parts of sub-Saharan Africa, Latin America, and the Middle East. However, various zoonotic Onchocerca species can also be occasional parasites of humans. Onchocerca lupi is a parasite of wild and domestic dogs and cats in Europe and North America. It was first described from the eye of a wolf in the Republic of Georgia and typically manifests as an ocular infection in its natural hosts. Before 2013, there were only 5 reported human cases, from Albania, Turkey, Tunisia, and Iran. In 2013, the first human case was reported in the United States, the patient was a 22-month-old American aboriginal female residing in Arizona.[33] From 2013 through 2016, a total of 5 more cases were recorded from the southwestern United States.[34] As with the human parasite O. volvulus, transmission occurs from the bite of infected black flies. It is uncertain what caused the recent surge in cases in the Southwest, but there appears to be a natural cycle present there among cats, dogs, and black flies. The life cycle of O. lupi in animals, and the extent to which humans are contributing to the epidemiology of the disease in this region, remains unclear.

Before the first O. lupi case in 2013, there had been periodic case reports of zoonotic onchocerciasis in North America with ocular involvement.[35,36] In most cases, the parasite could not been confidently identified to the species level, although in a case from Colorado, the parasite was tentatively identified as O. cervicalis, a parasite of veterinary importance in horses.[37]

Clinical manifestations and pathologic features: There are too few documented cases to get a concise picture of the clinical presentation associated with O. lupi infection. Human cases from Albania, Turkey, Tunisia, and Iran, prior to the first United States case in 2013, all had ocular infections involving the conjunctiva. The 6 cases from the southwestern United States manifested as periorbital nodule of the superior rectus muscle (n = 1), palpable nodules on the scalp or arms (n = 2), or subcutaneous cervical spinal nodules (n = 3). The patient with the periorbital nodule had presented with left upper eyelid drooping and periorbital edema. The patients with cervical nodules reported 1 or more of the following symptoms: headaches, stiff neck, sore throat, and dysphagia. With the 2 subcutaneous cases, the nodules were palpable; in 1, the nodule was tender and erythematous, but in the other case was neither tender nor erythematous.[34]

On histopathological examination, the worms were often enclosed within fibrous granulomas. Two of the cases presented with gravid female worms, which are not common in most zoonotic filarial infections.[34]

Laboratory Diagnosis: All of the current United States cases of O. lupi were diagnosed by the finding of adult worms in histopathologic sections of biopsy specimens. In none of the patients were microfilariae detected by skin snips or slit-lamp examinations of the eye.

Molinema species (zoonotic filariasis).General considerations: Molinema is an enigmatic genus of filarial nematodes that primarily parasitize rodents and carnivores as definitive hosts and various sanguinivorous insects as vectors. Human cases are rare but have been documented in Canada, Oregon, and Kansas under the generic names Dipetalonema or Acanthocheilonema.[32,35] It is not usually possible to confidently identify zoonotic Molinema to the species level, but cases from North America have been tentatively attributed to M. arbuta and M. sprenti, which are natural parasites of porcupines and beavers, respectively. For both species, the vectors are mosquitoes.

Clinical manifestations and pathologic features: Cases of human Molinema infection in North America have involved a foreign-body ocular sensation in the eyes of patients. Removal of the worms proved curative.[32,35]

Laboratory Diagnosis: All cases were diagnosed by the removal and examination of intact L4 larvae from the anterior chamber of the eye. Because the worms were not sexually mature, a definitive diagnosis to the species level could not be made.

Brugia species (Zoonotic Filariasis).General considerations: Human filariasis caused by Brugia species is usually attributable to B. malayi and B. timori, which cause lymphatic filariasis in Southeast Asia and the Pacific Islands. However, in the Americas, there are sporadic cases of infection with zoonotic Brugia species, usually discovered on finding worms during histological examinations of excited lymphatic tissue. There have been roughly 30 cases documented from the United States, widely scattered across the continent. Most of the species in North America probably parasitize rodents or carnivores as definitive hosts and use mosquitoes as vectors. Because the internal anatomy in cross-section has not been described for most nonhuman Brugia species, identification to the species level is not possible in most cases diagnosed by histologic examination.[5,32]

Clinical manifestations and pathologic features: Most patients with zoonotic Brugia infection present with a tender mass in the cervical, axillary, or inguinal regions. Microscopic examination reveals a coiled nematode in a dilated lymphatic vessel surrounded by follicular hyperplasia and eosinophilia. Dead worms are usually encased in granulomas.[5] Excision of the nodule is considered curative.

Laboratory Diagnosis: Infections with zoonotic Brugia endemic to North America are diagnosed by finding adult worms during histopathologic examination of lymphatic tissue. Although in some cases female worms were gravid, microfilariae have never been detected in peripheral blood.

Miscellanaeous Spiruroid Nematodes

In addition to the filarial nematodes, several other nematodes in the order Spirurida cause zoonotic infections in humans, including members of the genera Physaloptera, Gnathostoma, Thelazia, Gongylonema, Spirocera, and Rictularia. All of these worms have multihost life cycles with at least an insect or other arthropod serving as an intermediate host or vector. The focus herein will be on members of the genera Gnathostoma, Thelazia, and Gongylonema, which have been reported only sporadically as agents of human infection in North America.

Gnathostoma spinigerum (gnathostomiasis).General considerations: Four species of Gnathostoma have been reported to infect humans. However, G. spinigerum is the only species currently documented to cause human disease in Central America (Mexico).[38]

Gnathostoma spinigerum parasitizes cats as its primary definitive host, with adults residing in tumors in the stomach. Gravid females release unembryonated eggs into the stomach of the host, which are eventually passed in feces. After approximately 7 days in water, the eggs embryonate, and L1 larvae are released. The L1 larvae are ingested by freshwater microscopic crustaceans (eg, copepods or water fleas) and develop into L2 larvae. When infected crustaceans are eaten by a vertebrate intermediate host (fish, frogs, eels, birds, or reptiles), they develop into an infectious L3 larvae and encyst in the host tissues. Cats become infected after eating infected intermediate hosts. After consumption, the larvae are liberated into the stomach and migrate to the liver or abdominal cavity. After approximately a month, they return to the stomach, mature to adult stage, and mate.[39]

Human infection is usually caused by the consumption of undercooked vertebrate intermediate hosts or the incidental ingestion of infected crustaceans. Cases from Mexico have usually been attributed to the ingestion of undercooked fish in ceviche.[40,41] Gnathostoma species can colonize several organs and organ systems (skin, muscle, liver, mesenteries, CNS, and eyes) in humans as L3 larvae and usually do not develop further.

Clinical manifestations and pathologic features: After ingestion, larvae migrate from the intestine through the liver to muscular and subcutaneous tissues. During this larval migrans, patients may present with lack or loss of appetite for food, vomiting, abdominal pain, fever, and nausea. During the chronic phase, periodic migratory swelling might occur, made up of nodules that are well-defined, nonpitting, hard, red, and painful or pruritic. Cutaneous gnathostomiasis often manifests as a creeping eruption.

Also, Gnathostoma species can migrate to the CNS; eye; ear; or respiratory, gastrointestinal, or urinary tracts, resulting in localized symptoms. However, they do not migrate back to the gastric mucosa, as seen in the definitive host. Differential diagnoses include other parasitic infections such as visceral larval migrans, sparganosis, loaisis, ectopic paragonimiasis and fascioliasis, and myiasis. Histopathologic examination may show intact worms, or worms in varying stages of degradation surrounded by granulomatous inflammation, histiocytes, foreign body giant cells, and fibrosis.[5,6]

Laboratory Diagnosis: Cutaneous and visceral gnathostomiasis is usually diagnosed by observing worms in histopathologic preparations of biopsy specimens (Figure 4E). Ocular gnathostomiasis is usually diagnosed by morphologic identification of intact larvae removed from the eye of the patient. Serology is available in Mexico, Thailand, and other countries but not currently in the United States for routine clinical diagnosis. Because Gnathostoma species do not develop to adults in the human host, O&P examination of stool is not useful.

Thelazia californiensis, T. gulosa (Thelaziasis).General considerations: There are 5 species of Thelazia known from North America, 2 of which have been implicated in human disease in the West: T. californiensis and T. gulosa. The latter of those was only recently recorded from humans for the first time in a patient from Oregon.[42]

Thelazia species have a 2-host life cycle involving a vertebrate definitive host and a dipteran intermediate host. Hosts for T. californiensis include dogs, cats, coyotes, bears, sheep, and deer; the primary hosts for T. gulosa are cattle, in which this parasite is of veterinary importance in North America, Central Asia, Europe, and Australia. Adult worms reside in the conjunctiva of the definitive host, and gravid females release L1 larvae into the lacrimal secretions of the host. The L1 larvae are picked up by dipteran intermediate hosts as they feed on the secretions; the primary vector for T. californiensis is Fannia canalicularis, for T. gulosa, it is Musca autumnalis. Larvae migrate to the abdomen of the fly and then to the main body cavity (the hemocoel), where they become infectious L3 larvae. The L3 larvae then migrate to the fly's mouthparts and are inoculated into the conjunctiva of a new host when the fly feeds on ocular secretions. The parasite develops to adulthood in the conjunctival sac and tear film of the eye.[42]

Clinical manifestations and pathologic features: Thelaziasis usually presents with conjunctival inflammation, follicular hypertrophy of the conjunctiva, and increased lacrimation. Many patients have described the sensation of something moving in their eye. In more severe infections, worms migrating across the surface of the eye have caused corneal abrasions and even blindness.[43] Because worms are usually removed intact from the conjunctiva, the associated host tissue response is not described herein. Extraction of the worms is curative; chemotherapy is not recommended.

Laboratory Diagnosis: Thelaziasis is diagnosed by the morphologic examination of adult worms removed from the conjunctiva. Adults are characterized by their cup-shaped buccal cavity and prominent transverse cuticular striations (Figure 1E).

Gongylonema pulchrum (gongylonemiasis).General considerations: Gongylonema pulchrum is a spirurid nematode that causes zoonotic infections in humans, in rare instances. The parasite occurs nearly worldwide; sporadic human cases have been documented in the United States, Europe, Japan, Iraq, Morocco, China, Sri Lanka, Australia, New Zealand, and Egypt.[44]

Gongylonema pulchrum has a complex life cycle involving a mammalian definitive host and an arthropod intermediate host. The parasite can infect a broad range of hosts; definitive hosts in nature include livestock, dogs, cats, skunks, hedgehogs, and rabbits. Adult worms reside in the submucosa of the oral cavity, esophagus, and tongue and move through the skin by means of mucosal secretions, feeding on epithelial cells and inflammatory exudates. The worms form serpentine trails as they move, which are often grossly visible. Embryonated eggs are shed by gravid females and are swallowed and passed in the feces of the definitive host. Eggs containing infective L3 larvae are ingested by coprophagous insects (ie, those that feed on excrement), such as dung beetles and cockroaches. The definitive host becomes infected after eating insects harboring infectious L3 larvae. The larvae are released in the upper gastrointestinal tract and migrate up the esophagus and settle in the submucosa of the upper esophagus and oral cavity. Worms molt twice and become adults approximately 1 month after initial infection.[45] Human infection also occurs after ingestion of infected insects harboring L3 larvae.

Clinical manifestations and pathologic features: Clinical manifestations occur as worms burrow in the mucosa and can vary from local irritation to severe stomatitis and pharyngitis. The most common presentation is a crawling sensation in the mouth and soft palate. Serpentine trails are grossly visible. The most common sites of colonization are the lip, gums, palate, tonsils, and esophagus. Eosinophilia can occur. The pathologic response to Gongylonema infection is not well understood. Histopathologic findings reveal sections of worms or eggs within the burrows.[5]

Extraction of the worm is considered curative; often, chemotherapy is not warranted. In cases of heavy parasite loads or for patients in whom reinfection is a concern, albendazole therapy may be recommended.[46]

Laboratory Diagnosis: Diagnosis of gongylonemiasis is made primarily by the identification of adult worms removed from their tracks in the mucosa or from finding worms and their eggs in histopathologic preparations of biopsy specimens. The anterior end of males and females are characterized by rounded swellings (bosses) (Figure 1D). The posterior end of the female is simple, but the posterior end of the male is asymmetric and contains 10 pairs of small papillae (microscopic bumps on the cuticle). On rare occasions, eggs have been detected in O&P examinations of stool. Eggs are usually shed in an embryonated state and have a thick hyaline shell, measuring 50–70 μm long by 25–37 μm wide (Figure 1D, inset).[1]

Strongylid Nematodes

The strongyles (order Rhabditita, suborder Strongylida) encompass a large group of nematodes that parasitize the gastrointestinal and respiratory tract of vertebrate animals. Some of the most medically important members of this group include Strongyloides stercoralis and the human hookworms in the genera Ancylostoma and Necator. Also, zoonotic infections are caused by animal hookworms and members of the genera Trichostrongylus and Angiostrongylus.

Ancylostoma caninum, A. braziliense (Cutaneous Larval Migrans, Creeping Eruption). General considerations: Cutaneous larval migrans (CLM; also known as creeping eruption or ground itch) is a zoonotic condition caused by hookworm species that normally do not use humans as definitive hosts. The most common causes of human infestation in North America are Ancylostoma caninum and A. braziliense, which use dogs and cats, respectively, as primary definitive hosts.

Human infection is more common in the warmer and more humid regions of the Southeast and occurs when infective L3 (filariform) larvae of the hookworms directly penetrate the skin of the host while the host walks barefoot or wears sandals in regions where the soil or sand is contaminated with dog or cat feces. These worms cannot develop to adults in the human host and eventually die in the skin; on rare occasions, they may burrow deeper into the skin and migrate to other organs.

Clinical manifestations and pathologic features: The feet are the most common site of infection. Initially, itching, erythema, and vesiculation usually occur at the site of skin penetration. Grossly, the skin develops linear, raised serpentine tracts that become edematous and pruritic. Scratching the lesion can result in secondary bacterial infections. If left untreated, the condition can last for weeks before the larvae eventually die in the skin. Because the clinical picture is highly suggestive of CLM, biopsies are usually not recommended; as such, the host pathologic response is not well-defined.[5] On some occasions, larvae will travel to the bowel, resulting in eosinophilic enteritis.

Because the condition is usually self-limiting, treatment is usually not required. However, treatment with albendazole or ivermectin is curative, especially with severe or relapsing cases.[15]

Laboratory Diagnosis: Diagnosis of CLM is based almost exclusively on clinical presentation in combination with a known exposure history. Biopsy specimens are rarely collected, and because these particular hookworm species cannot develop to adults in the human host, O&P examination of stool is not useful for making the diagnosis.[5]

Angiostrongylus cantonensis (Angiostrongyliasis, Eosinophilic Meningitis).General considerations: Angiostrongylus cantonensis is a nearly worldwide parasite of rats. Historically, human disease was believed to be restricted to Southeast Asia and the Pacific Basin, but as the epidemiology became better understood, additional cases have been described from Australia, Cuba, Puerto Rico, Brazil, Ecuador, Costa Rica, Madagascar, mainland Africa, and the Unites States. In the United States, human disease is most prevalent in Hawaii, where rats and the intermediate hosts (various terrestrial and freshwater mollusks) have become serious pests. In the continental United States, sporadic human cases have been reported from Louisiana, Texas, and Tennessee.[47] Given the ubiquitous presence of rats and the low host specificity for the molluscan host, it is surprising that human infection is not more common on a global scale.

In the natural cycle, adults live in the pulmonary vessels of rats. After mating, gravid females release embryonated eggs into the blood that become lodged in the capillaries of the lungs. The eggs hatch, and L1 larvae migrate up the bronchial tree to the tracheae and are eventually swallowed and passed in the rodent's feces. L1 larvae are ingested by various terrestrial or freshwater mollusks, including snails, slugs, and semislugs. In the molluscan host, L1 larvae develop to infective L3 larvae. The definitive host becomes infected after eating infected mollusks or paratenic hosts (such as freshwater crustaceans, frogs, reptiles, and planarians) that have consumed infected mollusks. The L3 larvae are liberated in the stomach and migrate down to the small intestine, where they enter the bloodstream and are carried passively to the rodent's brain. In the brain, they develop to L4 larvae and then eventually adults. After maturation to adults, they leave the brain and re-enter the bloodstream, where males and females pair up and mate. The adults eventually settle in the pulmonary vessels for laying eggs.[47]

Humans can also become infected after eating undercooked mollusks, fresh produce contaminated with mollusks or parts thereof, or infected paratenic hosts. The initial part of the life cycle in humans is similar to that in rats; however, the worms typically die as L4 larvae in the brain of the human host. Angiostrongylus cantonensis typically cannot develop to sexual maturity in the human host.

Clinical presentation and pathologic features: The most common presentation of A. cantonensis infection in humans is eosinophilic meningitis due to the host response of dying larvae. Initial infection usually presents with fever, malaise, vomiting, and abdominal pain. Invasion of the meninges and brain parenchyma can result in bitemporal headache, nausea, stiff neck, and vomiting. The severity of cerebral symptoms is directly related to the parasite burden, with neurologic manifestations being initiated on the death of and inflammatory response to the larvae in the brain. In less-severe infections, patients may be asymptomatic, and the disease can be self-limiting; however, in more serious infections, patients may develop chronic neurologic issues and even die.[5]

Pathologically, worms can be found in meninges surrounding blood vessels. Dead and degrading worms are usually surrounded by eosinophilic granulomas. Trails made by wandering worms may hemorrhage and may contain host inflammatory cells. CSF examination will show an increase in eosinophils and, occasionally, L4 larvae.[5,6,8]

Treatment for eosinophilic meningitis is usually supportive, with the use of analgesics for pain and corticosteroids for inflammation. No antihelminthic drugs have proven to be effective in treatment.[15]

Laboratory Diagnosis: Eosinophilic meningitis caused by A. cantonensis can be difficult to diagnosis and is often made based on clinical presentation in conjunction with positive laboratory results and a detailed epidemiologic investigation after other etiologies (viruses, bacteria) have been ruled out. NAATs using PCR are available at select specialty laboratories for detecting A. cantonensis in CSF specimens.[48] These tests have been implemented by the Hawaii Department of Health because that state is where the disease is most prevalent within the United States. Serologic testing is available in Asia but not currently in the United States, to our knowledge.

Also, worms may be observed in biopsy or autopsy specimens of brain tissue or in CSF specimens and can be identified based on characteristic morphologic features (Figure 1F). Because A. cantonensis does not develop to adult stage in the human host, O&P examination of stool for eggs or larvae is not appropriate.

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