71 Occasional, miscellaneous, and opportunistic parasites and fungi

A variety of organisms are mentioned and these are either not closely related to groups in earlier chapters or are free-living and can opportunistically infect man. The parasites presented are usually under their most important clinical presentation and the fungi are presented separately as a group. As they are usually rare, these infections do not often generate suspicion among health providers. Often they are difficult to differentiate from more common infections, and some can be fatal if misdiagnosed.

Naegleria fowleri, at least 6 Acanthamoeba spp., i.e. A. cuthbertsoni, A. castellani, and Balamuthia mandrillaris are free-living and occur worldwide. Naegleria fowleri, an amoeboflagellate recently classified under Super Group Excavata: Vahlkampfiidae (Adl et al. 2005), causes acute, rapidly fatal meningoencephalitis usually in healthy children and young adults. Acanthamoeba spp. and B. mandrillaris amoebae, both in Super Group Amoebozoa: Acanthamoebidae, cause insidious, fatal encephalitis; Acanthamoeba mainly in immunosuppressed (HIV/AIDS, transplant patients, steroid recipients) or debilitated (drug, alcohol abusers) individuals; Balamuthia in these but also in immunocompetent individuals, though particularly the young, elderly and malnourished. All three amoebae contain bacteria including a number of pathogens, i.e. Escherichia coli 0157, Legionella, etc., but their role as reservoirs is undetermined.

Naegleria fowleri, thermophilic (>30°C) in freshwater, is acquired in warm recreational water (lakes, ponds) particularly in the summer months, and in thermally heated rivers, as well as spas, pools, etc., inadequately treated with chlorine. It has been found in the nasal passages and throat of healthy individuals.

Contact with warm waters, particularly immersing the head, allows amoebae into the nostrils. Incubation may be 5–7 (1–14) days. Parasites enter the brain parenchyma through phagocytosis by olfactory neuroepithelial cells, the cribiform plate and sub-arachnoid space. The amoebae are highly destructive, producing haemorrhagic and necrotic meningoencephalitis involving particularly the olfactory and fronto-temporal regions. They feed on cells with amoebastome feeding cups, perforins and phospholipases disrupt membranes, and the amoebae may trigger apoptosis (Visvesvara et al. 2007). The cerebral hemispheres are swollen, oedematous, and congested. Fibrinopurulent exudates contain predominantly PMNs with large numbers of trophozoites but no cysts. Signs include sudden onset headache, fever, nuchal rigidity, nausea, vomiting, with later nerve palsies, seizures, and coma. Infection is rapidly fatal in 2–10 days from increased cranial pressure, brain herniation, and resultant cardiopulmonary problems.

The binucleate Sappinia probably S. pedata has been isolated from a patient with a haemorrhagic, necrotizing, inflamed lesion.

Human infection occurs worldwide with no seasonal pattern. Acanthamoeba is ubiquitous in the environment and tolerates a wide range of osmolality and pH. Cysts survive desiccation for many years. Acanthamoeba are present in soil, dust, fresh and brackish water, including thermally heated water (cooling towers, ventilating systems, pools, tubs, spas, etc.), sewage, contact lens fluids, even sea water, etc., and cysts can be airborne (Khan 2006). Acanthamoeba can be cultured from the nasopharynx of 1–24% of healthy people. Balamuthia mandrillaris in contrast has been only occasionally isolated from soil. Human cases are recorded primarily in South and North America, (a preponderance of cases are in Hispanics for reasons unknown—contact with soil, genetic), but also in Asia, Australia, and Europe. Cases of either amoeba can present anywhere acquired elsewhere.

Infection possibly through olfactory nerves but entrance most probably is through broken skin and the respiratory tract (possibly intestinal tract) and, with or without cutaneous, nasopharangeal or repiratory tract lesions, subsequent haematogenous spread to the brain. Acanthamoeba binds to epithelial and endothelial cells with a 136 kDa mannose-binding protein, Balamuthia to laminin probably by a galactose-binding protein. There is apoptosis, amoebastomes aid engulfment of the cells, and proteinases, i.e. serine and metalloproteases, that cleave collagen, elastin, fibronectin, plasminogen, etc., and target tight junctions, facilitate invasion. IL6-mediated early inflammation increases permeability probably facilitating entry through cells (Khan 2007; Siddiqui and Khan 2008). Infection may have occurred weeks to months before the onset of central nervous system (CNS) disease. A few Acanthamoeba cases and >50% of Balamuthia cases may be preceded by cutaneous (occasionally respiratory) lesions that can persist for months before invasion of the CNS. The latter becomes rapidly fatal within days to weeks.

The lesion(s) is a single or multiple space–occupying mass(es) of necrosis, haemorrhage, oedema, and infarcts mainly in the cerebral hemispheres. Histology reveals multinucleated giant cells, necrosis, and neovascularization, suggestive of a tumour, but trophozoites and cysts are scattered through the tissues. There is thrombosis and cuffing with PMNs and amoebae. The giant cells may form granulomata particularly in fairly immunocompetent patients. Signs include headache, stiffness, mental changes, nausea, vomiting, ataxia, facial palsy, photophobia, seizures, coma, and death.

Amoebic encephalitis is relatively rare and so does not generate suspicion being similar clinically to more common infections but rapid diagnosis and aggressive treatment is essential as mortality is exceedingly high.

The cerebrospinal fluid (CSF) of PAM patients may be grayish, with elevated PMNs, the number of rbc increases with disease progression, and an immediate CSF wet mount may show actively moving N. fowleri trophozoites. CSF of GAE patients very rarely reveals Acanthamoeba or Balamuthia but there is pleocytosis (increased lymphocytes and PMNs) and elevated protein.

Computerized tomography (CT) of GAE cases shows usually low density mass(es); magnetic resonance imaging (MRI) with enhancement, ring enhancing lesion(s); but these mimic abscesses, etc. Arterial occlusions and infarctions have been described. Images of PAM patients may show cerebral oedema and obliteration of cisternae and the subarachnoid space over the cerebral hemispheres (Singh et al. 2006). Particularly early in the disease the scan can be normal in as many as 40% of patients (Schumacher et al. 1995).

Circulating antibody tests (immunofluorescence, ELISA) must be interpreted with care. High titres against these organisms can be useful for diagnosis but then many patients have impaired immune systems and there rarely is time for antibody production to Naegleria although IgM might be useful. Antibody to any of the amoebae may be present in 3% to a high proportion of unaffected individuals.

Brain (or skin) biopsy will reveal trophozoites and cysts of Acanthamoeba or Belamuthia but no cysts in the case of N. fowleri, the organisms differentiated by immunostaining. Acanthamoeba and Naegleria are readily cultured on non-nutrient agar coated with enterobacteriaceae as food but may take days to develop. The latter grows at 45°C. Balamuthia usually requires mammalian cell culture (i.e. monkey kidney, human lung fibroblasts, human brain endothelial cells). All three are cytopathic to cell cultures. All three can be cultured axenically. Naegleria is 12 (10–25) µm with a single nucleus, large, central nucleolus, and moves with broad lobopodia. Under certain conditions (i.e. low osmolality) it becomes a temporary, pear-shaped, biflagellate possibly related to dispersal. Acanthamoeba and Balamuthia trophozoites are 12–60 µm, uninucleate, with a large central nucleolus (occasionally 2/3 in Balamuthia). Acanthamoeba has fine, tapering, thorn-like acanthopodia, Belamuthia pseudopodia are thicker and exhibit filamentous structures. The cysts are uninucleate and 10–30 µm with two (light microscopy) and three (EM) layers to the cyst wall.

Polymerase chain reaction (PCR) analysis of nuclear and mitochondrial SSU 18S, 16S rRNA, ITS1, ITS2, or nested PCR can be used to confirm diagnosis and for analysis of strain in patients and the environment (Réveiller et al. 2002; Schuster et al. 2003; Zhou et al. 2003; Booton et al. 2005). 18S rRNA has defined 3 morphological groups and 12 genotypes of Acanthamoeba of which T4 is the most frequently isolated from the environment (53%), keratitis cases (94%). and other body tissues (79%). A few brain isolates have been of rare genotypes (T1, 10, 12). Potentially T4 predominates in disease due to either virulence or abundance in the environment. PCR of 16S rRNA commonly is used to confirm B. mandrillis and nested PCR for N. fowleri infections. Recently, rapid real time multiplex PCR to simultaneously detect any of the three amoebae has been developed (Qvarnstrom et al. 2006).

There are very few recoveries from amoebic encephalitis due to late diagnosis and relatively ineffective drugs. Naegleria fowleri has been treated with aggressive intravenous and intrathecal amphotericin B and miconazole. Azithromycin, rifampin and fluconazole have been used. Acanthamoeba and Balamuthia have been treated with combinations of flucytosine, pentamidine, sulphadiazine and fluconazole, or itraconazole and clarithromycin, and miltefosine, but the side effects of the drugs, particularly pentamidine, means discontinuance is likely (Khan 2006). Also, there is potential for re-activation of cysts in the brain at a later date. Surgical removal of any cutaneous lesion might reduce the parasite load but possibly is too late. Steroids could facilitate spread but then decrease cerebral oedema.

Naegleria fowleri can be killed by adequate chlorination (1 mg/L free chlorine) in well-run pools, spas, etc. (Visvervara and Schuster 2008). In some countries where problems could arise in recreational waters monitoring of water has been carried our (i.e. lakes in Australia, cooling tower heated river waters in France). Only advice, i.e. not putting your head underwater, can be given for rivers, ponds, lakes. Acanthamoeba are ubiquitous, resistant to chlorination, and can even multiply in water treatment sand and activated carbon filters so that adequate back-washing is essential (Thomas et al. 2008).

Halicephalobus gingivalis, formally Micronema (H) deletrix, belongs to a group of usually free-living nematodes. Morphological descriptions and genetic identification of it come from soil isolates and infections with females, larvae and eggs in a few human cases in the USA, Europe, Japan, Egypt, and Columbia, and from CNS, viscera, jaw and nasal bones of horses (Nadler et al. 2003).

Halicephalobus gingivalis in man presents as a non-suppurative meningoencephalitis with rapid, fatal progression. There are multimodal necrotizing granulomata containing macrophages, multinucleate giant cells, lymphocytes, eosinophils, and parasites. Infection is thought to be through oral and nasal wounds, though other mucosa and the skin could be involved. Haematogenous spread is suggested as parasites frequently are found in and near blood vessels in the brain.

Nematodes are identified in sections or teased from tissues. Small (15–20 µm wide by 311–411 µm long) pathogenetic females have a rhabditiform oesophagus. The ovary is posterior with 9–12 oocytes and the terminal end curved ventrally. The anterior oviduct and uterus contain one egg and the terminal end is bent dorsally and posteriorly. Eggs, 50 x 18 µm, have flattened sides. First stage larvae (L1) and third stage larvae (L3) average 168 and 203 µm, respectively. The presence of females and eggs rather than just larvae differentiates H. deletrix from the closely related Strongyloides. Treatment has not been successful upon CNS involvement though high dose ivermectin given every 2 weeks had reported effect in a horse with a confined bone abscess.

Opportunistic Acanthamoeba spp. can cause vision-threatening keratitis and corneal ulceration. In developing countries amoebae gain access mainly through corneal abrasion/trauma. In the USA, UK, etc., infection occurs particularly in contact lens users with affected individuals more likely to use home-made solutions (amoebae present in home water tanks), disinfect lenses less frequently, and more likely to swim wearing lenses. The amoebae can bind to biofilms on the lens. Further, some strains are resistant to some commercially available solutions, particularly some more convenient, multipurpose solutions that were developed with reduced disinfection to decrease carcinogen risk (Polat et al. 2007; Patel and Hammersmith 2008). Tolerance of Acanthamoeba to high temperature and high osmolality correlated to pathogenicity in keratitis. Intense pain, photophobia, tearing, usually in one eye, occurs often within days of infection. Although several thousand cases are reported (about 0.15–2/100,000 with more in wearers of extended use lens) (Schuster and Visvesvara 2004; Khan 2006) infection may be misdiagnosed as herpes virus keratitis delaying the appropriate therapy.

Progression of the lesions is described by Patel and McGhee (2009). In the early stages the cornea is destroyed by the cytopathic amoebae with development of a characteristic, complete stromal ring of PMNs in as many as 50–80%. In the later stages there is ulceration, descemetocoele formation, and perforation. A non-healing ulcer, refractory to antibiotics, and the pain due to radial neuritis around the corneal nerve are indicative. Amoebae and cysts can be identified by confocal microscopy or corneal scraping (the highest likelihood of diagnosis is a combination of the two) and culture or PCR using 18S rRNA gene (Khan et al. 2001).

Presentation and duration at diagnosis are important. Rapid diagnosis and treatment gives good prognosis, the progressively deeper the disease the greater the treatment challenge and threat to vision. Awwad et al. (2007) reported five enucleations in a series of 118 patients where four had severe, ischaemic, posterior segment inflammation. Treatment must be aggressive and prolonged with polyhexamethylene biguanide, chlorhexadene gluconate, Brolene (propamidine/dibromopropamidine), or combinations of these and other drugs, i.e. micafungin, as they have good cysticidal activity reducing chances of recrudescence (Khan 2006; Visvesvara and Schuster 2008). Drug resistance does occur. Steroids can increase amoeba multiplication but decrease cyst formation, these resistant to drugs. Penetrating keratoplasty has been used to restore vision once amoebae have cleared. Corneal transplantation may be needed (Awwad et al. 2005). Cases do not progress to granulomatous amoebic encephalitis although a case of uveitis was associated with the latter (Visvesvara et al. 2007). The involvement of opportunistic Hartmannella in keratitis is disputed.

Contact lens wearers and those with corneal damage must be warned that amoebae can be present even in potable water. Anywhere the water can heat up, i.e. in pipes outdoors, water tanks, etc., can aid growth. Disinfection of lenses must be thorough, lens cases cleaned and replaced regularly. Solutions containing hydrogen peroxide, i.e. 3%, were the most effective at killing trophozoites and cysts in 24 hours (Johnson et al. 2009). Contact lens wearers should continue to seek monitoring and expert advice to prevent complacency, change to possibly cheaper solutions, and reduction in hygiene; in one study the risk was poor hand-hygiene.

Thelazia callipaeda is common in the conjunctiva of dogs, cats, foxes and rabbits in Asia, and may remain undiagnosed in people in poor communities in China and is described in many areas of Asia. It can occur in 60% of dogs in southern Italy and is emerging in northern Italy, southeastern France, southern Germany, and southern Switzerland and is emerging in man (Otranto and Dutto 2008). Thelazia californiensis is described in western USA.

The fly host, drosophilid Phortica males (Otranto et al. 2006), acquires T. callipaeda L1 lapping and later the developed L3 migrates out of the mouthparts of a fly lapping secretions from the eyes of dogs and wild carnivores. Fannia spp. have been infected with T. californiensis. Human infection occurs at any age but is most common in young children. Worms on the conjunctiva cause floating filaments, pain, conjunctivitis, excess lachrymation, possibly keratitis and ulceration. Male only infections may be asymptomatic. Rare infections in the vitreous and subconjunctival space are described.

Adults, 0.5–1.7 cm, have a serrated cuticle and hexagonal buccal capsule. They can be removed physically with fine forceps. Topical moxidectin shows effect against some animal species.

Oestrus ovis is an occasional parasitic zoonoses of the conjunctival sac. This is covered in more detail in Chapter 68.

A Cheilospirura worm, normally in the gizzard of birds, possibly ingested in an insect intermediate host, was described in a conjunctival sac in man in the Philippines.

Acanthamoeba dermatitis presentation is firm, often non-tender, erythematous nodules, possibly multiple chronic ulcers, and abscesses, seen mainly in HIV/AIDS patients particularly on the chest and limbs, and only rarely do CNS signs not develop concurrently or subsequently (Torno et al. 2000). Balamuthia dermatitis occurs as single, possibly multiple, plaques a few mm thick and up to several cms across that may ulcerate, particularly on the nose, face, and ear, but also on trunk and extremities. Skin lesions may be present in 50% of CNS disease patients, and are almost invariable in some South American patients, but North American patients present primarily with CNS signs. The lesions contain trophozoites and cysts. In addition to aggressive treatment with the antibiotics used for CNS disease, cutaneous application of chlorhexidine, ketoconazole and related creams have occasional reports of efficacy.

Dracunculus medinensis, ‘the guinea worm’, is one of the oldest known worms, probably depicted as the serpent and staff of Aesculapius, the Roman god of medicine. Formerly a scourge in arid and semiarid areas of Asia, the Middle East, and northern Africa, this parasite has been the subject of an intensive global eradication campaign. However, outbreaks still occur when clean water systems have failed in six countries from Mali to Ethiopia and Sudan. The dog and other mammals occasionally are infected but seem incidental to epidemiology. In North America rare human Dracunculus is due to Dracunculus insignis from raccoons, mink, and other carnivores.

Females protrude from skin ulcers to lay Ll in water. Cyclops are intermediate hosts, and tadpoles and frogs suitable paratenic hosts. Acquired mainly through drinking Cyclops in dirty water, parasites migrate through the peritoneal cavity and subcutaneous musculature for many months before moving to the extremities. The female emerging induces an allergic rash, red papule, then blister on an extremity. The long female is coiled near this. Secondary infection or worms that fail to emerge and degenerate cause severe abscessation.

L1 (500–760 µm with a very striated cuticle and long pointed tail) may be obtained after placing cold water on a ruptured blister. The worm is surgically excised or manually extracted. Histology reveals the female worm amid inflammation. For worms that are difficult to remove, corticosteroid therapy, perhaps with accompanying albendazole or ivermectin, might be helpful, though conclusive efficacy has not been demonstrated.

Gnathostoma spinigerum occurs in gastric nodules in wild and domestic Canidae, Felidae, and other carnivores, and is the most widespread species infecting man in south east Asia, China, Japan, the Indian subcontinent, and recently in Central Africa. Cases of human G. hispidum and G. doloresi of pigs and boars in Europe, Asia, Australia, and G. nipponicum of weasels, etc., in Japan are described. Gnathostoma binucleatum of opossums, etc., seems to be the species increasingly reported in man in northern Latin America and occasionally the USA.

L1 hatch in water and develop in freshwater copepods. Mature L3 occur in viscera and muscles of fish intermediate hosts, i.e. swamp eels, eels, catfish, snook, cichlids, bream, trout. L3 also occur in amphibians, reptiles, rodents, pigs, and birds infected either from copepods or fish. In definitive hosts larvae migrate in the connective tissue and muscles to return to the stomach. Humans acquire infection primarily from raw fish in ethnic dishes such as ‘hu-sae’ in China and ‘ceviche’ in Mexico, but potentially from raw frogs, snakes, wild boar, poultry, etc., and possibly copepods in water. As many as 35% of villagers by a lake in Mexico were seropositive. Rare L3 skin penetration in food handlers and prenatal infection are described. Cases in immigrants and travellers from south east Asia and Latin America are increasing in frequency, and travellers are identifying infected areas, i.e. Zambia, Myanmar, infection previously unrealized as residents do not eat raw fish. Imported, chilled fish poses a threat. Infection in urban Japan was attributed to fish from Taiwan, Korea, or China, and in The Netherlands to imported trout.

In man, transient gastrointestinal symptoms (fever, anorexia, vomiting, pain) may occur within 24–48 hours for 2–3 weeks from the larva in the intestinal wall or liver (Herman and Chiodini 2009). Cutaneous gnathostomosis develops from a week to >5–12 months later and manifests primarily as episodes of migrating swelling, possibly with subcutaneous haemorrhages, cutaneous eruption or nodules mainly on the trunk but also involving the upper limbs, head, throat. etc., and lasting perhaps 1–2 weeks or more. Although intermittent, these signs can persist for years. Eosinophilia may be present. Occasionally an abscess develops. Systemic infection varies with organ, i.e. liver, lung, gut, etc. Neurological migration produces intracranial necrotic tracks and subarachnoid haemorrhage, severe radicular pain and/or headache and paralysis, and has long term side effects and 8–25% mortality. Ocular migration may occur sometimes years later.

Migrating swellings, usually with eosinophilia, history of residence/travel, and dietary preferences are suggestive. Subcutaneous swellings differentiate gnathostomosis from other larva migrans (Herman and Chiodini 2009). The worm can be very difficult to recover from CNS or cutaneous lesions (it migrates as much as one cm/day) so blind excision may not be helpful although histopathology is described as useful (Magaña et al. 2004). An ocular larva is visible. Larvae are 2–15 mm long, reddish-white, with a characteristic head bulb bearing usually 3–4 rows of hooklets and rows of small cuticular spines. Larger parasites and their damage and migrating lesions might be visible on imaging. Serological diagnosis can be obtained in south east Asia. The fewest cross-reactions on ELISA were with IgG₂ antibodies (Herman and Chiodini 2009). On western blot, 24 and 21 kDa antigens of crude extracts, particularly using IgG₄ antibody, were considered specific for confirmation of IgG immunoblots (Anataphruti et al. 2005; Laummaunwai et al. 2007). A multi-immunodot test has been developed to differentiate some eosinophilic meningitides (Eamsobhana et al. 2006).

The parasite can be removed surgically from the eye. Spontaneous recovery from cutaneous gnathostomiosis is possible but cutaneous migration, facial in particular, could lead to CNS or ocular complications. Albendazole (400 mg twice daily for 21 days) has been effective (Nontasut et al. 2005) and could be useful in cerebral gnathostomiosis. Ivermectin (200 µg/kg for two days) seems effective. Repeated treatment is advised as relapse can be 20–50%.

Although only 50–100 cases of Lagochilascaris minor have been described, in rural, neotropical forest areas from Mexico to Brazil, Trinidad and Tobago, infection may be more common and infected dogs and cats are described further north and south than this. The normal hosts seem to be sylvatic Canidae, Felidae, opossums, with adults in the rhino-oro-pharynx and a wild rodent intermediate host.

Human infection probably is acquired by eating larvae in agouti or other rodents. Parasites mature and eggs and larvae develop in persistent, purulent, discharging abscess(es) in the soft tissues of the neck, ear, mastoid process, or throat. Fatal (6%) brain or lung infections are described.

Surgical debridement and excision will reveal rough-shelled eggs (55–80 µm long with a reticulate pattern) and larvae ( Sakamoto and Cabrera 2002). Adult females up to 2 cm have three obvious lips and small lateral alae over most of the body. As many parasite stages are present and multiplying, anthelmintics should be given. Prolonged or repeated courses of ivermectin, levamisole, or albendazole are described as effective in individual cases.

Rhabditis (Pelodera) strongyloides is free living in organic matter but also is carried as a larva in the intestine of wood mice with related species in the skin of rodents, presumably using rodents for nourishment and dispersal. The larvae occasionally have been associated with dermatitis in varied domestic animals and several human cases now are recorded in Europe, the USA, and Japan. Skin scrapings show the large larvae (600–750 by 30–40 µm) distinguished by their rhabditiform oesophagus, distinct buccal capsule, and lateral alae (Saari and Nikander 2006).

Over 100 human infections with mainly Mammomonogamus laryngeus and M. nasicola are recorded in the Caribbean and Brazil, but also Mexico, China, Thailand, and Korea. Infected ruminant definitive hosts are common in much of Central and South America, south east Asia, the Indian subcontinent, and tropical Africa. Mammomonogamus gangguiensis is described in China. Infection also is seen in primates.

Eggs in bovine faeces embryonate to L3. Probably eggs, or hatched L3, are eaten accidentally on vegetables. A paratenic host, e.g. earthworm, snail, might be involved and infection in China and Thailand was related to eating turtle meat or blood. Worms attach to the laryngeal/tracheal/bronchial mucosa and suck blood.

Patients have a ‘crawling sensation’ or ‘lump in the throat’ with chronic, non-productive cough, possibly paroxysmal with haemoptysis or vomiting. Some have severe ‘asthma’ symptoms because of obstruction of air passages. An unusual duodenal infection presented with pain and haemoptysis.

Patients in Western countries usually have a recent history of travel in the Caribbean. Eggs in sputum or faeces are ellipsoid and average 75–95 x 40–50 µm, larger than hookworm eggs, with a thicker shell and initially two cells. Males and females, up to 2 cm, are red/brown with a cup-shaped buccal cavity bearing basal teeth, and live in permanent copulo in a Y configuration. They can be visualized and removed by bronchoscopy from the larynx, trachea, and sometimes bronchi, but with their red colour may be difficult to discern against an inflamed mucosa. Benzimidazoles have been used.

Originally considered site specific, human vaginal, intestinal, and particularly oral Trichomonas spp. have been identified in the respiratory tract of man, as have avian intestinal Tetratrichomonas gallinarum and bovine reproductive tract Tritrichomonas foetus. Trichomonas foetus also occurs in the intestine of diarrhoeic and normal cats, i.e. 31% at cat shows. Pentatrichomonas hominis has been found in cats’, dogs’ and pigs’ intestines, human adapted strains are possible though (Duboucher et al. 2008).

Trichomonads have been found in 60–100% of Pneumocyctis pneumonia (PCP) patients and in 30% of acute respiratory distress syndrome patients (and correlated with higher mortality), in cases of emphyaemia and in varied other respiratory diseases. Probably secondary contaminants the trichomonads seem able to establish and multiply in the more anaerobic respiratory tract, some trichomonads can damage cells and are pathogenic in their own site/host in their own right, so their potential contribution to the respiratory disease must be considered.

Identification is difficult and Duboucher et al. (2008) describe the amoeboid, non-flagellated forms that develop without revealing their flagellae or undulating membrane. Immunostaining or PCR (ITS1-5.8S rRNA-ITS2) are required (Duboucher et al. 2007). Trimethoprim-sulphamethoxazole for PCP is considered active against trichomonads. Metronidazole could be useful.

Gongylonema pulchrum adults lie in a zipper fashion in the oesophageal wall of ruminants, pigs, other ungulates, bear, and monkeys, in many countries. More than 50 human cases have been described worldwide, including Europe, Russia, Asia, Australia, and North Africa.

Beetle and cockroach intermediate hosts ingest eggs in ruminant faeces and humans presumably acquire infection eating these. Also, L3 are said to emerge from cockroaches in water. In man, G. pulchrum is found coiled in a filamentous nodule or blister in the oral epithelium and the lump often moves, patients describing a creeping sensation.

Some cases initially have been considered delusionary (Molavi et al. 2006). The worm is extracted surgically or by curette and patients themselves scratch them out. They are recognized by asymmetrical alae and cuticular bosses that lie in eight longitudinal series anteriorly.

Moniliformis moniliformis (normal hosts, rodents, particularly Rattus spp., dogs, cats, foxes) and Macracanthorhynchus hirudinaceus (domestic and wild pigs) have some 20 records in man (intestine) worldwide. Other records are: Macracanthorhynchus ingens (raccoon and skunk) in the southern USA, Bolbosoma spp. (Cetaceans, particularly seals) in Japan, Acanthocephalus rauschi (probably of marine fish) found in the peritoneum of an Eskimo in Alaska, Corynosoma strumosum (Cetaceans, Alaska) and Pseudoacanthocephalus bufonis (toads, south east Asia) may have been spurious infections.

A cystacanth develops in arthropod intermediate hosts (beetles, cockroaches, millipedes, for acanthocephalans parasitic in land animals; crustaceans for those in aquatic vertebrates). Moniliformis moniliformis in cockroaches may be accidentally eaten by children; other infections may be from beetles eaten as food in pig rearing areas in China and south east Asia; those of sea mammals in crustaceans. Cystacanths can re-encyst if eaten by non-definitive host vertebrates, so snake, frog or fish paratenic hosts could be responsible. Adults may cause weakness, abdominal pain, and diarrhoea from eosinophilic enteritis and occasional intestinal perforation by the proboscis with the worm entering the peritoneal cavity, but many infections do little harm.

Faecal eggs are ellipsoid or spindle-shaped, dark brown, and measure 110–120 by 56–60 µm (M. moniliformis) and 80–100 by 45–65 µm (M. hirudinaceus). They have four membranes of which, in terrestrial species, one is very thick and may be pitted. Eggs contain an ‘acanthor’ larva provided with an anterior circlet of hooks. Adults are cylindrical and 1–1,000 cm long with a ‘thorny head’, this a cylindrical or oval, invaginable proboscis armed with hooks.

In pigs, doramectin (300 µg/kg), or ivermectin (100–200 µg/kg in feed for 7 days) had good efficacy. Benzimidazoles have been used.

Adults occur in the large intestine of non-human primates and O. bifurcum occurred at high prevalence in man in north west Ghana and north east Togo and sporadically elsewhere and T. deminutus is sporadic in man, particularly described in Zimbabwe, but also in East and Central Africa, Surinam, and Thailand. Recent molecular analyses of O. bifurcum cDNA in Ghana revealed 3 or 4 variants, in Patas or Mona monkeys, humans, or Olive baboons. This may indicate human-to-human transmission and certainly primate infections can be common in areas where there is no human infection (Gasser et al. 2006). However, additional cross infection studies are required as O. bifurcum from humans did infect primates, albeit relatively poorly, and non-human primates presumably remain a reservoir for sporadic infections in Africa and Asia. Oesophagostomum aculeatum in Indonesia and O. stephanostomum in Brazil and tropical Africa have been recorded rarely.

Humans presumably eat L3 on vegetation or in soil. L3 have a remarkable ability to shrink on desiccation and revive months later. Oesophagostomum L3 enter the mucosa of the proximal colon but also terminal ileum and L4 develop in nodules and remain in the nodules or emerge to develop to adults in the lumen. Ternidens larvae develop in the lumen. Two types of pathology are produced by O. bifurcum. Uninodular disease comprises a single large (3–11 cm) nodule, frequently protruding into the lumen or adhering to the periumbilical abdominal wall (‘Dapaong tumour’), containing thick pus around one or several larvae. Pain and fever are from intestinal obstruction or abscessation. Multinodular disease comprises hundreds of ≤ 1 cm mucosal/serosal nodules containing pus and a worm presenting as abdominal pain, diarrhoea, and weight loss in about 2%, most infections being asymptomatic. These latter on ultrasound usually having ≤10–15 visible nodules with possibly additional smaller, less pathogenic nodules. Rarely nodules occur elsewhere. Adult infections do little harm. Nodules become prevalent in the early dry and increase in size through the dry when disease is most likely to present, decreasing in number through the late dry to mid rainy season.

Immature O. bifurcum (up to one cm) may be identified after surgical removal of a nodule. Faecal examination is a problem as eggs resemble hookworm eggs, Ternidiens eggs slightly larger, 70–94 by 40–60 µm; Oesophagostomum differentiated on cultured L3 (700–950 µm)—larger than Necator, with prominent intestinal cells and a long ‘hair-like’ tail to the transversely striated sheath. Adults are about 1 cm long: O. bifurcum has a cylindrical buccal capsule, double leaf crown, cephalic vesicle, and distinct ventral groove; T. deminutus a globose buccal capsule, mouth collar, and leaf crown. Multiplex PCR has been used to simultaneously differentiate O. bifurcum, Ancylostoma dudodenale and N. americanus (Verweij et al. 2007).

Surgery may be necessary for large abscesses. Albendazole, 400 mg for adults, is very effective. Experimentally, treatment twice in a year decreased prevalence from 53 to 5% and pathology from 38 to 6% changing to uninodular rather then multinodular (Ziem et al. 2006a, b). Four rounds of treatment decreased prevalence to 0.8%.

Balantidium coli is cosmopolitan in pigs. In Europe infection can occur on >75% of farms and reach 60% in piglets and 100% in adults. Prevalence in free-roaming pigs and wild boar is from >19% to 100%. It infects captive and free-living non-human primates (13–100%) and occasionally other animal species.

Sporadic human infection is worldwide, and occasionally relatively common in farm workers and rural dwellers where free-ranging pigs occur, i.e. south east Asia, China, Western Pacific Islands, Latin America. Travellers to these areas may become infected. Infection is by ingestion of cysts from pig (occasionally primate) faeces, in soil or via contaminated food/water, occasionally inhalation. Infection may be from captive monkeys and human-to-human transmission in institutions has been reported. Recent prevalence has ranged from 0.02–1% and up to 30% in man, and 0.8–2.4% in diarrhoeic children. Infection usually is asymptomatic but acute, explosive diarrhoea and dysentery may present when trophozoites invade the large intestinal mucosa in an ulcer, mainly in the malnourished and immunocompromised. Intestinal perforation and occasional infection of the peritoneal cavity and genito-urinary tract are reported. Recent infections in the West have been respiratory, i.e. a thick-walled infected cavity in a farmer in contact with aerosolized pig manure, and pneumonia in immunosuppressed patients.

Cysts, 40–60 µm, or trophozoites, 60–70 µm long, are shed irregularly in the faeces. They have a large, kidney-shaped macronucleus, cilia, contractile vacuoles and large funnel-shaped peristome. Barium and biopsy define the ulcer and reveal trophozoites.

Metronidazole at 750 mg to 1.25 g (for adults) in three divided doses daily for 10 days is described as effective.

Entamoeba polecki a parasite of pigs and monkeys, has foci of infection in man in south east Asia and Papua New Guinea. Infection is recorded sporadically in immigrants and in other countries, e.g. Venezuela, India, France, Tasmania. Infection is acquired as B. coli. Infection normally is asymptomatic, although rare reports of abdominal cramps, diarrhoea, and nausea were coincident with excretion of large numbers of cysts. Cysts are uninucleate, 14–16 µm in diameter, with a large, 3–4 µm nucleus and diffuse but central karyosome. Diloxanide furoate and metronidazole are used.

Other amoebae live harmlessly in humans but must be differentiated from Entamoeba histolytica. Some also infect animals, particularly pigs and monkeys. Most are common worldwide. Entamoeba dispar is a commensal species identical to E. histolytica differentiated molecularly. Entamoeba coli has large (usually 20–30 µm) cysts with eight nuclei, an eccentric karyosome, coarse chromatin, and chromatoid bodies have a splintered, not rounded shape. Entamoeba hartmanni has small cysts (5–10 µm) with four nuclei and chromatoid bars of the E. histolytica type. Endolimax nana has a small oval cyst with small curved chromatoid bars, four nuclei, and a large, often eccentric, usually irregular, and sometimes fragmented karyosome. Iodamoeba butschlii is uninucleate with a large vacuole containing glycogen that stains brown with iodine. Dientamoeba fragilis, binucleate and occasionally associated with abdominal pain, is now considered a trichomonad flagellate. Entamoeba gingivalis in the mouth is a non-encysting amoeba, 10–20 µm, with a central karyosome.

Several normally free-living Rhabditis spp. described occasionally in the intestine of man in Asia possibly are pseudoparasites after accidental ingestion. A Reticularia female worm of rodents or bats, presumably eaten in an insect intermediate host, was identified in the mucosa of the appendix at autopsy in New York.

Pentastomids now are considered modified crustaceans related to the branchurians. Human infection with Linguatula serrata is sporadic, but cosmopolitan. Incidence has been high where definitive host dogs fed viscera of ruminants carry adults in their nasal cavities, e.g. the Middle East, Turkey, parts of North Africa, the Indian subcontinent, and infection occurs occasionally in Latin America, but is rare in USA and southern Europe, although cases present in immigrants. Armillifer armillatus in West and Central Africa and Armillifer moniliformis and Porocephalus spp. in China and south east Asia, primarily Malaysia, can be common locally in humans. Armillifer grandis has been described occasionally in the Congo. Adults of these species normally occur in the trachea and lungs of large snakes, Python, Bitis spp. Individual cases of Armillifer agkistrodonits and Pentastoma najae of snakes in Asia and Sebekia mississipiensis (dermatitis) of alligators (Costa Rica) have been described. There is an unconfirmed report of Leiperia cincinnalis of crocodiles (Africa) and a subcutaneous creeping eruption from Raillietella hemidactyli of lizards (south east Asia).

Eggs are immediately infective in the secretions and faeces of canids and intestine and faeces of snakes. The clawed, oval, four to six-legged larva develops to a nymph in the MLN, liver, and occasionally peritoneum, omentum, and lungs of intermediate host lagomorphs or ruminants (Linguatula) or rodents and monkeys (Armillifer) or fish (Sebekia spp.).

Man is usually an intermediate host. Water, food, and soil contaminated with faeces are sources of infection as is close contact with dog secretions. Heavy infections with Armillifer have been related to trapping snakes for skins and eating snake meat containing many eggs or an adult female worm. There is potential for infection when cleaning aquaria of pet snakes of unknown origin.

The nymphs develop under the peritoneum of the abdominal viscera and wall, in the liver, abdominal lymph nodes, mesenteries, lungs, and on the pleural surface. Nymphs usually die and calcify within two years of infection. Most human infections (porocephalosis) are asymptomatic. Some present as abdominal pain or prolonged cough in heavy infection. Rare, acute, fatal cases have involved massive infection, including the brain. Rare ocular presentation has occurred.

Man also is a temporary definitive host for L. serrata. The nymph, acquired eating raw liver or lymph nodes of domestic ruminants and lagomorphs, attaches on to the nasopharyngeal mucosa and causes severe irritation and a Type I hypersensitivity reaction with coughing (perhaps paroxysmal) and sneezing within 1–24 hours. Symptoms (called ‘halzoun’ or ‘marrara’ in the Middle East and Sudan) are self-limiting after 1–7 (14 days) as the worm is discharged. As many as 20% may describe the symptoms. Very rarely, parasites develop to adulthood. In a few patients, possibly sensitized by previous adult or larval infection, acute congestion and oedema of the nasopharyngeal and laryngeal mucosae have more severe consequences.

Nymphs have a ventral mouth and two pairs of cranial hooks, hence pentastomes. Linguatula serrata nymph(s) in the nasopharynx are tongue-shaped, slightly flattened anteroventrally, annulated with rows of spines, and up to 6–10 mm, and are physically removed by endoscopy. Most abdominal or lung nymph infections are diagnosed accidentally on surgery or radiography. Radiography can reveal crescent-shaped calcifications, 0.5–2 cm across. Occasionally nymphs are viable in cysts with little host reaction, commonly they are dead in a necrotic granuloma, or a scar contains remnants of cuticle/hooks, or crescent-shaped calcifications, 0.5–2 cm across, remain. The nymph, if still present, is or horseshoe-shaped. Linguatulua nymphs are like those in the nasopharynx. Armillifer nymphs are 12–20 mm and cylindrical with spiral rings resembling a screw (Tappe and Büttner 2009). Histology reveals ring-like sclerotized openings in the cuticle. Ivermectin might be useful in acute infection with large numbers of nymphal stages. Advice must be given on dietary habits, contact with dogs and snakes, and their treatment, perhaps with macrocyclic lactones, attempted.

This minute nematode (<500 µm long) in the Muspiceoidea occurs within myofibres. It multiplies here and larvae break out (Spratt et al. 1999; Basuroy et al. 2008). Myostitis and eosinophilia occur. Although related parasites occur in marsupials and mice, the source of infection for the few human cases in Australia is unknown. Diagnosis by biopsy and treatment with 400 mg albendazole/daily for 4–8 weeks has been successful. Steroids are not recommended.

Only a few human cases are described, most in North America, but also Russia, China, Iran, south east Asia. Australia, and Spain. The parasite also occurs in South America. Normal hosts are piscivorous mustelids and canids, mainly mink in North America. A related Eustrongylides spp. of piscivorous birds has been described in eastern USA.

Eggs passed in urine develop in water and hatch when swallowed by an aquatic oligochaete annelid intermediate host. Oligochaetes in drinking water are infective, as are raw fish and frog paratenic hosts. Infective larvae penetrate the gut soon after infection and develop in the peritoneal cavity, then kidney. The adult worm in a thick-walled cyst containing haemorrhagic debris, usually found in or on the right kidney, has been confused with a tumour. Some are asymptomatic, others induce loin pain, haematuria, and worms have been expelled from the urethra. One lesion abscessed through the skin over the kidney. Worms might be found in the peritoneal cavity or liver. In two cases, a dioctophymid L3, possibly Dioctophyma or Eustrongylides, occurred in a subcutaneous nodule on the chest. Eustrongylides, acquired from minnows, usually migrate out of the oesophagus, stomach, and intestine causing peritonitis and abscesses.

At least one D. renale infection was detected by eggs (70–80 by 40–50 µm, barrel-shaped, brownish yellow with a thick, pitted shell and clear areas at the poles) in the urine. Ultrasound reveals echo-dense masses (the same echo-density as renal parenchyma). The blood-red worm reaches 1 m by 1 cm but seems to disintegrate after 1–3 years or more. Eggs remain in the granulomatous tissue of the cyst wall but the ‘double-walled rings’ of eggs can easily be confused with radially striated Liesegang-like rings.

The cyst and kidney (if atrophied) are removed surgically.

A very large number of fungi, growing mostly in soil enriched with decaying matter, induce opportunistic infections in man. Incidence has increased considerably in the last three decades as a result of a growing number of immunosuppressed patients (Cornely 2008). The fungi may remain localized, or disseminate though the infected organ, or disseminate to almost any organ, the most serious complication being CNS involvement. Risk increases with Human Immunodeficiency Virus (HIV) infection, newer aggressive therapies for stem cell and solid organ transplantation, haematological malignancies, neutropaenia, chemotherapy, corticosteroid use, new immunotherapies including TNF- and other cytokine-antagonists, and increased survival of critically ill patients. Concomitant diseases such as diabetes mellitus, COPD, liver cirrhosis, etc. also are risks. Infection in otherwise healthy persons, usually is asymptomatic, but can disseminate even in these. Mainly inhaled, a few infections enter through penetrating skin injury. Some produce surface lesions.

Some of these fungi occur worldwide, others are mainly tropical or subtropical, others occur in restricted geographic areas. The fungi might be common, but even in endemic areas, as opportunistic and uncommon, signs do not generate suspicion of a fungus, signs being similar to viral, and bacterial infections, and malignancies. Furthermore, increased travel and migration means disease presents in any country, particularly as some fungal infections may remain latent in healthy persons to activate and produce disease many years later. The diseases often have high mortality if untreated. Even if treated, the lack of suspicion and difficulties in diagnosis often mean diagnosis in delayed and, accompanied by drug efficacy often being limited with some species insusceptible to the drugs, and with the nature of the patients, mortality remains high (Cornely 2008).

Anti-fungals, particularly amphotericin B, the newer triazoles, i.e. itraconazole, voriconazole and the azole, fluconazole, and the echinocandins, i.e. caspafungin, micafungin, are the main therapeutic agents (reviewed by Cornely 2008). Maintenance therapy may be required for months, even years. Institution of prophylaxis in at risk patients increasingly has been shown useful in reducing incidence of infection but remains controversial. There is potential for increasing the rate of development of resistance to the limited number of groups of drugs, but this must be weighed against the poor prognosis associated with the infections. Combination therapy also remains controversial. In acquired immune deficiency syndrome (AIDS) patients, highly active anti-retroviral treatment (HAART), in others immunotherapy can be instituted. However, in some patients immune reconstitution inflammatory syndrome (IRIS) may ensue, the immunopathology, usually granulomatous inflammation, not understood, but associated with the developing immune response to usually the opportunistic infection that previously may have been clinical or subclinical (French 2009). Screening for opportunistic infections is important. Management of IRIS is described by Marais et al. (2009).

Pneumocystis species now are considered to be host specific organisms but PCP still is included here to update the recent speciation and epidemiological studies versus the earlier supposition that P. carinii was an important zoonoses.

First described as a protozoan, DNA data has shown Pneumocystis to be an atypical fungus (Aliouat-Denis et al. 2008). Species status has been assigned on phenotypic and genetic differences and cross infection studies in severe combined immunodeficiency syndrome (SCID) mice (Frenkel 1999; Springer et al. 2002; Durand-Joly et al. 2002). Pneumocystis jirovecii is separated as host specific to humans, P. carinii specific to rats, and host specific species are being identified in other animals. Different strains also have been identified in man (Springer et al. 2002; Aliouat-Denis et al. 2008).

Cysts release uninucleate trophic forms that align, in the appropriate host, with Type I pneumocytes and produce filopodia to anchor to, deeply interdigitate with, but not penetrate the alveolar cell cytoplasm. Organisms of inappropriate species are eliminated within three days. Trophic forms evolve through sporocyte stages progressing from uninucleate to eight nucleate, to a thick or thin walled cyst containing eight spores. Consistent with possible inclusion in the ascomycetes perhaps the cyst should be renamed an ascus as most fungal asci contain eight ascospores. Binary fission of trophic forms and conjugation remain undetermined, most forms are haploid, but a few diploids and a meiotic pathway have been seen (Aliouat-Denis et al. 2008; Burgess 2008).

Transmission is assumed to be airborne and Pneumocystis DNA has been identified in air outdoors and in patient rooms. The current hypothesis is a ‘transient infection scenario’, possibly with reinfection, with human to human transmission. Identification by PCR on deep nasal and oropharyngeal swabs now has identified P. jirovecii asymptomatic carriage in a variety of groups. While none of 28 and 30 healthy adults were infected in Chile and France, respectively, P. jirovecii DNA was found in 20% of 50 healthy adults in Spain and 20% of these were infected six months later. Prevalence increases in different groups: 10–40% of people with chronic pulmonary disease revealed P. jirovecii DNA as did 15.5% of third trimester pregnant women, and prevalence increases in the elderly; these two groups potentially increasing infection in young children. Manifestation of severe disease occurs in the immunocompromised and transmission between them and to healthy care workers has important implications for health care centres. The immunocompromised also can be asymptomatic carriers.

First described as interstitial pneumonia in premature infants and occasionally patients with malignancies and transplants, PCP became a common presenting sign in AIDS and remains a major problem in those not receiving HAART or unaware of their HIV-status with CD4 cells <200/µl. The host response and mechanisms whereby Pneumocystis survives in the host are described by Thomas and Limper (2007). There is fever, progressive shortness of breath, non-productive cough, malaise, chest pain and sometime low fever. Alveoli are filled with foamy exudate containing organisms, immune cells (CD8 lymphocytes and macrophages), and necrotic tissue, and there is interstitial inflammation. Exudate and trophic forms on the alveoli prevent gas exchange resulting in hypoxaemia. In persons, immunosuppressed for solid organ transplants, cancer therapy, or receiving corticosteroids, the disease tends to be more fulminant and rapid in progression. Occasionally there can be a granulomatous response. Mortality can be up to 10–60%, highest in immunocompromised cancer patients.

Giemsa, methamine silver or immunofluorescent antibody stains may reveal pleomorphic trophic forms (1–5 µm) and rounded cysts (5–10 µm) containing eight spores. Broncho-alveolar lavage (BAL) in HIV positive individuals shows abundant cysts and exudate, primarily lymphocytes and macrophages. BAL in HIV-negatives shows abundant inflammatory cells, particularly neutrophils, and cysts are present but less abundant. Molecular diagnosis by agarose gel separation and PCR amplification of diagnostic 346 and 550 bp bands is sensitive and specific. Radiography in HIV-positives reveals bilateral interstitial and alveolar infiltrates as ground glass opacities of particularly perihilar distribution. In HIV-negatives the exudates are diffuse. CT shows extensive ground glass opacities in the central, not peripheral lung, and there can be consolidated nodules, etc.

Trimethoprim-sulphamethoxazole remains the first choice for treatment and for prophylaxis in at risk patients (<200 CD4 cells/µl) although there is a relatively high rate of intolerance and treatment failure, i.e. sulpha-allergic persons and resistance due to mutation in dihydropteroate synthase. A generally preferred second line treatment is primaquine/clindamycin. Other treatments include pentamidine though with high toxicity, parfuramidine has proved less toxic in trials, dapsone-tirmethopim, atovaquone that also is used for prophylaxis, and dapsone-perimethamine used for prophylaxis (Thomas and Limper 2007). In persons receiving immunotherapy IRIS is a problem, 4–60% can develop this.

Human-to-human transfer has important implications in medical centres dealing with immunocompromised individuals and could promote spread of drug resistant strains. Strict isolation of P. jirovecii positive/suspected patients now seems important.

While Histoplasma (Chapter 69) is the most common other dimorphic fungi can cause severe disease.

Cryptococcus spp. are saprophytic, basidiomycetous, dimorphic fungi that develop from saprophytic hyphae to basidiospores (1.8–3 µm) and then yeast cells on infection. Hyphae are rarely seen in lesions. It is probably basidiospores that are inhaled in dust but cutaneous implantation also can initiate disease. Close human transfer might be possible as poorly encapsulated yeasts can be in sputum in large numbers during respiratory disease. Disease in lower animals manifests primarily in the nasal cavities, head and neck, so affected pets might be a risk. Transfer from humans or animals have only rarely been demonstrated (Ma and May 2009). Cryptococcus neoformans (serotypes A, D, and hybrids, A predominant) occurs worldwide, and produces disease primarily in immunosuppressed individuals, affected immunocompetent persons often have an underlying disease. Cryptococcus neoformans is found particularly in pigeon droppings and soils and debris enriched with these, but other birds can be involved; 27% of pet canaries in two Italian towns, and 10% of wild birds, particularly parrots, in Mexico, were infected. Cryptococcus gatti (serotypes B, C, hybrids), the main species seen in immunocompetent persons, is tropical and subtropical and found mainly in debris associated with red gum trees but also other trees, i.e. almonds, firs, so it is a rural disease in Africa, Australia, south east Asia, southern California, occasionally Europe, but now is emerging in temperate areas in Canada and north west and south east USA, for example. Occasionally, C. gattii x neoformans hybrids and other species are isolated from man.

Virulence is associated with ability to grow at 37°C, the capsule, melanin, mannnitol, and enzyme production, many of these secreted in vesicles, plus phenotypic switching from a smooth to more virulent mucoid form (Ma and May 2009). The thick polysaccharide capsule, composed of 90–95% galactoxylomannan (the structure of which defines the serotype) and connected to the yeast with glucans, has negative charge that inhibits phagocytosis and digestion, induces complement consumption, antibody unresponsiveness, and macrophage, dendritic cell, and cytokine dysregulation. Melanin, produced using for example dopamine in the brain, protects Cryptococcus as an anti-oxidant. Mannitol also protects against oxidative killing by PMNs and cell-free oxidants. Hydrolytic enzymes, particularly production of phospholipase that correlates with virulence, may promote destruction of membranes and lung surfactants.

Incidence in immunocompetent persons is <1.5/100,000 in the USA. Disease occurs mainly in AIDS patients with an incidence of 2–7/1,000, and prevalence in Africa can reach 13–45% and in developed countries 5–10%. As many as 3% of solid organ transplant patients develop cryptococcosis. Mortality can be high particularly when CNS lesions develop.

The yeast enters small air passages and compresses tissue but induces little host response. Most infections remain latent and asymptomatic for many years in healthy persons and seroprevalence can be high. In mainly the immunocompromised, the yeast disseminates after reactivation or new infection. Disease due to C. gattii may occur 2–11 months after infection, C. neoformans may be longer. Although entry is respiratory, most patients present with CNS signs of severe headache, fever, nausea, vomiting, altered mental status, coma, etc. Reasons for CNS predilection are not known. There is chronic meningitis or focal parenchymal lesions, the latter being more common with C. gatti. Increased CSF pressure may in part be related to yeasts or capsules blocking CSF uptake by arachnoid villi but mannitol and the capsule increase osmolality and so promote brain oedema. About 20–50% of patients also show pulmonary disease, this more common in C. gattii. There may be asymptomatic pulmonary nodules or acute disease of cough, dyspnoea, fever, and there can be involvement of other tissues, joints, heart, skin, genitourinary tract, and eye. The skin, nodules, ulcers, molluscan-type lesions or cellulites, is involved in about 10% of patients.

Diagnosis has been reviewed by Saha (2009). Because of the severity of CNS disease lumbar puncture is needed irrespective of presentation. In immunosuppressed patients direct examination of blood, urine, skin nodules, using indian ink or nigrosin stains, may reveal roundish, budding yeasts, 5–15 µm with a birefringent, polysaccharide capsule that stains red with mucicarmine. The yeast grows at 37°C, pseudohyphae are absent, it produces urease, and phenyloxidase, and a brown melanin like pigmentation on medium containing diphenolic compounds. Methenamine silver and PAS-stained histological sections are useful. These methods have 50–58 and 100% sensitivity and specificity, respectively. The sensitivity of latex agglutination and EIA antigen (galactomannan) detection tests in CSF, serum, urine, can be 93–99% in patients with culture-confirmed cryptococcal meningitis. Patients with Aspergillus or Penicillium may also react. PCR using primers for 18S rDNA can have high sensitivity and specificity. CT or MRI scans show ventricular enlargement and cerebral atrophy although, occasionally, the ventricles are small and there is cerebral oedema or a Cryptococcus mass.

CNS disease is fatal if untreated and still has a high mortality with treatment (10–40% at 10 weeks). Liposomal amphotericin B accompanied by 5-flucytosine is a first line therapy. Resistance has developed in sub-Saharan Africa. Alternates are fluconazole, better for maintenance, or itraconazole. Lumbar puncture can relieve increased intracranial pressure. Subsequent maintenance therapy is important as a high percentage, will relapse. Immunotherapy may be considered.

Coccidioides immitis affects persons particularly in California, and C. psosdasii elsewhere in south west USA, northern Mexico, and parts of Central and South America, particularly Argentina and Paraguay. The fungi are found in sandy soils and incidence in Arizona has increased to 60/100,000 with migration to the area and increased construction in desert areas. Ten to 50% of people in endemic areas may have been exposed and later activation is possible such that, should immunosuppressive, i.e. transplant therapy be considered in an inhabitant, they should be screened. A rainy summer for growth and dry and windy winter for dispersal is favourable for inhalation of arthroconidia.

Infection was recognized first in agricultural workers as a progressive skin disease and then as an acute respiratory syndrome (‘Valley fever’). In the terminal bronchioles the arthrospores transform to multinucleated spherules that grow to contain thousands of endospores. Rupture releases the endospores that transform to spherules and so on.

In immunocompetent persons coccidioidomycosis is asymptomatic in two thirds or produces mild or moderate flu-like respiratory disease (Parish and Blair 2008). There can be acute lobar or segmental pneumonia with headache, pleuritic chest pain, fever, cough, dyspnoea, etc. Cutaneous abnormalities, i.e. erythema nodosum, are more likely than in other pneumonias and indicate a favourable outcome reflecting an immune response. Diffuse pneumonia in heavy infection or in the immunocompromised produces severe illness. Most cases of acute pneumonia resolve spontaneously but a small proportion develop a chronic progressive pneumonia with consolidation and possibly cavitation, haemoptysis and weight loss. The residual effect of acute pneumonia is 1–2 cm nodules or walled cavities usually asymptomatic.

Disseminated disease occurs in <5% of immunocompetent persons but is likely in about 30% in HIV, transplant immunosuppression and haematological malignancies, with other risks including Filipino and African ancestry, age <1 year or the elderly, and late pregnancy. Disseminated disease may occur long after pulmonary infection and affects any organ but particularly skin, lymph nodes, bone, but infrequent CNS disease occurs with substantial morbidity despite treatment. There may be hydrocephalus, vasculitis, infarctions, and abscesses and headache, mental changes, and cranial nerve defects (Adam et al. 2009).

Spherules may be seen on cytology or histology and culture is diagnostic. Immunodiffusion and latex agglutination to detect particularly IgM and IgG antibodies are useful; complement fixation titres reflect severity and response to treatment; but antibodies may be absent in as many as 50% of patients. The CSF usually is culture negative and must be diagnosed by CSF antibodies, elevated WBC and protein, and low glucose.

Lipid formulations of amphotericin B are useful in severe disease, a triazole in moderate infections, and fluconazole in CNS disease (Parish and Blair 2008) with indefinite triazole therapy in immunocompromised patients as relapse on discontinuance of fluconazole is not uncommon. Nodular or cavitational lesions can remain untreated unless near pleural surfaces where rupture is a complication.

This fungus occurs in soil in Latin America where it is the most prevalent systemic mycosis. There could be 10 million infected with disease in 2%, and again infection can remain dormant for many years to appear in immigrants in any country (Manns et al. 1996).

Children and young adults comprise <5% of cases but their disease can be severe with hypertrophy of the lymphoreticular system, bone marrow dysfunction, funginaemia, and infecting other organs, skin, bone, etc. This acute or subacute disease has high mortality if untreated and after treatment organisms may remain in lesions. Most cases are chronic and in males >30-years-old progressing slowly over months to years. Non-specific pulmonary signs occur in most, not uncommonly accompanied by other signs, most frequently oral and nasal mucosal ulcerations, skin lesions, lymph node and adrenals involvement, but occasionally these latter will be evident in the presence of a localized, asymptomatic lung lesion.

Diagnosis involves direct examination, histopathology, culture, and antibody and/or antigen detection using monoclonal antibodies to gp43 and/or gp70. Detection of antigen in CSF or BAL is more sensitive than in serum for CNS and lung disease. Radiography shows nodules, cavities and diffuse fibrotic pattern.

Treatment uses itraxonazole or amphotericin B. Trimethoprim-sulphamethoxazole, though used, seems less effective. A common sequel is fibrotic scarring particularly of the lung.

Most common in foci in mid west, south east and south central USA, New York and Canada along the Great Lakes and St Lawrence, Missouri, Mississippi, and Ohio River regions, and northern Mexico, occasional cases occur in the Pacific regions, South America, Africa, India, and the Middle East. The fungus develops in moist soil containing decaying vegetation along rivers and streams and in forests. In Canada, exposure and inhalation occurred mainly in the summer. About 50% remained asymptomatic, but a peak occurred of either localized or acute pneumonic disease in autumn or diffuse chronic pneumonia with alveolar or interstitial infiltrates and mass lesions in spring. Dissemination occurs in up to 40% of those with chronic disease with manifestation primarily in the skin as verrucose and ulcerative lesions (entry through skin breaks is possible with chancre at the inoculation site), bone, genitourinary system, but also viscera. CNS involvement is rare except in AIDS patients where meningitis and mass lesions may occur in 40% (Mason et al. 2008).

The fungus is relatively easily recovered from BAL in lung disease, histopathology is used for other tissues. The bud attachment bases are fairly characteristic. An antigen detection test is described but there is cross-reaction, particularly with H. capsulatum (Durkin et al. 2004). Antibody tests are not recommended.

Guidelines for treatment (Chapman et al. 2008) are lipid amphotericin B for moderate to severe disease lung and disseminated disease, and itraconazole for mild to moderate disease, both followed by itraconazole for 6–12 months, possibly lifelong for immunosuppressed patients.

It is not certain whether P. marneffei is saprophytic or primarily a zoonoses from mainly bamboo rats in Asia (northern India, China, Taiwan, Thailand, and Vietnam) (Vanittanakom et al. 2006). It is the third most common opportunistic infection in Thailand and presents in immigrants in non-endemic areas. Fever, skin lesions (papules with central necrosis on the head and neck and elsewhere), anaemia, weight loss, lymphadenopathy, hepatosplenomegaly, and respiratory disease may occur. The yeast can be identified in scrapings or biopsies. It cross-reacts with antibodies to Aspergillus but they can be differentiated morphologically. Serological testing has been variable and PCR has been used in endemic areas. Even when treated with amphotericin B mortality can be high.

Other dimorphic and yeast-like fungi include Sporothrix schenckii, this a complex of species, on plants and soils that enters through pricks by roses and particularly through handling sphagnum moss. Lesions develop mainly in the skin and subcutaneous tissues 3 (1–12) weeks later, though spread to the bone is possible. A painless nodule is followed by others that resemble boils and ulcerate and are slow to heal. Inhalation and disseminated infections may occur. Terbinafine, itraconazole, and potassium iodide are useful. Trichosporon spp. are very invasive with funginaemia, pulmonary, skin, visceral, and eye infections. Break though infections have been seen in those with haemotological malignancies and neutropaenia on amphotericin B, fluconazole or echinocandins. Newer triazoles show in vitro efficacy. Geotrichum spp. (=Blastoschizomyces capitatus) is rare but seen mainly in Europe though reported elsewhere. Amphotericin B and voriconazole seem drugs of choice. Rhodotorula spp. induce funginaemia, endophthalmitis, peritonitis or meningitis and are susceptible to amphotericin B and flucytosine or ravuconazole versus other triazoles and echinocandins in vitro.

Aspergillus fumigatus is a very common cause of opportunistic fungal pneumonia. Bearing conidospores with large terminal, flask-shaped vesicles with sterimata on which conidia are formed and ubiquitous in decaying material means inhalation of the conidia is very common (Segal 2009). Other species are emerging, i.e. A. flavus and A. nidulans in sinus and granulomatous disease and A. terreus is resistant to amphotericin B.

Invasive aspergillosis presents acutely in the immunocompromised and can account for 90% of fungal infections in patients with haematological malignancies, 10–20% of stem cell transplants, and is seen in neutropaenia, bone marrow failure, and other transplant immunosuppression, AIDS, etc., and occasionally post-surgery. It is suggested that fluconazole prophylaxis increases colonization and that gene changes occur making Aspergillus more virulent. Hyphal invasion of vessels produces necrosis and tissue infarction particularly in the sinuses, also eroding local bone, and pulmonary infection produces fever, cough, dyspnoea, chest pain. Progression involves the mediastinum and chest wall with possible haematogenous spread to any organ. CNS involvement may be an abscess(es), meningitis or subarachnoid haemorrhage with seizures or focal neurologic changes.

In those less severely immunosuppressed and those with pre-existing lung disease there can be a slowly progressive pneumonia, over months or years, with variable levels of necrosis or cavitation or a fungal mass (aspergilloma) occupying a pre-existing lung cavity.

In immunocompetent persons, a sinusitis or chronic asthma from a Th2 allergic bronchopulmonary responses can manifest in 1–2% of patients with asthma and 1–5% of cystic fibrosis patients. There are pulmonary infiltrates and possibly bronchiectasis.

Diagnosis still remains difficult (Maertens et al. 2009). Histologic demonstration of hyphae is useful. The septate, branched hyphae help differentiate Aspergillus from some, i.e. Zygomycetes, but not other fungi. Conidia, needing oxygen, are seen only in the lungs. Culture confirms diagnosis. Sandwich ELISA that detects fungal wall galactofuranose on galactomannan in serum or broncho-alveolar lavage (BAL) is more sensitive and specific than is EIA for glucans, though false positives with Histoplasma occur and the latter excludes Pneumocystis, Cryptococcus and the Zygomycetes. Complement fixation and immunodiffusion tests detect antibody. PCR analyses of ITS and 18S rRNA are used. Radiographs may show nodular lesions about 80% of which have a ground glass ‘halo’ sign of haemorrhagic inflammation, or cavitation, but these are not pathognomonic.

Voriconazole for CNS disease or posaconazole are first line treatments (Maertens et al. 2009). Fluconazole is not effective against moulds. Treatment failure can be high and multi-resistant Aspergillus have been described. Other treatments include liposomal amphotericin B and caspofungin. Surgical debridement or removal of localized lesions and fungal masses is important. Prophylaxis is controversial, also anti-fungals can decrease detection of galactomannan. Nonetheless, prophylactic amphotericin B decreased aspergillosis in neutropaenic patients from 14 to 4%. Oral azoles are more convenient with less nephrotoxicity; posaconazole was more efficient than fluconazole in stem cell transplant patients with GVHD and in neutropaenic patients though it did produce more adverse affects (Cornely et al. 2007).

Other filamentous fungi with septate hyphae also can be severe and fatal and are emerging causing 27% of fungal invasions in solid organ transplant patients in the USA and occurring elsewhere. Fusarium spp. are angioinvasive and tend to produce superficial or localized sinopulmonary disease in immunocompetent persons but have greater funginaemia and cutaneous manifestations than aspergillosis and also dissemination to the CNS in severely immunosuppressed and neutropaenic patients. Colonization of a hospital water system has been implicated in transmission. Relatively resistant to anti-fungals, six species were susceptible in vitro to terbinafine and one to amphotericin B. Fusarium can be fatal despite treatment related to the degree of immunosuppression and extent of invasion. Several genera of the the Zygomycetes in soil and decaying matter are pathogenic causing, depending on the group, an acute, rapid angioinvasive disease or a chronic, progressive disease. Infection occurs primarily in neutropaenic and immunosuppressed patients affecting sinuses, lungs, skin, also CNS, gastrointestinal tract, and a renal presentation. Diabetic patients are at risk. These infections have occurred as breakthrough infections in patients taking voriconazole and other anti-fungals including echinocandins. Lipid amphotericin B remains the therapy and posaconazole has been described as an effective salvage therapy though infection can be fatal despite aggressive treatment. Invasive Acremonium, Paecilomyces and Trichoderma species are resistant to amphotericin B.

More than 100 species and 60 genera of septated filamentous dematiaceous fungi, with melanin pigmented, thick walls, found in soil and decaying material, cause infections worldwide but are more common in tropical and subtropical countries (Revankar 2006). Entrance is through penetrating injury. Chromoblastomycosis in the skin and subcutaneous tissues occurs as verrucose, scaly plaques. The tuberculoid granulomata contain round sclerotic, ‘muriform’ bodies, 5–12 µm, in giant cells or microabscesses that can be revealed in scrapings and histologically. The organisms stain with Fontana-Masson for melanin and the hyphae in tissues are more fragmented than Aspergillus. Mycetoma (‘Madura foot’, fungal abscesses) is a deep infection usually of the lower extremities containing the mycotic granules. Phacohyphomycoses occurs as skin and subcutaneous cysts or abscesses containing hyphae. Pneumonia and CNS disease are uncommon but induced by some genera primarily in immunosuppressed patients. Several genera cause keratitis after trauma. Allergic sinusitis and pulmonary disease are caused by two genera. Different species and genera are resistant to amphotericin B and other anti-fungals. Surgery and newer triazoles seem effective.

Though not considered by all to be within this group as possibly not as melanized, Scedosporium apiospermum in soil and stagnant water enters a penetrating injury and causes subcutaneous mycetoma in immunocompetent patients and invades producing osteomyelitis and arthritis. It often colonizes cystic fibrosis patients. The immunosuppressed may show disseminated lung disease, multiple skin lesions, and CNS disease. This may occur early after transplant in those receiving amphotericin B or fluconazole, etc., prophylaxis. It is relatively insusceptible to most anti-fungals. New triazoles may be effective. Scedosporium prolificans, asymptomatic to invasive, also is relatively unaffected by anti-fungals. Surgery, immunotherapy and voriconazole or itraconazole plus terbinafine have been effective.