Paragonimus species (Paragonimiasis)

Human paragonimiasis is a chronic and debilitating parasitic disease caused by the lung flukes of the genus Paragonimus. Lung flukes are hermaphroditic trematodes. More than 50 species have been described (9). Several species have been reported in humans, including species of the Paragonimus westermani and P. skrjabini complex, P. africanus, P. caliensis, P. heterotremus, P. hueitungensis, >P. kellicotti, P. mexicanus, P. miyazakii P. siamensis, and P. uterobilateralis (5, 21). >P. kellicotti is the only species native to North America, P. caliensis and P. mexicanus occur in Central and South America and P. africanus and P. uterobilateralis have been described from West Africa. P. heterotremus, P. hueitungensis P. miyazakii, P. skrjabiniP. westermani are endemic in Asia (11). Human Paragonimus spp. may also be prevalent in wild feline reservoir hosts or in household pets (mainly cats and dogs). An infection with Paragonimus spp. occurs through the ingestion of raw or insufficiently cooked freshwater crabs or crayfish infected with metacercariae. Wild boar can act as paratenic hosts and humans become infected after eating uncooked wild boar meat (5). Parasite eggs, produced by the adult worms in the lungs of the final host, are released via sputum and / or feces. Eggs which encounter suitable environmental conditions for embryonation develop into miracidia. Miracidia penetrate the intermediate host snails, mainly species of Thiaridae and Pleuroceridae. After a complex process of multiplication and different developmental steps, cercariae are released, which infect the second intermediate crustacean hosts (5, 34).

Epidemiology

An estimated 293 million people are at risk of paragonimiasis, with two-third of them (195 million) concentrated in the People's Republic of China (20), Paragonimiasis also occurs in other Asian countries such as Japan, the Republic of Korea, the Philippines, Lao People's Democratic Republic (Lao PDR), Thailand and Vietnam, eastern Nigeria, southwestern Cameroon, and other parts of West Africa (1), and in the Americas, such as Brazil, Colombia, Ecuador >(7)>, and Peru. More than 23 million people are infected, causing a global burden of 196,710 disability-adjusted life years (DALYs) (12).

The habit of eating freshwater crab or crayfish raw or inadequately cooked is the key risk factor of acquiring a Paragonimus infection. Traditional dishes, such as "drunken crab" (live crabs immersed in wine for at least 12 hours), raw crab sauce or jam, and crayfish curd are common in the People's Republic of China. Moreover, raw juice and meat of crab or crayfish is used in traditional medicine treating measles and episodes of fever and diarrhea. In the People's Republic of China, marinated crabs are consumed to relieve back pain. In Africa, there is a local custom of eating raw crustaceans as it is believed to enhance fertility. In Latin America, "ceviche" (chunks of raw fish and crabs immersed in citrus juice) is a very popular traditional dish. Another source of infection is contamination of utensils and chopping blocks during food preparation (5).

The ecologic requirements of the first and second intermediate hosts, in combination with the presence of the reservoir hosts and the widespread habit of the local population to consume raw or insufficiently cooked crab and crayfish govern the focal transmission of paragonimiasis and explain patchy distribution patterns of the disease (21). The true extent of animal reservoir hosts for human infection is not known. But in many area paragonimiasis must be considered as zoonosis.

Clinical Manifestations

The lung is the target organ, although ectopic infections such as abdominal, cerebral, and spinal paragonimiasis have also been described 26). In light infections, most individuals are asymptomatic. Patients may present with only mild symptoms and appear well despite heavy infection intensity and severe pathological findings.

Pulmonary Paragonimiasis: Clinical manifestations depend on the stage of infection. Indeed, while pleurisy is found in the early stage, parenchymal lesions of the lung are seen in the later stage (39). Pleural effusions typically occur early during infection as the flukes migrate into the pleural cavity. The prevalence of pleural effusions in patients with pulmonary paragonimiasis varies from 2% to 54% (15, 17). Although illness typically does not occur until the parasite has settled in the lung, an acute illness may develop within the first few weeks of infection (characterized by abdominal pain, diarrhea, fever, urticaria, and peripheral blood eosinophilia). Once penetration of the diaphragm and migration into the pleural cavity has occurred (2 to 8 weeks postinfection), patients may have pleuritic chest pain, which is often bilateral. Migration of the parasite into the lung parenchyma results in an irritating cough, chest pain, and general malaise (less common symptoms during this stage of infection include low grade fever and blood-streaked sputum). As pulmonary parenchymal involvement occurs, leukocytosis and prominent blood eosinophilia are commonly seen. Additionally, pulmonary eosinophilia may commonly be seen. Eosinophilic pneumonia should prompt an in-depth investigation for parasitic causes (i.e. Ascaris lumbricoides, hookworm, filarial disease, Paragonimus spp., Strongyloides stercoralis, visceral larva migrans), other infectious causes (e.g. Paracoccidioides braziliensis) and non-infectious causes (e.g. drugs) (2). Once mature flukes have inhabited the lung (in the absence of treatment, this stage of infection may persist for 20 years in humans), the most common complaint is recurrent hemoptysis with chocolate-colored sputum (which is a mixture of blood, inflammatory cells, and Paragonimus eggs) and a chronic cough. Pulmonary tuberculosis is the most important differential diagnosis. However, paragonimiasis should always be ruled out in individuals from endemic areas who present with hemoptysis and negative diagnostic tests for pulmonary tuberculosis. Moreover, it should be noted that ~20% of Paragonimus infections are asymptomatic. Despite recurrent hemoptysis, patients often feel well with fever and severe weight loss generally being absent (3).

Radiographic findings correlate well with the stage of the disease (17, 41). However, chest radiography findings may be normal in 12.8% to 20% of patients with confirmed paragonimiasis (38). The penetration of juvenile worms through the diaphragm into the pleural cavity can cause pleural effusion or pneumothorax. Once the parasites reach the lung, patchy airspace consolidation can occur, a phenomenon that reflects the presence of an exudative or hemorrhagic pneumonia which can cavitate. Contrast material-enhanced computer tomography (CT) performed during this stage may show hypoattenuating fluid-filled cysts (5-15 mm) surrounded by hyperattenuating consolidation in the adjacent lung. Linear areas of increased opacity or hyperattenuation indicate peripheral atelectasis or worm migration. Worm cysts, whose diameters range from 0.5 cm to 1.5 cm, are better visualized after the consolidation resolves and manifest as either solitary or multiple nodules or gas-filled cysts depending on their content and their communication with the airway. Chest radiographic and CT findings include a ring shadow usually less than 3 mm thick and a crescent-shaped area of increased opacity or hyperattenuation within the cyst that represents worms attached to the wall. Complications of cysts include pleural effusion, empyema, and pneumothorax (14, 15, 17, 29, 30, 42). Clinical and radiographic findings may resemble those of lung cancer (having high fluorodeoxyglucose uptake on positron emission tomography (PET) with 18-fluorodeoxyglucose) (16, 22, 45), tuberculosis 16 mesothelioma, or metastatic malignancy (27).

Cerebral Paragonimiasis: Central nervous system (CNS) involvement, caused by aberrant migration of juvenile flukes through the foramina of the skull (commonly via the jugular foramen) has been estimated to occur in 0.8% of all cases of paragonimiasis (8). However, it is the most common extrapulmonary (ectopic) manifestation and accounts for up to 25% of all paragonimiasis-related hospitalizations (23). Up to 10 round or oval cysts are found in the temporal and occipital lobes, near the jugular foramen. It is rare for cerebral symptoms to occur without evidence of chest disease and, in the majority of cases (70%), pulmonary symptoms occur first (14). CNS involvement may manifest as: (i) space-occupying lesions, (ii) hemiplegia, (iii) seizure (late onset epilepsy), (iv) visual impairment, or (v) eosinophilic meningitis. With progression, patients may have papilledema, facial palsy, hemiplegia, paraplegia, seizures, and coma. Death may occur during the acute attack (26). Cerebrospinal fluid pleocytosis with high eosinophil count is common.

Whenever high eosinophil counts are encountered in patients presenting with meningitis (eosinophilic meningitis), infectious causes need to be considered. Parasites are most common etiological entity and the differential diagnosis includes Angiostrongylus cantonensis, Bayliscaris procyonis, Gnathostoma spp., Paragonimus spp., Toxocara spp. and amebic encephalitis (e.g. due to Balamuthia mandrillaris, Naegleria spp.). Further causes include fungal pathogens (e.g. Coccidioides immitis) and non-infectious etiologies (e.g. hematologic malignancies) (32).

CT and magnetic resonance imaging (MRI) in early disease show characteristic grape-like clusters of ring-enhancing lesions with surrounding edema. Chronic disease produces soap-bubble calcifications that are highly specific for cerebral paragonimiasis (14). Definitive diagnosis is made by the finding of characteristic operculated ova in cerebral specimens.

Abdominal Paragonimiasis: Symptoms include abdominal pain, bloody diarrhea, palpable nodules, and may appear several days after consumption of the infected intermediate hosts. Later, abscess formation in the liver, spleen, and abdominal cavity may occur. The unspecificity of some of these symptoms renders differential diagnosis difficult.

Spinal Paragonimiasis: Numbness and weakness of the legs, paravertebral pain, urinary difficulty, and motor disturbance in the lower extremities have been described.

Migratory Subcutaneous Paragonimiasis: Migratory subcutaneous nodules occur in 10% of cases with paragonimiasis. The most common sites are the lower abdomen, inguinal region, and thigh.Vesical paragonimiasis, in which parasite eggs can be localized in the bladder, was recently described as an extremely rare manifestation of extrapulmonary disease (52).

Laboratory Diagnosis

The diagnosis of paragonimiasis may be challenging, as most symptoms, radiographic abnormalities, and laboratory findings are nonspecific (5, 18, 25). Prominent leukocytosis with eosinophilia occurs during early pulmonary parenchymal involvement but later resolves or is minimal. Definitive diagnosis is achieved by detecting parasite eggs in the sputum, pleural fluid, tissue specimens (e.g. of the brain) or feces; but requires well-trained microscopists (4). Additionally, larvae can often be found at bronchial brushing. Parasite egg detection rates in sputum or bronchoscopic aspirates are about 50% (39) and 24-hour sputum collection enhances the sensitivity of egg detection. It is important to note that Ziehl-Neelsen staining or modified acid-fast staining techniques (e.g., Kinyoun stain), that are commonly employed for the microscopic diagnosis of pulmonary tuberculosis, also have a high sensitivity for detection of Paragonimus eggs in sputum samples (36). Transbronchial biopsies may also confirm the diagnosis. Pleural effusions are exudative and laden with eosinophils.

Eosinophilia and/or an elevated serum IgE level are commonly seen in paragonimiasis patients. Indeed, about 80% of patients with paragonimiasis have eosinophilia or elevated serum IgE level. Therefore, paragonimiasis should always be included in the differential diagnosis for patients having lung lesions associated with eosinophilia and/or elevated serum IgE level, especially for those living in endemic areas.

Enzyme-linked immunosorbent assay (ELISA) and immunoblot serologic tests are also available and can point to the diagnosis (35). However, cross-reactivity with other Paragonimus species is variable; thus negative serology does not completely rule out Paragonimus infection. Likewise, a positive serology does not definitely diagnose infection with the P. westermani species; rather, it confirms infection with one of many Paragonimus species (5). Most cases have negative seroconversion 6 months after treatment. Intradermal skin tests have been utilized for epidemiologic surveys but are no longer popular since novel techniques have become available (5). More advanced serological tests, which are currently being researched, include a colloidal gold immunochromatographic strip for detection of P. skrjabini infections (44), and protein microarray for the rapid, sensitive, and high-throughput diagnosis of disease specific antibodies of paragonimiasis and other helminth infections (10). In recent years, different molecular techniques have been developed to diagnose an infection with Paragonimus spp., such as a real-time fluorescence resonance energy transfer polymerase chain reaction (PCR) technique (37).

Pathogenesis

Within the lung, which is the main habitat of adult Paragonimus flukes, the parasites form areas of inflammation surrounded by eosinophils, neutrophils, and later mononuclear leukocytes. Local necrosis occurs, with formation of a thin layer of fibrous tissue. Within this fibrous capsule, the flukes mature and begin egg production, typically 8 weeks post infection.

SUSCEPTIBILTY IN VITRO AND IN VIVO

No recent in vitro and in vivo chemotherapeutic studies have been carried out with Paragonimus spp. In the late 1970s and early 1980s bithionol, menichlopholan, and the current drug of choice – praziquantel – were studied against P. westermani, P. ohirai, and P. miyazakii (13, 28, 51).

ANTIPARASITIC THERAPY

Drug of Choice

Praziquantel (25 mg/kg tid for 2 days) is the drug of choice for paragonimiasis (21, 46). Praziquantel is a heterocyclic azoquinoline compound that is effective against pulmonary paragonimiasis and all forms of ectopic infections. The mechanism of action is not known, but it has been suggested that praziquantel causes a rapid increase in permeability of the worm musculature to mono- and divalent cations, especially Ca²⁺. A massive influx of Ca²⁺ results in muscle contraction, which occurs within 10-20 seconds and leads to spastic paralysis of the flukes. Adverse events are usually mild and transient and may include abdominal pain, headache, general malaise, fever, and dizziness. Rarely, severe anaphylactic reactions have been described. However, desensitization to praziquantel and subsequent treatment with this drug may still be considered in such cases if no alternative treatment options are available (24).

Alternative Therapy

Bithionol (Bitin, Actamer), 2, 2, 2'-thiobis (4, 6-dichlorophenol), is rarely used today; 30 to 50 mg/kg given orally on alternate days for 10 to 15 doses have been recommended.

Triclabendazole, a benzimidazole fasciocidal drug, is effective in treating paragonimiasis. The action of triclabendazole is mediated through its active metabolite, TCBZ-SO, a sulphoxide derivative. Food does not interfere with, but conversely enhances systemic absorption of triclabendazole. Triclabendazole has been shown to have a better clinical tolerance, a more rapid parasitologic response, and comparable resolution of clinical symptoms when compared to treatment with praziquantel (6). Single doses of 10 mg/kg and two doses of each 10 mg/kg in a single day have been used (19). At present, triclabendazole is registered for human use in only four countries (Egypt, France, Islamic Republic of Iran, and Venezuela), none of which is endemic for paragonimiasis.

Mefloquine, an anti-malarial drug, has not been used to treat human paragonimiasis. However, preliminary studies in dogs showed a significant reduction of the mean worm burden if mefloquine 50 mg/kg daily for 5 days was administered (49).

ADJUNCTIVE THERAPY

Corticosteroids

Unlike adjunctive treatment for neurocysticercosis in which corticosteroids are introduced to reduce mounting cerebral inflammation in response to cysticercus larva lysis after antiparasitic treatment, there are no convincing data to support the benefit of corticosteroids used as adjunctive therapy for cerebral paragonimiasis.

Surgery

Surgery plays a diagnostic rather than therapeutic role in paragonimiasis, especially abdominal paragonimiasis whose clinical manifestation can mimic tumor, thus requiring a definite tissue diagnosis (48).

Pleural Drainage

Pleural effusions in pulmonary paragonimiasis have good clinical response to antiparasitic treatment and the resolution of pleural fluid occurs within weeks. However, a large amount of pleural effusion, particularly chylothorax, can cause shortness of breath, so intermittent thoracocentesis may be required for relieving chest symptoms.

ENDPOINTS FOR MONITORING THERAPY

After treatment, paragonimiasis symptoms improve rapidly and disappear within a few months. Eggs are cleared from the sputum within a few weeks, while resolution of radiographic pulmonary abnormalities takes months (41). There are few data about the clinical course of the resolution of cerebral paragonimiasis. The CT findings of chronic cerebral paragonimiasis are multiple nodular calcifications surrounded by low attenuation area, cortical atrophy and ventricular dilatation (40). Recent studies suggest that complete resolution of pulmonary morbidity is not achieved in all individuals (43).

VACCINES

Vaccines for Paragonimus infection are currently not available.

PREVENTION OR INFECTION CONTROL MEASURES

Since paragonimiasis is closely associated with deeply rooted traditions and human behavior (i.e. consumption of raw or insufficiently cooked freshwater crabs and crayfish), ecologic features, and socioeconomic status, supportive control measures, such as information, education, and communication (IEC) strategies, stressing the importance of adequately cooking crustaceans as well as sanitation improvement have been shown to be effective preventive measures. These measures in combination with preventive chemotherapy using praziquantel (47) are adequate in settings where paragonimiasis cases have been confirmed (50). However, the effectiveness of this community intervention has not yet been documented. Community diagnosis tools such as lay-informant questionnaire or routine direct examination of sputum in tuberculosis programs have been suggested as low-cost, non-invasive means for rapid identification of high-risk communities (31) in endemic countries.

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