Summary

The intestinal roundworm Ascaris lumbricoides is the most common helminth infection of humans worldwide, typically causing nutrient depletion and obstruction due to the physical presence of worms in symptomatic individuals, as well as immune-mediated reactions to migrating larvae. Epidemiological surveys have variously found A. lumbricoides infection to be either a predisposing factor for allergy and asthma, or actually protective in nature. Four allergens have been characterized to date, however, at least nine additional IgE-binding components in Ascaris extract could be potential allergens, and cross-reactivity has been demonstrated with a number of nematodes, arthropods, and crustaceans.

Epidemiology

Worldwide distribution

'Ascariasis’, or infection by Ascaris spp., is the most common helminth infection of humans worldwide, with most individuals harboring a low to moderate parasite burden and a few hosts infected by heavy intensities of parasites. There are no up-to-date figures on the percentages of clinical cases, however, in 2010 an estimated 819 million humans were affected by ascariasis, while a survey in 2017 reported approximately 447 million A. lumbricoides infections, resulting in 3,206 deaths and a loss of over 860,000 disability-adjusted life years (DALYs). At a human population level, the intensity of infection with A. lumbricoides decreases with age after peaking in the first decade of life in high-intensity areas, but IgE antibodies can persist for some time.

Risk factors

Ascariasis is associated with poverty, and a lack of proper sanitary infrastructure, poor socio-economic conditions, and poor personal hygiene favor the transmission of the parasite and intensity of infection.

Pediatric issues

Infection intensities in children are often higher than those found in adults, and a recent systematic review reported a stronger predisposition to heavy infection with A. lumbricoides in children than adults, and for females as compared to males. Infection has been reported in children as early as 5 months of age.

Route Of Exposure

Main

Oral ingestion of embryonated Ascaris spp. eggs initiates the parasitic life cycle within humans.

Clinical Relevance

The majority of A. lumbricoides infections in endemic areas are asymptomatic or cause mild symptoms due to low numbers of worms. However, a small percentage of individuals can host high parasite burdens. Ascariasis can mimic a number of diseases and conditions; the clinical manifestation is directly related to the intensity of infection, underlying conditions, and the parasite life cycle.

Two main forms of pathology are caused by A. lumbricoides infection: nutrient depletion and obstruction due to the physical presence of worms in the gastrointestinal tract, and immune-mediated reactions to migrating larvae. Pathology of the liver and lungs is also possible. Moderate to heavy infection intensities in children have been associated with asthenia, weight loss, impaired physical development, cognitive impairment, and defective immune regulation.

Following an incubation period of 4 to 16 days, patients with ascariasis can present with fever, cough, dyspnea, urticaria or other rashes, abnormal breath sounds, and tender hepatomegaly. As the life cycle progresses, mild symptoms of infection with adult worms can include nausea, bloating, abdominal discomfort, recurrent abdominal pain, abdominal distension, and intermittent diarrhea. Complications can include intestinal obstruction, volvulus, hemorrhage, biliary colic, recurrent pyogenic cholangitis, cholecystitis, obstructive jaundice, cholelithiasis, pancreatitis, anorexia, and malnutrition. Löffler syndrome, or eosinophilic pneumonitis, an immune-mediated type I hypersensitivity reaction to Ascaris larvae migrating through pulmonary tissue may occur in initial or intermittent infections, but may last up to 3 weeks and can be fatal.

Nematodes characteristically raise a strong Th2 inflammatory response with synthesis of multiple interleukins, eosinophilia, and mucus hyper-secretion. As Ascaris parasites travel through the human body during their life cycle, multiple tissues produce high levels of both polyclonal IgE and specific IgE against Ascaris allergens. Invasive larvae can also promote allergic responses directed to non-parasite allergens (e.g. aeroallergens). Persistent hyper-responsiveness in the lungs can resemble an extreme form of allergic airway disease with impaired respiratory function, and ascariasis has been associated with more severe symptoms of asthma and allergy.

Conversely, studies have associated heavy or chronic parasitic infection, including ascariasis, with suppression of the immune system, as the organisms release potent substances to promote their long-term survival and facilitate immune evasion. The role of A. lumbricoides as a risk factor for asthma and allergy is still unclear, and the confounding effect of cross-reactivity between Ascaris and other allergens, as well as the presence of other infections such as active tuberculosis, should be considered in this complex relationship between infection and immunomodulation.

Diagnostics

Of note, parasite infections increase total serum levels of IgE, however, few of these IgE-binding components are actually allergens, so total IgE may not be the best diagnostic parameter of allergy in the tropics. Component resolved diagnosis should be considered to remove bias from cross-reactivity or other confounding issues.

Cross-Reactivity

A high prevalence of Ascaris IgE seropositivity has been observed in populations from developed countries where ascariasis is not expected to be endemic, and cross-reactivity should be considered as a potential confounding factor when assessing the effect of ascariasis as a risk factor for asthma and allergy.

Humans with ascariasis have shown variable IgG antibody responsiveness to ABA-1 (Asc l 1), one of the most abundant proteins synthesized by Ascaris; the genetic basis for this variability is unknown. A molecular cloning study showed significant similarity between ABA-1 from Ascaris and a soluble protein produced by adult Brugia, a nematode that causes lymphatic filariasis.

Asc l 3 is a tropomyosin, an invertebrate pan allergen that is phylogenetically conserved and widely recognized as a major allergen with extensive cross-reactivity. Approximately 50% of the total IgE response to Ascaris extract could be due to specific IgE to tropomyosin. Asc l 3 is expected to show variable cross-reactivity with other tropomyosins such as Group 10 allergens in mites (e.g., Der p 10, Der f 10, Blo t 10, Lep d 10, Tyr p 10), Group 1 allergens in crustaceans and molluscs (e.g., Pen a 1, Met e 1, Pen i 1, Hom a 1, Pan s 1, Cha f 1, Cra g 1, Tur c 1, Tod p 1), Group 7 allergens in cockroach (e.g., Bla g 7, Per a 7, Per f 7), and Group 3 allergens in nematodes (e.g. Ani s 3 from Anisakis spp.).

Asc l 5 belongs to the SXP/RAL-2 protein family, which is exclusive to nematodes and contains a number of allergens with similar sequencing including As16 and As14 (Ascaris suum), Ag2 (Bayliascaris schroederi), and nematode infection markers such as SPX antigens from Brugia malayi and Wuchereria bancrofti. Of note, three allergens from the parasitic nematode that causes anisakiasis (Anisakis simplex: Ani s 5, Ani s 8, and Ani s 9) also belong to the SXP/RAL-2 protein family.

Co-exposure to A. lumbricoides and house dust mites induces a strong Th2 and immunomodulatory response with complex interactions that can either potentiate or suppress cross-reactivity between their respective allergens by several mechanisms. As exposure to mite allergens is perennial, cross-reacting allergens from mites could stimulate and sustain high levels of total IgE and specific IgE responses to some Ascaris allergens. In one study, 70% of 100 subjects allergic to house dust mite allergens (14–240 kDa; Blomia tropicalis, Dermatophagoides pteronyssinus, and D. farinae) exhibited positive IgE-reactivity to A. lumbricoides allergens (15–250 kDa), while conversely, 20–28% of 60 ascariasis subjects demonstrated positive IgE-reactivity to the house dust mite allergens, suggesting multi-allergen sensitization. Another study reported a strong correlation between IgE levels to GST from A. lumbricoides and GST from other invertebrates such as cockroach and house dust mite. However, the authors noted that the study population (asthmatic patients) was co-exposed to the allergenic sources so it was not possible to know if the correlations resulted from co-sensitization or cross-reactivity.

Pre-sensitization with antigens from Ascaris spp. has been shown to accelerate the mite-specific IgE response upon mite antigen inhalation, supporting a potential cross-reactivity between Ascaris and arthropod antigens. Additionally, pre-existing allergic sensitization to house dust mite may drive a CD4+ Th2-mediated eosinophil-dependent immune response that mimics a primary Ascaris infection, and protects against early larval helminths prior to their establishing long-lasting infections in the host.