Ascaris lumbricoides is a large, 15-35 cm long white roundworm that is specific to humans. Ascaris is one of 63 species of nematode infecting humans, and the adult roundworm has a biologically inert surface, so the main antigenic stimuli to the host are excretory and secretory antigens from the orifices. A. suum is the related pig species which may migrate through human tissues in the larval stage,36 but cannot complete its life cycle in man.
The female Ascaris worm produces about 200 000 eggs/day, which embryonate in soil in about 3 weeks to become infectious, but are sensitive to excessive heat, drying and sunlight. Ingested eggs moult to form larvae (0.2 mm long) which penetrate blood vessels or lymphatics and travel to the lung via the portal vein or thoracic duct to pulmonary capillaries and alveoli, where they moult, grow in size, migrate up the airways and down the esophagus, and mature and reproduce in the small intestine. Adult Ascaris are large white roundworms (females 2-4cm long) which, unlike hookworm and Trichuris, do not attach to the mucosa but live free in the small-intestinal lumen. The duration of the life cycle from ingestion of Ascaris ova to new egg excretion in feces by the mature worm takes about 2 months. Adult worms are expelled from the intestine after about 18 months.
Ascariasis is one of the most prevalent infections in the world affecting approximately 1400 million people (23% of the world population) with 59 million (mostly children) at risk of morbidity, including 95% of the population of Africa and 45% of inhabitants of Central and South America.37 Highest prevalences are found in countries where sanitation is deficient, and children have higher mean worm loads than adults. There is some evidence of a predisposition to high infestation of Ascaris worms due to a genetic or immunological predisposition. Morbidity is related to worm load, which is indirectly assessed by egg concentration per gram (epg) of feces (e.g. light infection, < 5000epg, heavy infection, > 50000epg). Community prevalence levels greater than 70% are associated with high worm burdens, likelihood of morbidity and rapid reinfection, so warrant anti-helminthic control programs (see below).38 Geophagy (eating soil) is a risk factor for ascariasis in African schoolchildren.39,40
An important principle of helminth immunology is that very few responses elicited by infection are likely to be functionally protective and some have severe pathological consequences for the host. Immune responses can also be divided into innate (immediate response on exposure with little memory and broad molecular specificity not involving lymphoid cells) and adaptive (lymphocyte-mediated and antigen-specific with memory).41 Although immune responses in the intestinal mucosa are similar to systemic responses, an important difference is the predominance of IgA antibodies.
Immune responses against helminth invasion rarely eliminate them directly. Effective immunity against reinfection is also difficult to demonstrate for helminth infections, since worms persist in the face of specific immune responses, although age-related declines in infection rates do occur in endemic areas. However, detailed epidemiological and animal model studies have demonstrated that acquired protective immunity is important for control of hookworm, Trichuris and schistosomiasis.41 Ascaris produces the lipid-binding protein ABA-1 which can stimulate IgE antibodies, high levels of which correlate with protection against Ascaris.42
The traditional view of the host immune response was that with time it reduced their fecundity and survival via mechanisms such as induction of intestinal mast cells and eosinophils. More recent evidence suggests that other indirect host responses may result in parasite starvation or depletion of energy sources for defending itself against the host's immune responses, leading to reduced fecundity or survival.43 However, there is also a cost to the host from mounting an immune response to the parasite, particularly on nutritional status in children. For example, zinc deficiency may prolong nematode survival in the host by its known effect on mucosal immune function.44 In addition, many helminths release immunomodu-latory molecules which inactivate components of the host's immune response, but this may also predispose the host to other infections such as tuberculosis (TB) or AIDS. There is also evidence that ascariasis impairs immune responses to vaccines in that albendazole treatment increased the seroconversion rate and antibody titers after cholera immunization, mediated by suppression of interleukin (IL)-2 responses.45,46 Moreover, treatment of helminths in HIV-infected individuals was associated with significant reductions in viral load.47
Immune-mediated inflammation occurs in most parasitic infections, particularly involving IgE antibodies, eosinophils, cytokines and T cells, but there are important differences between helminths and protozoa. First, although protozoa may be phagocytosed by macrophages, cell-mediated immunity against helminths involves attachment to its surface with antibody or complement-mediated mechanisms and release of mediators which damage its surface. Second, whereas protozoa tend to elicit T-helper lymphocytes with activation of macrophages, cytokines (IL-12) and specific IgG antibodies (Th1 responses), helminths elicit Th2 responses with IL-4 stimulating IgE antibodies and inflammatory cells (e.g. eosinophils and mast cells). Thus, compared to controls, cytokine responses in Ascoris-infected subjects involved mononuclear cell IL-4 and IL-5 stimulation with no difference in IL-10 and interferon-/ responses, consistent with a highly polarized Th2 cytokine response.48
Helminth infections are characterized by increased mast cells and eosinophils. The key function of IL-5, which is produced by activated CD4 T cells, is control of eosinophils, although early differentiation of eosinophils is controlled by granulocyte-macrophage-colony-stimulating factor (GM-CSF) and IL-3. It is now recognized that eosinophils, together with antibody and complement, have a role in the killing of infective larval stages of most helminths, but not of adult worms. Recent studies in mice suggest that the effect of IL-5 and eosinophils differs for each parasite species, but they do have a role in host protection which is not yet clearly defined.49,50
IgE antibodies are an important component of host-protective immune responses against helminthic parasites, including both parasite-specific IgE and non-specific polyclonal IgE mediated by IL-4. Excessive polyclonal stimulation of IgE synthesis by helminths, which is prevented by anthelminthic treatment, suppresses allergic reactivity by saturating mast cell receptors and inhibiting specific IgE antibodies (e.g. to inhaled antigens such as house dust mite) and skin test reactivity.51 Compared to urban children, rural Kenyan children's total IgE and Ascaris-specific IgE antibodies were much higher, and evidence of atopy (skin testing, bronchial hyper-reactivity) were much lower.52 A Venezuelan study examined two groups of children with comparable living conditions and Ascaris prevalence but with very different prevalences of allergic disease.53 Those in the atopic group had an intrinsic propensity for specific over polyclonal IgE responses to the parasite and had significantly lower intensities of infection than the non-atopic group, suggesting that the atopic state conferred a selective evolutionary advantage.
Immune responses are useful as a means of diagnosing infection by ELISA tests. The major drawback of antibody-based tests is that a positive test does not prove current infection in an endemic area, although use of particular classes of antibody (e.g. IgG4, IgM) may improve the specificity. Newer diagnostic tests by antigen-capture ELISA for coproantigens in feces are becoming available, which are highly sensitive and specific.
Ascaris infection is not associated with mucosal damage, increased intestinal permeability or lactose malabsorption,54,55 since 85% of infected individuals have light infections which remain asymptomatic. Heavy infection (ingestion of > 2000 eggs) may induce a pneumonitis from migrating pulmonary larvae, with cough, wheeze, eosinophilia and transient patchy infiltrates which may be difficult to differentiate from pneumonia, asthma or bronchitis. This syndrome of tropical pulmonary eosinophilia (Loeffler's) is rarely recognized clinically in children with Ascaris or hookworm, but is more often symptomatic with filariasis or toxocara infections.56
The most common clinical feature of ascariasis is intestinal obstruction from a bolus of worms, which occurs in 0.2% of infections in children, accounting for 72% of all complications of Ascaris.57 The mean age of cases is under 5 years and the case fatality rate about 5.7%. Surgical management can invariably be avoided with experience with this syndrome, and daily nasogastric administration of anthelminthics with supportive therapy until the bolus is passed. Worms are often vomited or passed in stool on presentation of febrile children with severe malaria or bacterial infections, which invariably prompts comments from health workers about them 'abandoning a sinking ship'. Fever, acute phase reactants and certain irritants (e.g. carbon tetrachloride, a former hookworm therapy) are associated with worm expulsion or aberrant migration. Less frequent complications of migrating Ascaris worms are biliary colic, pancreatitis, appendiceal abscess and appearance through a surgical abdominal wound.
The diagnosis of ascariasis is based upon identification of the characteristic eggs on microscopy of stool or identification of the adult worm passed spontaneously or after treatment. Eggs are plentiful in feces since each female produces a mean of 200 000 daily, although the correlation between eggs per gram of feces and intensity of infection is imperfect.
If human feces are used as fertilizer for growing vegetables, they need to be stored at 30°C for 40 days to ensure destruction of ova. A number of reports have examined environmental risk factors for ascariasis. A Brazilian study, for example, gave the following relative risks with 95% CI for ascariasis intensity: over crowding 2.2 (1.0-4.5), poor household water availability 2.4 (1.1-5.0), poor hygiene 2.4 (1.0-5.6), less than 4 years' schooling 5.9 (2.6-14.3) and no recent anthelminthic treatment 2.0 (1.0-4.0).58 A Kenyan study found that household overcrowding and the absence of latrines increased the risk of hookworm infection, whereas a lack of soap and other household children under 5 years increased the risk of Ascaris infection.59 Since the lack of latrines and soap usage were identified as risk factors for infection, helminth control interventions should focus on these. Mass chemotherapy campaigns for geohelminths is discussed below.
The two major species of hookworms are Ancylostoma duodenale and Necator americanus (Figure 11.2). They will be considered together here, because they have similar life cycles and disease. However, Ancylostoma tends to be more virulent than Necator, and adult females are larger (10-13 vs. 9-11 mm), survive for a shorter time in the host (1 vs. 4 years), produce more eggs (10 000-30 000 vs. 5-10 000/day), cause greater blood loss (0.2 vs. 0.02 ml/day) and their larvae can rest dormant and infect via oral ingestion (unlike Necator).
The gravid female hookworm produces about 5000-30 000 eggs/day (60|im long) in feces, which require a moist shady environment to hatch into
rhabditiform larvae (300 |im long) which grow to become infective larvae (600|im) and enter the host's venules or lymphatics, usually when walked upon with bare feet. The larvae then migrate into the lungs and ascend up the respiratory tract and descend to the small intestine, where they attach and mature in the jejunum. The time from infection to egg production is almost 2 months.
Hookworm is probably the second most prevalent intestinal parasite after ascariasis, with 1200 million people infected worldwide (two-thirds by Necator), including 90-130 million with morbidity. Necator predominates in Central and South America (New World), and Ancylostoma in India, China, North Africa and tropical Australia, but mixed infections occur in many regions of Asia, Africa, Central America and the South Pacific. Ancylostoma extends into more temperate regions than Necator (e.g. North Africa, China and Europe) because its ova are more resistant to cold. In an urban Nigerian study of 862 schoolchildren with hookworm, 72.0% had Necator alone, 4.5% Ancylostoma alone and 23.4% both species of hookworm, but with Necator in higher numbers.60
Unlike Ascaris and Trichuris, hookworm transmission is closely associated with rural farming rather than urban slums. There are several other species of dog and cat helminths (e.g. Toxocara species) which can cause eosinophilic enteritis, cutaneous larva migrans or viscera larva migrans in humans. For example, studies in tropical Australia have described eosinophilic enteritis with abdominal pain caused by Ancylostoma caninum, a dog hook-
Hookworms attach to the mucosa with teeth (Ancylostoma) or cutting plates (Necator) and release anticoagulant polypeptides and neutrophil inhibitory factor which down-regulate the inflammatory response of the host. They also release hydrolytic enzymes which damage mucosal capillaries and exacerbate the blood loss. Hookworm larvae release Ancylostoma-secreted proteins (ASPs) during the early stages of infection, which are highly antigenic. The indirect evidence of reduced hookworm burdens in adults suggests an effect of host immunity, but humoral antibodies and cell-mediated immune responses correlate poorly with resistance to infection. The possibility of a hookworm vaccine to ASPs is under investiga-
Hookworm larvae entering skin can result in a papulovesicular rash at the site of entry (ground itch) or cutaneous larvae migrans for animal hookworms. Although eosinophilia accompanies the larval migration phase, pneumonitis is mild and rarely recognized in children. The main morbidity from hookworm is iron deficiency anemia, particularly with heavy infections. It was not uncommon in Caribbean and Pacific islands to have school children presenting in congestive heart failure with loud hemic murmurs and hemoglobin levels of <20g/l from hookworm. Blood transfusions are indicated only for heart failure, so can be avoided in most cases of hookworm infection in endemic areas due to its chronic anemia (unlike more acute malarial anemia). Heavy infections may result in hypoalbuminemia as well as anemia, but malabsorption or severe enteropathy do not appear to be common features of hookworm infection, unlike strongyloidiasis. Infantile hookworm infection occurs in China with severe manifestations, presumably due to Ancylostoma transmission transplacentally or via breast milk.63
The diagnosis of hookworm infection is based upon identifying hookworm eggs on microscopy of feces. The intensity may be gauged from a quantitative egg count, which is mostly used for epidemi-ological studies. Differentiation between eggs of Ancylostoma and Necator requires culture to the infective larval stage or newer polymerase chain reaction (PCR) techniques, but adult worm identification is easier (except after benzimidazole treatment, which may affect morphology). Eosinophilic enteritis due to animal hookworm may require endoscopy for definitive diagnosis, since stool microscopy will be negative. Charcot-Leydan crystals in stool reflect breakdown of eosinophils, which is a non-specific feature of early infection.
Measures to prevent hookworm include ceasing the use of human feces as fertilizer, use of toilets, wearing shoes and generally improving living standards. Mass treatment programs with albenda-zole have a transient effect, but need to be combined with improved sanitation and health education to prevent high reinfection rates.64 Iron supplementation has no effect on either reinfection rates or helminth intensities in children.65 In high prevalence areas of hookworm infection and schistosomiasis, regular mass deworming campaigns with albendazole and praziquantel are effective in reducing anemia rates.66,67
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