8.9.5 Gut and tissue nematode infections acquired

8.9.5 Gut and tissue nematode infections acquired by ingestion 1506

section 8  Infectious diseases 1506 worldwide may partly be a result of reduced exposure to the im- munosuppressive effects of helminths, and lead to concerns that mass deworming may have detrimental as well as beneficial ef- fects. A trial of experimental hookworm infection as a treatment for asthma did not demonstrate a significant benefit, however hookworm-​derived molecules have been demonstrated to have po- tent immunomodulatory effects in vitro and could form the basis for future drug development. FURTHER READING Bottazzi ME (2015). The human hookworm vaccine: recent updates and prospects for success. J Helminthol, 89, 540–​4. Buonfrate D, et  al. (2015). Novel approaches to the diagnosis of Strongyloides stercoralis infection. Clin Microbiol Infect, 21, 543–​52. George PJ, et al. (2015). Modulation of pro-​ and anti-​inflammatory cytokines in active and latent tuberculosis by coexistent Strongyloides stercoralis infection. Tuberculosis (Edinb), 95, 822–​8. Karagiannis-​Voules DA, et al. (2015). Spatial and temporal distribu- tion of soil-​transmitted helminth infection in sub-​Saharan Africa:
a systematic review and geostatistical meta-​analysis. Lancet Infect Dis, 15, 74–​84. Schär F, et al. (2013). Strongyloides stercoralis: global distribution and risk factors. PLoS Negl Trop Dis, 7, e2288. World Health Organization (WHO) (2017). Chistosomiasis and soil-​ transmitted helminthiases:  number of people treated in 2016. Wkly Epidemiol Rec, 92, 49–60. 8.9.5  Gut and tissue nematode
infections acquired by ingestion Peter L. Chiodini ESSENTIALS Ascariasis Ascaris lumbricoides (the human roundworm) is widespread in the tropics and subtropics where sanitation is poor and the soil is con- taminated with its eggs. Ascaris suum (the pig roundworm) is also capable of infecting humans. Some authorities consider them to be the same species, making A. suum a synonym of A. lumbricoides. Ingested eggs hatch in the small bowel, the larvae released mi- grate via the bloodstream and lungs, then return to the small bowel and develop into adult worms 15 to 30 cm long. Most infections are asymptomatic, but there may be pulmonary infiltrates with eosinophilia, abdominal discomfort and—​in children with heavy infections—​intestinal obstruction. Infection is diagnosed by finding eggs in the faeces. Treatment is with mebendazole, albendazole, or pyrantel pamoate. Anisakidosis This is caused by larvae of roundworms in the family Anisakidae, which are parasites of marine mammals. The larvae cannot mature to adult form in humans who thus represent dead-​end hosts for these parasites. After ingestion in uncooked fish or squid, immature larvae burrow into the gastric or intestinal mucosa and may cause abdom- inal pain. Diagnosis is usually made at endoscopy, with treatment by endoscopic removal (if possible) of the larvae, although symptoms resolve spontaneously in most cases. Capillariasis Intestinal capillariasis, caused by Paracapillaria philippinensis, is ac- quired by ingestion of larvae in undercooked freshwater fish and may cause a severe diarrhoeal disease. Diagnosis is by finding eggs in the stool. Treatment is with albendazole or mebendazole. Prevention is by properly cooking fish. Hepatic capillariasis—​caused by Capillaria hepatica, a parasite of wild rodents and other mammals. Ingested eggs hatch and larvae pass to the liver and cause a syndrome similar to visceral larva migrans (see next). Serology is rarely available and definitive diagnosis is made by identifying the parasite or eggs in a liver biopsy. Treatment is usu- ally with albendazole. Adjunctive corticosteroids have been used. Enterobiasis Enterobius vermicularis (threadworm) is cosmopolitan. Ingested eggs develop directly into adult worms in the intestine; fertilized female worms emerge from the rectum at night and deposit eggs on the perianal skin. Most infections are asymptomatic, but pruritus ani may be troublesome at night. Diagnosis is made by finding eggs on clear adhesive tape applied to the perianal skin or identification of worms found on the perianal skin or surface of the stool. Mebendazole or albendazole or pyrantel pamoate are effective in combination with sanitary measures. Recurrent threadworm due to reinfection can be troublesome in a minority of patients. Gnathostomiasis Gnathostomiasis is due to ingestion of the third stage larva, usually from Gnathostoma spinigerum, a parasite of domestic and wild fe- lines and canines, or G. hispidum, a parasite of pigs, via raw or under- cooked freshwater fish. It is endemic in Southeast Asia, the Indian subcontinent, Southern Africa, Mexico, and Peru, and is increasingly seen in ever-​more adventurous travellers. It causes both migratory cutaneous swellings and visceral disease. Toxocariasis This is due to invasion by larvae of Toxocara canis or T. cati, acquired by ingestion of eggs from dog or cat faeces contaminating the en- vironment. It occurs in three clinical forms—​visceral larva migrans, ocular larva migrans, and covert toxocariasis. Visceral larva migrans usually afflicts children; larvae migrate to the viscera and may be asymptomatic or cause protean manifest- ations including muscular pain, lassitude, anorexia, cough, urticarial rashes, hepatomegaly, and occasionally splenomegaly, lymphaden- opathy and skin lesions, and (rarely) central nervous system involve- ment resulting in convulsions. Eosinophilia is prominent. While definitive diagnosis is by finding larvae in a liver biopsy this should not be necessary to diagnose visceral larva migrans due to toxocar- iasis. A negative serological test for toxocara antibody rules out the diagnosis. Most patients recover spontaneously. Severe cases can be treated with albendazole plus adjunctive corticosteroid therapy. Ocular larva migrans is more commonly seen in older chil- dren and due to granuloma formation around a larva in the retina.

8.9.5  Gut and tissue nematode infections acquired by ingestion 1507 Diagnosis depends upon positive serology together with consistent fundoscopic features. Anthelmintic therapy is not routinely given. Covert toxocariasis results in relatively mild, non​specific symptoms. Trichinosis This is acquired by ingestion of larvae of Trichinella spiralis in under- cooked meat, usually pork. Adult worms in the small bowel produce larvae which seed the muscles and other tissues, where they develop. Most infections are asymptomatic, but heavy infections typically cause diarrhoea, followed by fever and myositis. Definitive diagnosis depends upon finding larvae in muscle biopsies, although this is usu- ally unnecessary; serological tests become positive several weeks after infection. Treatment is mainly symptomatic. Anthelminthic agents are used to kill adults and thus minimize the production of new larvae. Thorough cooking of pork is the best safeguard against infection. Trichuriasis Trichuris trichiura (whipworm) is most prevalent in the tropics and subtropics where sanitation is poor. Ingested eggs hatch in the small bowel and then develop within the gut into adult worms, the an- terior end of which becomes embedded in the large bowel mucosa. Very heavy infections may cause dysentery or rectal prolapse. Infection is diagnosed by finding eggs in the faeces. Treatment is with mebendazole or albendazole. Ascariasis (giant roundworm infection) Life cycle Ascariasis is an infection caused by the giant roundworm, Ascaris lumbricoides. Infection is acquired when an egg is ingested (Fig. 8.9.5.1). The infective larva hatches out in the small intestine (Fig. 8.9.5.2) and penetrates the intestinal wall to enter the portal cir- culation. From here it enters the systemic circulation and reaches the lungs, where it breaks out of the capillaries into the alveoli and undergoes another moult to become a fourth-​stage larva. From the lungs the larva moves up the bronchial tree to the mouth and is then swallowed. In the intestine it moults again to become a sexually ma- ture worm about 6 to 8 weeks after ingestion of the egg. The mature worm is cylindrical with tapering ends and creamy white to light-​ brown in colour (Fig. 8.9.5.3). The female measures 20 to 35 cm in length and 3 to 6 mm in width, whereas the male is 12 to 31 cm long and 2 to 4 mm wide and has a curved tail. Normally, the adult worms live in the lumen of the small intes- tine, primarily the jejunum. The worm is able to maintain its pos- ition in the small intestine by the activity of its somatic muscles; if these are paralysed by anthelmintics it is expelled by peristalsis. The lifespan of an adult worm is usually 1 to 2 years, after which it is ex- pelled spontaneously. The worms mate and eggs are passed in the faeces, with gravid females each producing 200 000 to 250 000 eggs daily. When freshly passed, these eggs are not infective and contain a single cell. This develops in the soil over the next 2–​6 weeks (faster in warmer temperatures) into an infective larva. The ova are resistant to chemicals and low temperatures, and may remain viable for up to 10 years in moist soil. Epidemiology and control Ascariasis is cosmopolitan, and is arguably the most common hel- minth infection. It is prevalent in areas where there is poor sanitation, with contamination of the soil with eggs. Infection is more common in tropical climates, especially where human faeces are used to fertilize vegetable gardens. Infection is usually acquired by eating contamin- ated food, or from soil ingested by children when playing and does not induce resistance to reinfection. It is relatively more common in children and intensity of infection peaks in the first decade of life in high transmission areas. In hyperendemic areas with constant warm temperatures and high humidity, children are continuously being in- fected, so that as some worms are being expelled, others are maturing to take their place. Transmission might only be associated with the Trachea Lungs Pharynx Swallowed female male Circulation Ingested HUMANS EXTERNAL ENVIRONMENT Fertilized Unfertilized Two cell stage Embryonated egg (infective stage) Eggs in faeces (diagnostic stage) Larva hatches in intestine Advanced cleavage Adults in small intestine Fig. 8.9.5.1  Life cycle of Ascaris lumbricoides and Ascaris suum. Fig. 8.9.5.2  Decorticated eggs of Ascaris lumbricoides, showing emergence of larvae. Copyright Viqar Zaman.

section 8  Infectious diseases 1508 rainy season in areas that are generally hot and arid. The pig ascarid A. suum can infect humans and mature into adult worms and is re- garded by some as a synonym of A. lumbricoides. Environmental sani- tation is the best control measure, but when this is not possible, mass chemotherapy given at intervals of 6 to 12 months to preschool age and school age children reduces the severity and intensity of infection. Clinical features The first passage of larvae through the lungs usually causes no symp- toms or pathological changes, but subsequent infections can be associ- ated with hypersensitivity reactions, causing Ascaris pneumonitis (Fig. 8.9.5.4). When this causes fever, cough, dyspnoea, bronchospasm, per- ipheral eosinophilia, and infiltrates on a chest radiograph that are often migratory, it is known as Löffler’s syndrome, but the syndrome is not spe- cific to ascariasis. The condition usually subsides after 7 to 10 days, unless reinfection occurs. In areas where pig farming is common, the larvae of A. suum may also produce severe pneumonitis and bronchospasm. Most people with established infection with A. lumbricoides are asymptomatic, especially if the worm burden is small. Some might complain of anorexia, nausea, and abdominal discomfort or dis- tension. Heavy infections in children can cause malnutrition and hinder normal development in terms of both stature and cogni- tive performance. Mechanical complications probably occur in less than 1% of infected individuals. Occasionally, usually in chil- dren, large numbers of worms may become entangled to form a bolus that blocks the intestinal lumen, usually near the ileocaecal valve, producing signs and symptoms of acute intestinal obstruc- tion. This might be complicated by perforation, intussusception, volvulus, and death. In some circumstances, such as fever, irrita- tion caused by drugs, anaesthesia, or bowel manipulation during surgery, the worms may migrate to ectopic sites. Migration into the common bile duct can be complicated with cholangitis and liver abscesses, whereas entry into the pancreatic duct might precipi- tate acute pancreatitis. Worms may migrate into the appendix, oc- casionally come out through the mouth and nose, and are rarely found in other ectopic locations. Diagnosis Ascariasis is usually diagnosed by finding plentiful numbers of the characteristically oval fertilized eggs measuring 60 × 30 to 70 × 50 μm in the faeces (Fig. 8.9.5.5). Sometimes the patient brings developing or adult worms that have been passed in the faeces or have emerged from the anus or nose of a sick child. Occasionally, adult worms are outlined in the intestines during barium-​meal examination, or are seen at upper gastrointestinal endoscopy. Treatment It is desirable to treat all infected individuals, even when the worm load is small. There are several effective drugs (listed next). None of them is recommended by its manufacturer for use in pregnancy, especially in the first trimester, or children under 1 to 2 years of age, although this has been disputed by some authorities. For preventive chemotherapy, the World Health Organization manual Preventive chemotherapy in human helminthiasis recommends that albendazole or mebendazole be offered in the second and third trimesters of pregnancy in targeted interventions where the prevalence of infec- tion with any soil-​transmitted helminth is greater than 20%. • Mebendazole is given is given as 100 mg twice daily for 3 days in adults and children over 2 years of age. It should not be given in the first trimester of pregnancy. Fig. 8.9.5.3  Adult Ascaris lumbricoides (scale in mm). Copyright Viqar Zaman. Fig. 8.9.5.4  Ascaris lumbricoides in the lungs, surrounded by an inflammatory reaction. Copyright Viqar Zaman. Fig. 8.9.5.5  Egg of Ascaris lumbricoides.

8.9.5  Gut and tissue nematode infections acquired by ingestion 1509 • Albendazole is given as a single dose of 400 mg in adults and chil- dren over 2 years of age. It should not be given in the first trimester of pregnancy. • Pyrantel pamoate given in a single dose of 11 mg/​kg body weight (maximum 1 g) is effective in curing more than 90% of cases of as- cariasis. Side effects are usually mild and the drug is well tolerated. It should not be given in the first trimester of pregnancy. In cases of intestinal obstruction caused by an Ascaris bolus, a pi- perazine salt given at a dose of 75 mg/​kg (maximum 3.5 g) daily for two consecutive days has been recommended as it induces flaccid paralysis of the worms, which may relieve the obstruction. This should be supplemented with decompression of the bowel through an intestinal tube with constant suction; rehydration and restoration of electrolyte balance with intravenous fluids. In most cases this con- servative therapy will relieve the obstruction and the child will rap- idly recover. If, however, the signs of obstruction persist, laparotomy is required. Obstruction of the bilary tract by Ascaris is diagnosed by ultrasound. Anthelminthics are given and worms not passed spon- taneously may be removed endoscopically, reducing the need for op- eration. Surgery is required for gangrenous cholecystitis. Anisakidosis Life cycle Anisakidosis (previously known as Anisakiasis) is an infection caused by the larvae of various species of nematode belonging to the family Anisakidae, most commonly Anisakis simplex and Peudoterranova decipiens. Adults live in the lumen of the intestine of cetaceans (whales, dolphins, and porpoises). Eggs are passed in water, embryonate, and release second-​stage larvae which are in- gested by crustaceans in which they develop to third-​stage larvae. When crustaceans are ingested by fish or squid they enter the muscles of these hosts. Cetaceans and humans become infected by eating infected saltwater fish or squid. Epidemiology and control The adult worms are commonly found in marine mammals in many parts of the world. Humans are infected when they eat raw or im- properly cooked fish or squid. The incidence is highest in Japan, countries on the northern European seaboard and the Pacific coast of the Americas, especially in the South. Infection is prevented by not eating raw, pickled, smoked, or undercooked fish and squid. Larvae are killed by cooking fully to at least 63°C; or freezing solid and storing at minus 20°C for 7 days; or freezing solid at minus 35°C and storing at minus 35°C or below for 15 hours. Clinical features The larvae do not develop to maturity in humans, but attach them- selves to, and then burrow into, the mucosa of the stomach (especially Pseudoterranova species) or small intestine (especially Anisakis spe- cies), and rarely the large bowel (Fig. 8.9.5.6). Symptoms commonly develop 4 to 24 h after eating infected fish. Gastric invasion produces severe epigastric pain, nausea, vomiting, and sometimes haematem- esis during the acute stage of the disease. Involvement of the intestine may cause severe lower abdominal pain, which might be misdiag- nosed as appendicitis. If symptoms are mild and the patient is left untreated the infection can become chronic, with pseudotumour formation around the parasite. Sometimes the larva precipitates an allergic reaction, with urticaria, angio-​oedema, or anaphylaxis. Diagnosis A definitive diagnosis is made by upper gastrointestinal endoscopy which reveals the lesion and the presence of white or yellow larvae up to 3 cm in length attached to the mucous membrane. Intestinal anisakiasis is more difficult to diagnose, but imaging studies might show thickening of the intestinal wall, and narrowing of the jejunum or ileum. Serology for anti-​Anisakis IgE or IgG is deployed in some specialist centres. Treatment In acute infection, an attempt should be made to remove the larva through an endoscope, although in most patients symptoms resolve spontaneously within 2 weeks. In chronic cases, surgical removal of the ulcerated areas or the tumour may be required. No chemo- therapy has been proven to be effective in a clinical trial, though albendazole has been reported to be beneficial in a case report. Capillariasis There are two forms of capillariasis: intestinal capillariasis caused by Paracapillaria philippinensis, and hepatic capillariasis caused by Capillaria hepatica. Intestinal capillariasis This infection is caused by a worm still generally referred to as Capillaria philippinensis, although it has been renamed Paracapillaria philippinensis. Fish-​eating birds are the definitive reservoir. Adult C. philippinensis measure 2.5 to 4.3 mm in length and produce eggs that are deposited in water and ingested by fish, in which they de- velop into infective larvae. Humans are infected by eating under- cooked freshwater or brackish-​water fish. In humans, the parasite has the capacity to autoinfect; female worms produce eggs that hatch into larvae that reinvade the intestinal mucosa, resulting in prolonged infection, so that the original source and time of infection Fig. 8.9.5.6  Third-​stage larva of Anisakis simplex, showing the tip of the boring tooth (arrow) (×400).

section 8  Infectious diseases 1510 may be forgotten. Autoinfection can result in extremely heavy worm loads, especially in immunocompromised patients. The parasite is endemic in parts of South-​East Asia, especially the Philippines and Thailand, and has more recently been found in Egypt. Infection is prevented by properly cooking fish. Intestinal capillariasis can be a severe and even fatal disease. Patients often present with abdominal pain, diarrhoea, and bor- borygmi. As the worm load increases, diarrhoea becomes more severe, with anorexia, nausea, and vomiting. Prolonged diarrhoea leads to cachexia. There might also be signs of hypotension and cardiac failure. The mortality rate in untreated cases approaches 20%. The diagnosis is made by finding eggs in the faeces, 36–​ 45 µm in length by 19–​21 µm in breadth (Fig. 8.9.5.7), which can superficially resemble those of Trichuris trichiura. Larvae or adult worms may also be present and repeated stool examination may be required in some cases. The parasite might also be found in je- junal aspirate or biopsy. The treatment of choice is albendazole for 10 days. If it is not available, the alternative is mebendazole for 21 days. Stools should be re-​examined to ensure the eradication of infection; if not, the course of treatment should be repeated. Supportive measures to overcome malnutrition and diarrhoea are required in severely ill patients. Hepatic capillariasis The adults of C. hepatica measure 52–​104 mm in length and live in the liver of various mammals, especially rats. Eggs are produced that are retained in the liver parenchyma; they measure 28 × 48 to 36 × 66 µm, and have bipolar plugs. The ova eventually reach the soil, ei- ther by decomposition of a carcass, or when the host is eaten by an- other animal and the eggs pass through the gut of that animal and are deposited in the faeces. Eggs embryonate in the soil and can sur- vive there for more than a year. Infective eggs are ingested by an- other definitive host, then hatch and the larvae reach the liver via the portal system. Human infection with C. hepatica occurs when eggs in the soil are accidentally swallowed, but human infection is rare and is usually a dead end for the parasite. Clinical features may resemble those of visceral larva migrans, with tender hepatomegaly, fever, and eosinophilia. The diagnosis is made by identifying the parasite or eggs in a liver biopsy (Fig. 8.9.5.8). The most effective treatment is unclear, although cases have been reported to respond to albendazole which is given as described for intestinal capillariasis. Enterobiasis (threadworm infection) Life cycle Enterobiasis is an infection caused by the threadworm or pinworm, Enterobius vermicularis. Infection is acquired by the ingestion of eggs (Fig. 8.9.5.9). Larvae hatch in the upper intestine and mi- grate to the region of the caecum, where they mature and copulate. Worms do not invade the tissues. About 1 month after infection, the white thread-​like gravid female worms, about 10–​13 mm long by 0.3–​0.5 mm in diameter, move down the bowel and pass out of the anus at night (Fig. 8.9.5.10). Each worm deposits approximately 10 000 eggs on the perianal skin. The worms then usually die, but sometimes migrate elsewhere, for example, into the vagina. The eggs are infective within a few hours of deposition. Epidemiology and control This worm is found worldwide and is extremely common, being found most frequently in children. Infections are commonly Fig. 8.9.5.7  Capillaria philippinensis egg (×1400). Fig. 8.9.5.8  Capillaria hepatica eggs in the liver (×250). Ingested Embryonated egg (infective stage) HUMANS Penetrates and develops in mucosa Larva hatches in intestine Gravid migrates to perianal region Egg on perianal skin (diagnostic stage) EXTERNAL ENVIRONMENT Fig. 8.9.5.9  Life cycle of Enterobius vermicularis.

8.9.5  Gut and tissue nematode infections acquired by ingestion 1511 clustered in families and institutions. Humans are the only res- ervoir of infection. Eggs can remain viable for up to 3 weeks, and can be transmitted via contaminated clothing, bedding, and dust. Resistance to reinfection does not develop and autoinfection may occur by contamination of the fingers. Clinical features Most infected people are asymptomatic. The most common pre- senting symptom is pruritus ani. This can be very troublesome and occurs more often during the night, causing restless sleep, especially in children. Persistent itching may lead to inflammation and sec- ondary bacterial infection of the perianal region. Occasionally, adult worms migrate to aberrant sites such as the urethra. In females they may enter the genital tract, causing vulvovaginitis or rarely salpin- gitis. E. vermicularis is sometimes found lodged in the lumen of the appendix (Fig. 8.9.5.11), but whether or not this causes appendicitis is controversial. Diagnosis The eggs are not usually found in the faeces. They are most easily found around the anus first thing in the morning by using cellulose adhesive tape applied with the sticky side against the perianal skin, which is then examined under the microscope; they are 33 × 55 μm in size and flattened on one side (Fig. 8.9.5.12). Sometimes intact worms are passed in the faeces and can easily be recognized by their size and shape. Treatment All the children and adults in a household should be treated at the same time. Several drugs are available, including mebendazole 100 mg in a single dose, repeated after 2 weeks; albendazole 400 mg in a single dose, repeated after 2 weeks; and pyrantel pamoate 11 mg/​kg to a max- imum dose of 1 g in a single dose, repeated after 2 weeks. Adult thread- worm live for no longer than about 6 weeks, so recurrent threadworm infestation is the result of reinfection. Therefore, attention to personal hygiene is an important part of treatment and prevention. The patient should be advised to keep fingernails short; wash hands with soap and water after defaecating and before preparing food; wear close fit- ting underwear in bed and change it every morning; shower or bath in the morning. The bed linen, mattress cover, soft toys, and towels should be washed at first diagnosis and at least weekly for six weeks thereafter. Over the same time period the bedroom, including the mattress, should be vacuum cleaned and the bathroom and kitchen damp-​dusted. Some individuals, often only one member of a household, suffer regular recurrences which can prove very distressing. There is no in vivo or in vitro assay for anthelminthic drug resistance to this para- site, so it is not possible to assess the potential contribution of drug resistance to this condition. Such cases require management in a parasitology clinic as they might need more intensive treatment re- gimens under expert supervision. Gnathostomiasis Life cycle There are 12 species of Gnathostoma, but only four are known to infect humans:  G.  spinigerum, G.  hispidum, G.  doloresi and G.  nipponicum. Most human cases are due to G.  spinigerum or Fig. 8.9.5.10  Adult Enterobius vermicularis (scale in mm). Copyright Viqar Zaman. Fig. 8.9.5.11  Histological section of Enterobius vermicularis in the lumen of the appendix (×250). Fig. 8.9.5.12  Enterobius vermicularis egg.

section 8  Infectious diseases 1512 G. hispidum (Fig. 8.9.5.13). Gnathostoma does not mature to the adult form in human infections. Its larvae are up to 12.5 mm long and 1.2 mm wide and have a cephalic bulb armed with rows of hooks (see Fig. 8.9.5.14). These enable the larva to move readily through human tissue and inflict substantial damage, especially if nervous tissue is involved. Epidemiology and control Humans are accidental hosts and become infected with the third stage larva after eating raw or undercooked freshwater fish or other intermediate hosts (e.g. snakes, frogs, and chickens, and possibly via ingestion of infected copepods). Given the large variety and wide distribution of its intermediate hosts, it is not possible to eradicate Gnathostoma from the environment, so individual protection is re- quired via thorough cooking plus avoidance of consuming raw or undercooked freshwater fish. Freezing to minus 20°C for 2 to 5 days is also effective. The common practice of marinating fresh fish in lime juice is not effective. Clinical features Cutaneous disease—​Gnathostomiasis can present as migratory cu- taneous swellings (nodular migratory panniculitis). Visceral disease—​Gnathostoma can produce a wide range of pres- entations, including pleuritic chest pain, pleural effusion, pneumo- thorax; ocular disease with uveitis, intraocular haemorrhage, or retinal detachment; central nervous system involvement with radiculomyeloencephalitis, eosinophilic meningitis, or subarach- noid haemorrhage. = Infective Stage = Diagnostic Stage L3 Gnathostomiasis Cutaneous Ocular Visceral Neurological Gnathostoma spinigenum Domestic and wild felines and canines are the definitive hosts Gnathostoma hidpidum Domestic and wild pigs are the definitive host. Unembryonated egg Embryonated egg in water. Infected second intermediate host ingested by definitive host. Second intermediate host Paratenic host L2 develops into L3. Copepod first intermediate host L1 develops into L2. Egg hatches and releases L1 larva. 2 1 5 6 4 3 7 L2 L3 L1 L3 develop into adult worms. L3 i i i i d d Fig. 8.9.5.13  Life cycle of Gnathostoma spinigerum and Gnathostoma hispidum. Courtesy of CDC. Fig. 8.9.5.14  Cephalic bulb of a Gnathostoma larva showing characteristic rows of hooks. Courtesy of P. L. Chiodini.

8.9.5  Gut and tissue nematode infections acquired by ingestion 1513 Diagnosis Clinical suspicion in cases of eosinophilia, migratory lesions, and ex- posure history. Occasionally a larva is extruded from the skin spon- taneously or removed intact from the eye by an ophthalmologist and its very characteristic morphology then makes diagnosis straightfor- ward. Serology by Western blot is available in specialist centres. Treatment Albendazole 400  mg twice daily for 21  days or ivermectin 200 micrograms per kilogram daily for two days. Repeat courses may be required. Surgical removal is required for ocular lesions. Toxocariasis Toxocariasis in humans occurs in two clinical forms, visceral larva migrans and ocular larva migrans, and is caused mainly by the migrating larvae of Toxocara canis, to a lesser extent T. cati and rarely other nematodes. T. canis and T. cati are parasites that live in the intestines of dogs and cats, which pass eggs in the faeces. Humans, usually young children, become infected by inadvertently ingesting embryonated eggs in the soil. The larvae hatch in the small intestine and migrate to various organs of the body, including the liver, lungs, eyes, and brain. The larvae, which are about 15–​20 μm in length, do not mature in humans, but granulomas eventually develop around them (Fig. 8.9.5.15). In a fully formed granuloma the larvae are surrounded by layers of fibrous tissue and inflammation subsides (Fig. 8.9.5.16). Eggs are never seen in human faeces. Toxocara in- fection occurs wherever there are large domestic dog and cat popu- lations in close association with humans and is more common in children. Deworming dogs and stopping children from eating dirt (pica) especially when playing in areas frequented by dogs, are im- portant control measures. Visceral larva migrans This disease is most often seen in young children, because of pica. Most people remain asymptomatic. In a minority, symptoms consist of muscular pain, lassitude, anorexia, cough, itching, and urticarial rashes. Physical signs might include wheezing and hepatomegaly. Occasionally there is splenomegaly, lymphadenopathy, and skin lesions. Central nervous system involvement can result in convul- sions. The acute phase generally lasts for 2–​3 weeks, followed by recovery. Sometimes the resolution of all the signs can take up to 18 months. Rarely, the infection ends fatally if a massive number of eggs has been ingested. The hallmark of visceral larva migrans is marked eosinophilia, which can reach a level of 75%. Serological tests for toxocara anti- body can be helpful; a negative test can rule out the diagnosis, but positive titres are often found in normal individuals. The defini- tive diagnosis is by finding larvae on biopsy, usually of the liver, but is seldom indicated. Most patients recover spontaneously; the larvae cannot multiply and eventually die. There is no proven therapy. Anthelmintics, including mebendazole, albendazole, and diethylcarbamazine have been tried, but may be ineffective or precipitate an inflammatory reaction. Corticosteroids and non-​ steroidal anti-​inflammatory agents have been suggested in order to suppress inflammation. Ocular larva migrans This condition is caused by granuloma formation around a larva in the eye and is most commonly seen in older children. If it is near the macula, impairment of vision or even blindness may re- sult. A rounded swelling, often near the optic disc, might be de- tected on fundoscopy. The features of visceral larva migrans are usually lacking in ocular larva migrans cases. There is usually no marked peripheral eosinophilia. Diagnosis depends upon posi- tive serology with consistent fundoscopic features; the major dif- ferential diagnosis is retinoblastoma. Antibody tests on vitreous or aqueous fluid can be positive when serum antibody tests are negative. Western blot is the assay of choice for use on aqueous or vitreous fluid. Anthelmintic therapy is not routinely given. Visible larvae can be photocoagulated by laser. Vitrectomy has been used in some cases and local and intraocular steroids are used to sup- press inflammation. Fig. 8.9.5.16  Histological section. Granuloma formation in the same animal as Fig. 8.9.5.15 at a later stage when the larva is completely surrounded by fibroblasts (×400). Fig. 8.9.5.15  Histological section. Granuloma formation in a monkey experimentally infected with Toxocara canis, showing many giant cells and some fibroblastic reaction. The arrow marks the larva (×400).

section 8  Infectious diseases 1514 Trichinosis (trichinellosis) Life cycle Trichinosis is an infection usually caused by Trichinella spiralis and related species. Humans become infected by eating undercooked meat, usually pork or pork products from domestic and wild pigs (boars) (Fig. 8.9.5.17). After ingestion the larvae are liberated in the stomach, then pass into the small bowel, where they invade the columnar epithelium and develop into adult worms living in the cytoplasm of a row of enterocytes. Male trichinellae are about 1.5 × 0.05 mm in size and female worms measure 3.5 × 0.06 mm. Over 2 to 3 weeks or so before they are expelled, female worms release about 500 newborn larvae (Fig. 8.9.5.18), which enter the bloodstream and seed the skeletal muscles. Over the next few weeks the larvae in the muscles increase in size, moult, coil, usually develop a cyst wall and become capable of infecting a new host (Fig. 8.9.5.19); they may remain viable in muscle for several years. Epidemiology and control Trichinella species are widely distributed in many geographical areas among many carnivorous hosts found in three classes of ver- tebrates: mammals, birds and reptiles (Table 8.9.5.1). Domestic pigs become infected by eating infected scrap from abattoirs or farms. Humans are incidental hosts and are usually infected with T. spiralis, but occasionally other species, depending upon the animal eaten. Infection is best prevented by properly cooking meat. Clinical features Most people with light infections are asymptomatic. In heavy in- fections, diarrhoea develops in the first week and is associated with abdominal discomfort and vomiting. Fulminating enteritis may develop in patients with extremely heavy infections. Symptoms of larval invasion develop during the second week, and include fever, myositis with pain, swelling, and weakness, usually first involving the extraocular muscles, then the masseters, neck muscles, limb flexors, and lumbar muscles. Some patients may develop one or more HUMANS Larva in mucosa Circulation SWINE, OTHER CARNIVORES Adults in small intestine Larva released in small intestine Encysted larva (infective stage) Encysted larva (diagnostic stage) Larva deposited in mucosa Encysted larva in muscle (diagnostic stage) Larva released in small intestine MEAT (Pork, wild boar, bear) Adults in small intestine Fig. 8.9.5.17  Life cycle of Trichinella spiralis. Fig. 8.9.5.18  In vitro preparation of infected mouse small bowel, showing adult worms of Trichinella spiralis surrounded by newborn larvae. Courtesy of D. I. Grove. Fig. 8.9.5.19  Trichinella spiralis third-​stage larvae in human muscle (×100). Table 8.9.5.1  Major Trichinella spp. and their epidemiology Species Code Distribution Most common hosts Cyst wall T. spiralis T1 Worldwide except Australasia Pig, horse, bear, rodent, fox Yes T. nativa T2 Arctic, subarctic Bear, fox, dog Yes T. britovi T3 Temperate, subarctic Dog, bear, cat, boar Yes T. pseudospiralis T4 Cosmopolitan Bird No T. murrelli T5 North America Bear, coyote, dog Yes Uncertain T6 Subarctic Bear Yes T. nelsoni T7 Sub-​Saharan Africa Hyena, cat Yes Uncertain T8 Southern Africa Lion, panther Yes Uncertain T9 Japan Bear Yes T. papuae T10 Papua New Guinea Pig, crocodile No T. zimbabwensis T11 Central Africa Crocodile, mammals No Uncertain T12 Argentina Cougars No

8.9.5  Gut and tissue nematode infections acquired by ingestion 1515 of cough, dyspnoea, headache, periorbital oedema, subconjunctival haemorrhages, and a petechial rash. These symptoms slowly subside over several weeks, although symptoms persist longer in a minority of patients. In fulminant infections a potentially fatal myocarditis or meningoencephalitis might develop. Diagnosis The diagnosis is suggested by a combination of fever, periorbital oe- dema, myositis, and eosinophilia in a patient who gives a history of eating undercooked meat, often in the context of an outbreak. Elevated creatine kinase and lactate dehydrogenase levels indicate considerable muscle involvement. Serological tests become posi- tive several weeks after infection. A definitive diagnosis depends upon finding larvae in muscle biopsies, although this is usually unnecessary. Treatment and prevention If the diagnosis is made early in the illness, treatment with albendazole or mebendazole for 14 days is given to kill adult worms in the bowel and thus reduce the load of larvae able to invade the muscles. In established infections these benzimidazole agents can be also be used, but usually have little influence on the course of the dis- ease. In established symptomatic infections the mainstays of treat- ment are rest and the administration of corticosteroids, especially in severe cases. Mortality rates as high as 5% have been reported with very heavy parasite loads. Trichinosis in the pig population can be greatly reduced or eliminated by hygienic rearing methods. Larvae in pork may be killed by freezing at –​18 °C for 1 week. Whether or not that is done, thorough cooking of pork is the best safeguard against infection in all endemic areas. Trichuriasis (whipworm infection) Life cycle Trichuriasis is an infection caused by Trichuris trichiura. Infection is acquired when an egg is ingested (Fig. 8.9.5.20). The infective larva hatches in the small intestine and enters the mucosal crypts of the caecum, where it moults several times to become an adult worm 30–​50 mm long. The anterior three-​fifths of the worm are thin and elongated, and the posterior two-​fifths bulbous and fleshy. The thin end is embedded in a syncytial tunnel in the large bowel epithelium (Fig. 8.9.5.21). Nearly 3 months after infection the fertilized female worms begin to produce about 10 000 eggs per day. Adult worms live for 1 to 3 years. After passage in the faeces, eggs embryonate in the soil and become infective after several weeks. Epidemiology and control Trichuriasis has a worldwide distribution, particularly in the warmer parts and is most common in areas where sanitation is poor, espe- cially where human faeces are used as fertilizer in vegetable gardens. Environmental sanitation is the best control measure. Ground-​ growing fruits and vegetables should be carefully washed. Clinical features Most infections are light and asymptomatic. In heavy infections there is colitis and/​or proctitis, with the passage of blood and mucus in the faeces. In some cases, prolapse of the oedematous parasitized rectum occurs. Chronic heavy infection can be associated with iron-​ deficiency anaemia and growth retardation. Diagnosis This is based on finding characteristically barrel-​shaped eggs 50 × 20 mm in size (Fig. 8.9.5.22) in the faeces. Sigmoidoscopy, proctoscopy, or colonoscopy may show worms attached to the mu- cous membrane and sometimes intact worms may be passed in the faeces. Treatment Benzimidazole anthelminthics (mebendazole or albendazole) are effective when given for between 3 and 5 days, depending upon the severity of infection. Repeat courses may be required. Ivermectin is an alternative if benzimidazoles cannot be used. EXTERNAL ENVIRONMENT HUMANS Embryonated egg (infective stage) Eggs in faeces (diagnostic stage) Penetrate and develops in mucosa Adults in large intestine Two cell stage Advanced cleavage Larva hatches in intestine Fig. 8.9.5.20  Life cycle of Trichuris trichiura. Fig. 8.9.5.21  Histological section. Anterior end of an adult Trichuris trichiura embedded superficially in the large bowel mucosa (×250).