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Paragonimus (Pathogen – Lung Trematodes)

Organism:
Paragonimiasis is a disease of humans and carnivores in which adult flukes of the genus Paragonimus are found in the lungs. Naterer first detected the lung fluke in 1828; however, Kerbert detected flukes in the lungs of a Bengal tiger in 1878 and named the worms Distoma westermani, after the director of the Amsterdam Zoo, Westerman. Both Manson and von Baelz in 1880 reported finding eggs in the sputum of humans, and Yokogawa in 1915 and Nakagawai in 1916 completely described the life cycle. Since 1899, the name Paragonimus westermani has been used. P. mexicanus is an important human pathogen in Central and South America, while P. kellicotti infections are found in North and South America. Most paragonimiasis infections are caused by P. westermani, which is the focus of this section 

Paragonimus spp. eggs (operculated)  
Diphyllobothrium latum egg (operculated)
Adult worm   Blue crab intermediate host
Adult worms in the lung

                                                      


Life Cycle:
The adult worm is a plump, ovoid, reddish brown fluke found encapsulated in the lung. Eggs deposited by the worms are ovoid, brownish yellow, unembryonated, and thick shelled, with an operculum at one end and opercular shoulders. The eggs measure 80 to 120 μm by 45 to 65 μm. P. westermani eggs are often confused with Diphyllobothrium eggs because they are operculated, unembryonated, and somewhat similar in size. However, unlike Diphyllobothrium eggs, P. westermani eggs have opercular shoulders and a thickened shell at the abopercular end. Eggs escape from the encapsulated tissue through the bronchioles, are coughed up and voided in the sputum, or are swallowed and passed out in the feces. The eggs hatch in the water in 2 to 3 weeks, releasing a miracidium to infect a susceptible snail host. Cercariae are released after sporocyst and redia generations. Crabs and crayfish are infected by cercariae via the gill chamber or upon ingestion of an infected snail. Cercariae encyst in the gill vessels and muscles. Humans are infected by ingesting uncooked crabs or crayfish containing metacercariae. The metacercariae excyst in the duodenum and migrate through the intestinal wall into the abdominal cavity. The larvae migrate around or through the diaphragm into the pleural cavity and the lungs. The larvae mature to adults in the vicinity of the bronchioles, where they discharge their eggs into the bronchial secretions. Although these worms are hermaphroditic, two worms are usually required for fertilization to occur.  The worms can live as long at 20 years, but most will die after about 6 years.

Acquired:
Although we generally think of infected raw crabs or crayfish as the most common sources of infection, a number of other foods and cultural practices can be implicated as well, including the ingestion of metacercariae in the flesh of paratenic hosts. 

Epidemiology:
There are approximately 200 million people at risk and 22 million people with paragonimiasis worldwide, and 10 species are recognized as causing human disease. P. westermani is the most common human pathogen.  Reservoir hosts include dogs and cats in areas of endemic infection (the Far East and Africa). Eggs expectorated or passed in the feces in the vicinity of lakes or streams where the intermediate hosts live serve as the source of infection. Snail intermediate hosts include Semisulcospira and Brotia spp. In Ecuador, the intermediate host for P. mexicanus is Aroapyrgus sp., a freshwater snail belonging to the family Hydrobiidae. Humans contract the infection through ingestion of raw, undercooked, pickled, or wine‑soaked crabs or crayfish; they may also become infected by the ingestion of uncooked meat from wild animals, such as wild boar. The migrating larvae in this meat may pass through the intestinal wall and continue their developmental cycle when eaten. Raw juice from crushed crayfish used as a home remedy for the treatment of measles has been a significant source of infection and may be a cause of cerebral paragonimiasis in children.

Clinical Features:
Migration of the larval forms through the intestinal wall into the abdominal cavity is generally not associated with any significant pathologic changes or symptoms. If the larvae remain in the abdomen, some patients may have abdominal pain, intra-abdominal masses, tenderness, fever, diarrhea, nausea, vomiting, and eosinophilia. Once the larvae have reached the peritoneal cavity, they begin to migrate through organs and tissues, producing localized hemorrhage and leukocytic infiltrates.  Symptoms of paragonimiasis depend largely on the worm burden of the host and are usually insidious in onset and mild in patients with chronic infections. Light infections may be asymptomatic, although peripheral blood eosinophilia and lung lesions may be noted on X‑ray examination. As the cysts rupture, a cough develops with increased production of viscous blood‑tinged sputum (rusty sputum, which may have a foul fish odor) and increasing chest pain. The patient may experience increasing dyspnea with chronic bronchitis and be misdiagnosed as having tuberculosis or bronchial asthma. The individual will generally have a moderately high peripheral blood eosinophilia and leukocytosis with elevated levels of IgG and IgE in serum.  Although some patients will exhibit symptoms continuously, others may remain asymptomatic for weeks to months between periods of hemoptysis.
Pulmonary Disease.  When the worms finally reach the lungs and mature, a pronounced tissue reaction occurs with infiltration of eosinophils and neutrophils. A fibrotic capsule forms around the worm. The cysts contain purulent fluid with flecks or "iron filings" composed of brownish yellow eggs. Many of the cysts perforate into the bronchioles, releasing their contents of eggs, necrotic debris, metabolic by‑products, and blood into the respiratory tract. The eggs may also enter the pulmonary tissue, or they may be carried by the circulatory system to other body sites, where they cause a granulomatous reaction.
Cerebral Disease.  Larval forms may end up in many ectopic sites other than the lungs; ectopic infections are generally associated with P. heterotrema, P. mexicanus, and occasionally P. westermani. Cysts have been detected in the liver, intestinal wall, muscles, peritoneum, and brain. The most serious consequence of paragonimiasis consists of the cerebral complications, which are commonly found in younger age groups. Unlike adult flukes in other extrapulmonary sites, worms found in the brain usually contain eggs.  The worms probably migrate from ruptured lung cysts and travel through the soft tissues surrounding veins into the brain area.  The worms eventually encapsulate, but before being walled off, they cause necrosis within the brain tissue, as well as possible cerebral hemorrhage, edema, and meningitis.  Most patients with cerebral or other extrapulmonary lesions have an associated lung lesion or a history of lung disease. Symptoms include fever, headache, nausea, vomiting, visual disturbances, motor weakness, localized or generalized paralysis, and possibly death.  More than half of these patients will also exhibit personality changes, possible disorientation, and a general decline in cognitive function.  Depending on the CNS location, symptoms may also include paraplegia, sensory loss, or vision problems.  Specific sites can include the cerebral cortex, cerebellum, basal ganglia, and medulla oblongata, and the spinal cord. When a worm dies, the lesion cavity becomes filled with necrotic material.  Cerebral paragonimiasis can be difficult to differentiate from brain disease caused by other parasites such as Schistosoma japonicum, Gnathostoma spinigerum, or Angiostrongylus cantonensis, as well as other infectious agents such as bacteria or viruses. 
Paragonimiasis in Other Body Sites.  Abdominal or subcutaneous masses are frequently seen in infections caused by P. skrjabini, P. heterotremus, P. hueitungensis, and P. mexicanus.  Migratory subcutaneous nodules can occur in 20 to 60% of patients with P. skrjabini infection and approximately 10% of patients with P. westermani infection.  The nodules are firm, tender, a few millimeters to 10 cm, and somewhat irritating.  They are often located in the lower abdomen, inguinal region, and thigh and are somewhat mobile.  Ulcers or abscesses can also occur in skin or subcutaneous tissue.  Involvement of the mastoid area has been seen in P. africanus infections.  Other body sites that have been infected include the breast, lymph nodes, heart, pericardium, mediastinum, kidney, adrenal gland, omentum, bone marrow, stomach wall, bladder, spleen, pancreas, and reproductive organs.   While ectopic lesions are usually thought to be caused by worm migration, dissemination of eggs to other body sites can also be responsible for pathology.
In China, P. skrjabini does not develop to the adult worm stage, but the disease is characterized by the presence of trematode larva migrans.  These migratory subcutaneous nodules are associated with a high eosinophilia, as well as necrotic liver lesions.  Brain involvement is common and is associated with subarachnoid hemorrhage. 

Clinical Specimen:
Stool:  Confirmation of the infection depends on finding the operculated eggs in a routine stool examination; multiple stool examination may be required to find the eggs.

Sputum:  Confirmation of the infection depends on finding the operculated eggs in a routine examination; they groups of eggs will resemble iron filings.  Egg morphology can be seen using the high dry objective (magnification of 400).

Laboratory Diagnosis:
Stool and Sputum:  Individuals with symptoms of chronic cough, vague chest pains, and hemoptysis who have resided in an area where infections are endemic and have a history of eating raw crayfish or crabs should be suspected of having paragonimiasis. Paragonimus eggs can be detected in the sputum and the stool, and concomitant examinations should be performed to improve the overall detection rate. In many individuals in whom the infection is eventually confirmed, small numbers of eggs are present intermittently in the sputum and feces. For patients with light infections, up to seven sputum examinations have been recommended. Frequently, pulmonary paragonimiasis is misdiagnosed as pulmonary tuberculosis. The Ziehl‑Neelsen method for detecting mycobacteria destroys Paragonimus eggs.  It is important to remember that the typical findings of cough, hemoptysis, and eggs in the feces or sputum may be absent in patients with ectopic or pleural infection with Paragonimus spp. 
Serum: In addition to the methods described in the Introduction, immunodiagnostic tests have been used to diagnose pulmonary and extrapulmonary infections. Complement fixation has been used to diagnose active infections; however, the test becomes negative soon after the death of the worms. An immunoblot test for the detection of antibodies to P. westermani by using adult worm homogenates is highly sensitive and specific. Only one false‑positive result was detected by this method, in a patient with a Schistosoma haematobium infection. ELISA with adult excretory‑secretory antigens is very sensitive for detecting parasite‑specific IgG and IgE. Pleural effusion fluid is more suitable than serum for detection of infections. Dot ELISA has also been used to detect parasite‑specific antigen in human sera. Monoclonal antibodies to detect species‑specific and stage‑specific antigens are highly sensitive and specific for the detection of active infections (56). The serologic assays are available in areas of endemicity or in specialized diagnostic centers. Most of these assays involve nonstandardized reagents and have not been used in clinical trials.
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Organism Description:
Egg:     The eggs are unembryonated, operculated, large, ovoid, and measure 80 to 120 μm by 45 to 65 μm. Paragonimus eggs may be confused with Diphyllobothrium latum eggs because of similarities in their size and shape.  However, most Paragonimus eggs have opercular shoulders and a marked thickening at the abopercular end, unlike D. latum eggs.

Laboratory Report:
Paragonimus spp.eggs recovered

Treatment:
The drug of choice is praziquantel at 25 mg/kg three times at 4‑h intervals after meals for 2 or 3 days.  Very few patients will require retreatment; 100% cure is usually obtained with the exception of certain patients with a heavy worm burden.  There is dramatic improvement in symptoms, and they are usually gone within a few months.  The dose required in cerebral paragonimiasis is generally higher and may need to be adjusted relative to the clinical outcome; convulsions and coma have been seen.  These patients should be hospitalized for therapy and should be monitored closely; corticosteroids may also have to be given when treating with praziquantel.  Bithionol is an alternative drug, which is available under an Investigational New Drug (IND) protocol from the CDC Drug Service, Centers for Disease Control and Prevention (Med Letter).
Triclabendazole at 10 mg/kg as a single dose or two doses is also recommended, but this dose may not be as easy to obtain. Patients should be examined at three months to determine the need for retreatment.  If a single dose has failed, the use of 20 mg/kg triclabendazole is recommended.  Triclabendazole is not currently available in the United States unless possibly available through a compounding pharmacy (Med Letter).
Pulmonary paragonimiasis is rarely fatal; however, cerebral disease is characterized by chronic morbidity and symptoms including epilepsy, dementia, and other neurologic sequelae.  About 5% of patients with cerebral disease will die due to hemorrhage in the first 2 years of the disease.
Garcia, L.S. 2007.  Diagnostic Medical Parasitology, 5th ed., ASM Press, Washington, D.C.

Control:
Measures devoted to public health education, warning people of the dangers of eating uncooked crabs or crayfish from areas of endemic infection, and sanitary care of utensils and fingers used to prepare food would reduce the risk of infection. Because the cycle depends on animals, the elimination of human paragonimiasis would have little effect on the overall prevalence of the disease.