Paragonimiasis Acquired in the United States: Native and Nonnative Species

Abstract

SUMMARY

Paragonimiasis is a parasitic lung infection caused by lung flukes of the genus Paragonimus, with most cases reported from Asia and caused by P. westermani following consumption of raw or undercooked crustaceans. With the exception of imported P. westermani cases in immigrants, in travelers returning from areas of disease endemicity, and in clusters of acquired cases following consumption of imported Asian crabs, human paragonimiasis caused by native lung flukes is rarely described in the United States, which has only one indigenous species of lung fluke, Paragonimus kellicotti. Clinicians should inquire about the consumption of raw or undercooked freshwater crabs by immigrants, expatriates, and returning travelers, and the consumption of raw or undercooked crayfish in U.S. freshwater river systems where P. kellicotti is endemic when evaluating patients presenting with unexplained fever, cough, rales, hemoptysis, pleural effusions, and peripheral eosinophilia. Diagnostic evaluation by specific parasitological, radiological, serological, and molecular methods will be required in order to differentiate paragonimiasis from tuberculosis, which is not uncommon in recent Asian immigrants. All cases of imported and locally acquired paragonimiasis will require treatment with oral praziquantel to avoid any potential pulmonary and cerebral complications of paragonimiasis, some of which may require surgical interventions.

INTRODUCTION

The trematode parasites include the blood flukes or schistosomes, the intestinal and liver flukes, and the lung flukes of a single genus, Paragonimus, with over 30 species distributed worldwide. Human paragonimiasis is a parasitic infection, primarily of the lungs and pleurae, caused by at least 10 species of lung flukes (Table 1) (1, 2). Most cases of paragonimiasis occur throughout eastern (China, Japan, Philippines, South Korea, and Taiwan), southeastern (Laos, Thailand, and Vietnam), and southwestern (China) Asia and are caused by Paragonimus westermani, the Asian lung fluke, and other indigenous Paragonimus species following consumption of raw, undercooked, or alcohol-pickled freshwater crabs or crayfish harboring the infective-stage metacercariae (1, 2). Some immunodiagnostic tests for paragonimiasis continue to rely on cross-reactive antibodies to P. westermani antigens for serological confirmation of paragonimiasis by related species.

Table 1.

Predominant Paragonimus species lung flukes capable of causing human paragonimiasis and their geographic regions of distribution

Paragonimus species	Geographic distribution
P. africanus	West Africa
P. caliensis	Central America, South America
P. heterotremus	Southeast Asia, Thailand, China
P. hueitungensis	China
P. kellicotti	North America
P. mexicanus	Central America, South America
P. miyazakii	Japan
P. skrjabini	Southeast Asia, China
P. uterobilateralis	West Africa
P. westermani	Asia

With the exception of imported P. westermani cases in immigrants, expatriates, and returning travelers and acquired cases following consumption of imported Asian crabs in the United States, paragonimiasis is rarely described in the United States, which has only one indigenous lung fluke, Paragonimus kellicotti. In the United States, P. kellicotti is found living in a broad range of mammalian hosts mainly in the midwestern and southern United States within the Mississippi River Basin. Most cases of autochthonous paragonimiasis in the United States caused by native P. kellicotti flukes are transmitted by the ingestion of raw or undercooked crayfish, the preferred crustacean intermediate hosts for P. kellicotti (1–3). The U.S. regional distribution of P. kellicotti-caused paragonimiasis cases is depicted in Fig. 1.

Fig 1.

Regional U.S. distribution of cases of paragonimiasis caused by Paragonimus kellicotti, the American lung fluke, with all cases reported from the Mississippi River Drainage Basin.

This review describes and compares paragonimiasis cases in the United States caused by native and nonnative Paragonimus species in order to detect any differences in risk factors for infection, to describe any differences in presenting clinical and radiographic manifestations, and to recommend disease control and prevention strategies.

HISTORY OF PARAGONIMIASIS

Although Naterer first detected lung flukes in 1828, Paragonimus westermani infection was first described in 1878, by Coenraad Kerbert, in a Bengal tiger with pneumonia at the Amsterdam Zoo (1, 4). The species was named for the tiger's zookeeper, C. F. Westerman (1, 4). B. S. Ringer made the first diagnosis of human paragonimiasis in 1879 by identifying parasites in the lungs (4). In 1880, Patrick Manson and Erwin von Baetz independently identified Paragonimus eggs in sputum, which remains a highly specific, but less sensitive, microscopic method for diagnostic confirmation of paragonimiasis (4, 5).

The only North American species, P. kellicotti, was first described in domestic animals in the United States in 1894, in Ohio in a dog by Kellicott and in Michigan in a cat by Ward (6, 7). In 1910, Abend described the first case of human paragonimiasis caused by P. kellicotti in the United States (8). Prior to 1984, human paragonimiasis was rarely described in North America outside imported cases of P. westermani paragonimiasis in travelers returning from regions of endemicity in Asia (1).

LIFE CYCLE OF PARAGONIMUS SPECIES

Paragonimiasis results from a parenchymal and/or pleural parasitic lung infection caused by invertebrate flatworms (class Trematoda) from a single genus, Paragonimus, with many species collectively known as lung flukes. Traditionally, P. westermani and other Asian species have been collectively referred to as Asian lung flukes, and P. kellicotti and Latin American species have been called American lung flukes. Although related taxonomically to other flukes in the class Trematoda (intestinal flukes, liver flukes, and blood flukes or schistosomes), lung flukes have a unique tropism in their definitive hosts, including humans, for encysting within the pleurae and lungs and, less often, in ectopic sites in subcutaneous tissues (trematode larva migrans), abdominal wall, mesentery and visceral organs, and brain (cerebral paragonimiasis). Adults will typically encapsulate as pairs within the parenchyma or on the pleural surfaces of the lungs. The adult flukes are large (7.5 to 12 mm by 4 to 6 mm), ovoid in shape, and hermaphroditic with lobed ovaries anterior to 2 branched testes (Fig. 2) (9). Although self-fertilization is possible in hermaphrodites, cross-fertilization in lung or pleura-encysted pairs results in the production of thick-shelled, golden brown, unembryonated eggs (80 to 120 μm by 45 to 70 μm) which are released into bronchioles, coughed up, mixed with sputum, and either expectorated or swallowed for later release in feces (Fig. 3 and 4) (9). The microscopic identification of unembryonated, operculated eggs with thick shell walls in sputum or, less commonly, in feces provides very specific confirmation of paragonimiasis, but this is less sensitive than immunodiagnostic tests and may be negative in pleural and ectopic infections (1, 9; www.parasitesinhumans.org/paragonimus-westermani-lung-fluke.html).

Fig 2.

P. westermani adult taken from a lung biopsy specimen, stained with hematoxylin and eosin (H&E). (Reprinted from an image from DPDx/CDC.)

Fig 3.

Unembryonated P. kellicotti egg in bronchial alveolar lavage (BAL) fluid specimen. Magnification, ×1,000; oil immersion. (Reprinted from an image from DPDx/CDC [courtesy of Gary Procop].)

Fig 4.

Unembryonated P. westermani egg in fecal wet mount. Note the operculum at the larger end. (Reprinted from an image from CDC/Mae Melvin.)

Paragonimus species exhibit a circuitous life cycle that requires two specific and sequential intermediate hosts before infection of one of many definitive mammalian hosts for maintenance in nature (Fig. 5). The life cycle begins as unembryonated eggs are passed from mammalian reservoir hosts in sputum or feces into freshwater ecosystems to embryonate into ciliated miracidia which invade the soft parts of freshwater snails, the molluscan first intermediate hosts (10). Following two asexual reproductive cycles (the sporocyst stage and 2 redial stages), snails release infective cercariae, equipped with tails and anterior stylets, into freshwater to seek and penetrate the gills and other vulnerable, soft tissue sites on the exoskeletons of freshwater crustaceans, the second intermediate hosts (10).

Fig 5.

The life cycle of the lung fluke, Paragonimus kellicotti, the causative agent of North American paragonimiasis, is similar to the life cycle of Paragonimus westermani, the causative agent of Asian paragonimiasis. All Paragonimus species exhibit the same complex life cycle, which requires 2 sequential intermediate transport hosts, a freshwater snail and a crustacean, to deliver infective metacercariae to mammalian reservoir hosts, including humans. (Adapted from an image from DPDx/CDC.)

In Asia and other tropical areas where P. westermani is endemic, the preferred first intermediate hosts are freshwater snails from the genera Brotia, Melanoides, Semisulcospira, Tarebia, and Thiara (Fig. 6) (10). Throughout Asia, Africa, and South America, the preferred crustacean second intermediate hosts for endemic Paragonimus species are freshwater crabs from the genera Eriocheir, Potamon, and Potamiscus, all of which are locally consumed by humans and may carry infective-stage metacercariae (Fig. 7) (10; www.parasitesinhumans.org/paragonimus-westermani-lung-fluke.html). As noted, the crustacean intermediate hosts are penetrated at vulnerable sites by cercariae which encyst and develop into metacercariae within viscera, gills, muscles, and legs (10). Freshwater crab second intermediate hosts may also acquire infection by eating infected snails (10).

Fig 6.

Semisulcospira kurodai freshwater snail. Semisulcospira freshwater species snails are the preferred first intermediate hosts for Paragonimus westermani throughout Asia, Africa, and South America. (Reprinted from an image from KENPEI, under a Creative Commons license.)

Fig 7.

Asian freshwater crab species, a preferred second intermediate crustacean host for Paragonimus westermani throughout Asia. (Reprinted from an image from DPDx/CDC.)

In North America, the preferred molluscan first intermediate host for P. kellicotti is Pomatiopsis lapidaria, or the slender walker snail, an amphibious freshwater snail that ranges from southern Canada and throughout the Mississippi River Basin of the midwestern United States (Fig. 8) (11). The preferred crustacean second intermediate hosts for P. kellicotti are freshwater crayfish of the Oronectes and Cambarus species, in which metacercariae develop almost exclusively in the heart and not in the viscera, gills, or legs as in the life cycles of many Asian Paragonimus species (Fig. 9) (1–4).

Fig 8.

The slender walker snail, Pomatiopsis lapidaria, is the preferred first intermediate host for Paragonimus kellicotti throughout the Mississippi River Drainage Basin of the U.S. Midwest. (Photo by Steve Cringan, reprinted from reference 44 with permission. © 2005, Friends of the Great Plains Nature Center.)

Fig 9.

Crayfish of the Oronectes species are the preferred second intermediate crustacean hosts for Paragonimus kellicotti throughout the Mississippi River Drainage Basin. (Reprinted from an image from Andreas R. Thomsen, from Wikimedia Commons.)

RESERVOIR HOSTS OF PARAGONIMUS SPECIES

Paragonimus enjoys a very broad range of mammalian hosts, which makes it difficult to separate primary from reservoir hosts. A variety of domestic and wild animals that consume freshwater crustaceans serve as reservoirs and as primary hosts for endemic Paragonimus species in Asia, Africa, and South America, including cats, dogs, pigs, swamp mongooses, wild boars, civet cats, and many species of other wild cats, such as Asian tigers (12). A variety of domestic and wild animals that consume crayfish serve as reservoirs and definitive animal hosts for P. kellicotti in the United States, including cats, dogs, sheep, skunks, red foxes, coyotes, raccoons, bobcats, and mink (1, 10, 11). The time from oviposition of unembryonated eggs to infection in a definitive mammalian host is 65 to 90 days for P. westermani, but it is considerably longer for P. kellicotti and may extend for 1 year or longer (1, 2, 10, 11).

TRANSMISSION OF PARAGONIMIASIS

When infected crustaceans are consumed raw or undercooked by mammalian hosts, including humans, metacercariae quickly penetrate the duodenum and traverse the peritoneal cavity, diaphragm, and parietal pleura to mature into hermaphroditic pairs within the pleural spaces or lungs within 6 to 10 weeks. Adults cross-fertilize within cystic cavities in the pleural spaces or lungs within another 4 to 16 weeks and release unembryonated eggs into bronchioles. The eggs are then coughed up, mixed in a bloody sputum (“rusty” sputum), and either discharged in sputum or swallowed and later excreted in feces (Fig. 3 and 4).

Less common modes of transmission of Asian paragonimiasis have included contamination of food utensils and uncooked food by food preparers with infective metacercariae from raw crustaceans (10). In addition, human consumption of raw or undercooked meat from animals infected with Paragonimus species after feeding on crustaceans containing infective metacercariae can also transmit paragonimiasis. This mode of transmission was responsible for a cluster of P. westermani-caused paragonimiasis cases in Japan following the consumption of raw wild boar meat (12). The course of infection by Paragonimus species in definitive mammalian hosts, including humans, may be prolonged, recurring over decades, or relatively asymptomatic, especially in infections with low parasite burdens.

NONNATIVE PARAGONIMIASIS IN THE UNITED STATES

Paragonimus species are widely distributed globally and have a broad diversity of domestic and wild animal hosts. Most cases, however, are caused by P. westermani and confined to southeastern and eastern Asia; rates of seroprevalence of P. westermani antibodies in humans exceed 30% in some parts of China where ethanol-pickled freshwater crabs (“drunken crabs”) are frequently consumed (13). In 2005, Keiser and Utzinger identified 293.8 million people living near freshwater bodies as being at risk for paragonimiasis worldwide, especially in Southeast Asia and the Western Pacific (14). The authors also predicted that the rapid growth of domestic aquaculture in these regions would support the continued emergence of food-borne trematodiasis, including paragonimiasis (14).

As immigration from eastern Asia to the United States and travel between Asia and the United States has increased over the years since the Vietnam War, more imported cases of P. westermani infections have been reported in Asian immigrants and in returning travelers (14, 15). In 1981, Collins and coauthors observed P. westermani eggs in the sputum of a Laotian immigrant with persistent cough, hemoptysis, and cavitary lung disease on chest X-ray (15). The authors concluded that pulmonary paragonimiasis should be included in the differential diagnosis of cavitary lung disease, along with tuberculosis, in Southeast Asian refugees entering the United States (15). The following year, Burton and coinvestigators in Chicago evaluated 3 Laotian refugee children ranging in age from 8 to 11 years old with a variety of chronic pulmonary complaints over a 2-year period, including chronic cough and hemoptysis in 2 patients, no fever or night sweats, and a negative family history for tuberculosis (16). Prominent physical findings included no fever or significant respiratory distress in all patients, rales and dullness to percussion over the chest, and clubbing in one patient (16). Chest X-rays demonstrated interstitial infiltrates in all patients and multiple small cystic areas in 2 patients (16). Moderate peripheral eosinophilia was present in all children, 2 children had P. westermani eggs present in stool specimens, 2 patients had eggs present in sputum specimens, and 1 patient had eggs present in a bronchoscopic specimen (16). All patients were treated with oral bithionol at 50 mg/kg every other day for 15 days and recovered completely clinically and radiographically following treatment (16). The authors noted that the diagnosis of paragonimiasis was delayed for up to 6 months in 2 patients due to the unfamiliarity of U.S. clinicians with the presenting manifestations of paragonimiasis, and they urged clinicians to consider lung fluke infections in Southeast Asian refugee children with chronic pulmonary symptoms and hemoptysis and to examine the stool and sputum for P. westermani eggs (16). Although bithionol is available from the Drug Service of the U.S. Centers for Disease Control and Prevention (CDC), bithionol therapy for paragonimiasis has now been replaced by oral praziquantel at 75 mg/kg/day in 3 divided doses over 2 to 3 days (17).

In 1983, Johnson and colleagues reported the largest case series of 25 Southeast Asian refugees and recent U.S. immigrants with P. westermani infections (18). Among these patients, 13 were diagnosed by the microscopic identification of P. westermani unembryonated eggs in sputum specimens, and the remaining patients were diagnosed by a combination of elevated complement fixation titers and radiographic findings (18). Nearly half of the patients (48%) had pleural effusions on chest X-rays, which were massive in 6 patients and the sole radiographic manifestation of paragonimiasis in 5 patients (18). The authors recommended that once cavitary tuberculosis was excluded, the diagnostic evaluation of pulmonary infiltrates and pleural effusions in immigrants from Southeast Asia should include serological and microbiological screening for P. westermani infections (18).

Patients with primarily pleural paragonimiasis may not present with a diagnostic triad of hemoptysis, Paragonimus eggs in the sputum and feces, and parenchymal infiltrates on chest X-rays (19). Minh and colleagues reported a Laotian immigrant patient with pleural paragonimiasis who presented without cough, hemoptysis, or Paragonimus eggs in the sputum or feces (19). Later, chest tube drainage of a chronic pleural effusion that did not resolve with bithionol therapy provided diagnostic confirmation of pleural paragonimiasis on the basis of Paragonimus eggs in the pleural fluid (19). The authors recommended that clinicians also search for Paragonimus eggs in the pleural fluid in cases of chronic pleuropulmonary disease, especially in Southeast Asian immigrants without evidence of tuberculosis or Paragonimus eggs in the sputum or stool (19).

Nonnative paragonimiasis may also occur in U.S. residents who are not recent immigrants from Southeast Asia or travelers returning from regions where Paragonimus is endemic, after eating imported raw crabs (20). In 2011, Wright and coinvestigators reported the first case of a true chylothorax caused by paragonimiasis in a U.S. resident who recalled eating live crabs imported from Asia in a California sushi restaurant 2 years prior to his illness but denied traveling outside the United States or eating any other crabs or crustaceans that may have been infected with native P. kellicotti (20). The patient was a 54-year old, previously healthy male who developed dyspnea after dust exposure and, during a work-up for asthmatic bronchitis, had a left pleural effusion with compressive atelectasis on chest radiograph (20). Later, 2,200 ml of viscous, chalky-colored fluid was drained from the left chest and confirmed as chyle by a very high lactate dehydrogenase (LDH) level (2,714 IU/liter) and a low glucose level compared to serum levels (20). Microscopic analysis of the pleural fluid demonstrated operculated eggs of P. westermani, and the serum IgG enzyme-linked immunosorbent assay (ELISA) for P. westermani measured 1:128 (positive titer, ≥1:32) (20). This case of nonnative paragonimiasis in a California native was unique for several reasons. First, although chylothorax may occur in filarial worm infections, it was the first case of chylothorax resulting from Paragonimus infection of the left hemithorax with disruption of the thoracic duct. Second, unlike other patients with paragonimiasis presenting with pleural effusions, this patient was not a recent Asian immigrant, expatriate, or returning traveler who reported eating raw crustaceans abroad. Third, the patient recalled eating live crabs imported from Asia in a local sushi restaurant in California and denied consuming any other native, raw crustaceans, including crayfish, that may have been infected with P. kellicotti. A chylothorax with a high eosinophil count, a very high LDH level, and a low glucose should raise clinical suspicion for parasitic infections of the pleura with Paragonimus organisms that may be either imported or native (20).

Boland and colleagues at the Mayo Clinic in Rochester, MN, reported four cases of pleural and/or pulmonary infections caused by P. westermani in U.S. residents, three of whom reported ingesting live crabs in sushi bars (21). In some of these cases, patients reported eating live crabs placed in their martinis, a new mode of transmission for P. westermani in the United States (21). All patients in this series presented with pulmonary complaints, abnormalities on chest imaging, and eosinophilic pneumonia on lung biopsy specimens (21). Paragonimus westermani adults and/or eggs were microscopically identified in specimens from 2 patients, and serological studies were positive for P. westermani in 3 cases (2 ELISAs and 1 immunoblot) (21). The authors emphasized that the combination of radiographic pleuropulmonary disease, eosinophilic pneumonia on lung biopsy specimens, positive live imported Asian freshwater crab ingestion histories, and targeted serologies were important diagnostic clues, even in the absence of microscopic confirmation of organisms or eggs (21).

NATIVE PARAGONIMIASIS IN THE UNITED STATES

Before 1984, human cases of paragonimiasis, unlike veterinary cases, were rarely described in the United States outside imported cases of P. westermani paragonimiasis in refugees from Southeast Asia and travelers returning from regions of endemicity in Asia (1, 2). In 2011, Diaz compiled 15 reported cases of P. kellicotti-caused paragonimiasis in the United States and conducted the first comparative analysis between 6 cases reported during the period 1984 to 2005 and 9 subsequent cases reported from Missouri during the period 1996 to 2010 (3, 22–29). Most cases (n = 14) were significantly associated with the consumption of raw or undercooked crayfish from freshwater river systems within the Mississippi River Basin (29).

To date, a total of 16 cases of indigenous P. kellicotti-caused paragonimiasis have been reported in the United States, with the largest number from Missouri (n = 10) (Fig. 1) (3, 22–29). All patients presented with fever, cough, pleural effusions, and, frequently, hemoptysis; one patient developed cerebral paragonimiasis, two patients required thoracic surgery for diagnosis and management of persistent lung infections mimicking tuberculosis, and one elderly patient died from pneumonic sepsis and a perforated viscus (3, 22–29).

All patients in the period 1984 to 2010 reported a history of consuming either raw or undercooked crayfish obtained from local rivers within the U.S. Mississippi River Drainage Basin, with the exception of one patient from Colorado, a cocaine abuser who reported eating sushi in Denver 2 years prior to presenting with hemoptysis and a consolidated right lower lobe (Fig. 1) (26, 29). The mean incubation period from consumption of P. kellicotti-infected raw or undercooked crayfish (and sushi as reported by the Colorado patient) to correct diagnosis was 23.4 (± 31.33) weeks (26). However, when the outlier Colorado patient with an incubation period of 104 weeks and another outlier Missouri patient with an incubation period of 83 weeks were eliminated from analysis, the mean incubation period from consumption of P. kellicotti- infected raw or undercooked crayfish to correct diagnosis was 10.93 (± 13.24) weeks, similar to the observed incubation period for Paragonimus westermani infections. Since the Colorado patient reported eating sushi in a Denver restaurant, this case may have been a nonnative case following consumption of P. westermani- or Paragonimus miyazakii-infected imported Asian freshwater crabs in sushi (26). This would have explained the patient's cross-reacting positive antibody responses on immunoblot testing for paragonimiasis with P. westermani antigens without identifying the causative species of Paragonimus.

Following microscopic or serological diagnoses, all patients were treated with oral praziquantel (25 mg/kg three times per day for 2 to 3 days) and cured, except for a 71-year-old male from Iowa who routinely consumed undercooked crayfish, presented with empyema, and died of pneumonic sepsis and a perforated viscus shortly after hospital admission (25). T1-weighted magnetic resonance imaging (MRI) of the brain in one case from Missouri identified a mass lesion in the right occipital lobe which resolved following praziquantel therapy and confirmed a codiagnosis of cerebral paragonimiasis (3). This was the first reported case of P. kellicotti cerebral paragonimiasis in the United States (3). In addition to lower respiratory tract symptoms and pleural effusions, 4 patients presented with migratory subcutaneous skin nodules (trematode larva migrans) on the face or extremities that also resolved completely following oral praziquantel therapy (3, 28, 29).

A collective descriptive analysis of the presenting demographic, epidemiological, behavioral, and recreational features of all 16 U.S. cases of authocthonous paragonimiasis reported during the study period, 1984 to 2010, is presented in Table 2. The male/female case ratio was 15:1; with over 90% of patients reporting consumption of either raw or undercooked crayfish from local rivers, most during camping, paddling, or floating trips. A categorical data analysis of behavioral risk factors for paragonimiasis identified the following statistically significant behavioral risk factors by Fisher exact tests for autochthonous paragonimiasis in the United States: (i) infection acquired in Missouri (P = 0.002), (ii) reported consumption of raw crayfish while drinking alcohol (P = 0.041), and (iii) infection acquired while on a river (floating or paddling) or camping trip (P = 0.002).

Table 2.

Collective descriptive analysis of the presenting demographic, epidemiological, behavioral, and recreational features of all reported cases of authocthonous paragonimiasis during the study period, 1984 to 2010

Feature	No.	%
Male	15	93.8
Female	1	6.3
Child <18 yr old	1	6.3
Camping, canoeing, or floating trip exposure	12	75.0
Alcohol consumption	7	43.8
Ate raw or undercooked crayfish	15	93.8
Treated and cured	15	93.8
Died	1	6.3

Table 3 presents a collective ranked analysis of the presenting clinical manifestations of all reported cases of autochthonous cases of paragonimiasis in the United States during the study period, 1984 to 2010. Over 80% of the patients presented with fever, cough, pleural effusions, and peripheral eosinophilia (mean percent eosinophils = 25.25% ± 10.06%). Over 40% reported fever and malaise, dyspnea, and hemoptysis. Migratory inflammatory, subcutaneous skin nodules, collectively known as trematode larva migrans, and pneumothoraces occurred in over 20% of the patients reported. The overall case fatality rate from P. kellicotti infections was 6.25%. However, when the fatal case in the 71-year-old male with pneumonic sepsis and a perforated viscus was removed from analysis, there were no fatalities among the autochthonous U.S. cases of paragonimiasis, consistent with the absence of fatalities among the imported U.S. cases of paragonimiasis.

Table 3.

Collective ranked analysis of the presenting clinical characteristics of all reported cases of autochthonous cases of paragonimiasis in the United States during the study period, 1984 to 2010

Clinical characteristic	No.	%
Fever with or without night sweats	13	86.6
Cough	14	87.5
Pleural effusion	13	81.3
Eosinophilia	13	81.3
Fever and malaise	8	50.0
Dyspnea	8	50.0
Hemoptysis	6	37.5
Migratory skin nodules	4	25.0
Pneumothorax	4	25.0
Headache	3	18.8

In 2011, Fischer and coinvestigators used PCR and DNA sequencing to characterize parasites isolated in crayfish obtained from three rivers in the Missouri Ozarks and in sputum or lung tissue obtained from 2 human cases in Missouri (30). Paragonimus kellicotti metacercariae were detected in 69%, 67%, and 37% of the crayfish collected from the Big Piney, Huzzah, and Black Rivers, respectively, all of which are popular for camping, paddling, and floating trips in Missouri (30). DNA sequencing in the human cases confirmed Paragonimus kellicotti infections with the same organisms in infected crayfish (30). In addition, gerbils that were intentionally infected by the intraperitoneal injection of 3 to 8 metacercariae displayed a strong antibody response to P. kellicotti antigen in Western blot analysis by 39 days after experimental infection (30). The investigators made the following conclusions. Paragonimus kellicotti infections are common in crayfish collected from rivers in the Missouri Ozarks (30). Experimental animals may be infected with a relatively small number of metacercariae (30). Humans may be infected by consuming P. kellicotti -infected raw crayfish during recreational camping, paddling, or floating trips on rivers in the Missouri Ozarks prior to the onset of the clinical symptoms of paragonimiasis (30).

In summary, a case-series analysis of all native species-associated paragonimiasis in the United States has demonstrated that young adult males who consume raw or undercooked crayfish, often while intoxicated and on camping, paddling, or floating trips in the U.S. Midwest, especially Missouri, are at significant risk of contracting autochthonous paragonimiasis. The infective dose of P. kellicotti metacercariae was unknown, but infection followed consumption of as few as one raw crayfish. Cerebral metastasis occurred in one case, and serious lung infections occurred in all cases, although asymptomatic cases of Paragonimus westermani infections (benign tropical hemoptysis) have been frequently described. Although cerebral paragonimiasis has been reported in patients with P. westermani paragonimiasis, only one case patient from Missouri demonstrated radiographic evidence of cerebral paragonimiasis caused by P. kellicotti (3). Lastly, molecular characterization techniques have now confirmed high prevalence rates for P. kellicotti infections in Missouri crayfish and in patients with P. kellicotti infections who have reported consuming raw crayfish during paddling or floating trips on Missouri rivers (30).

CLINICAL MANIFESTATIONS OF PARAGONIMIASIS

The reproductive life cycle of lung flukes within their animal hosts defines all clinical manifestations of human paragonimiasis, including rare prodromal stages of abdominal pain, fever, and diarrhea days after consuming infected crustaceans raw or undercooked and incubation periods of 2 to 16 weeks before a constellation of fever, cough, hemoptysis, and peripheral eosinophilia ensues. Asian paragonimiasis has often been referred to as benign tropical hemoptysis because the sputum contains red blood cells from ruptured mating cysts and has a rust-brown color. In addition, some patients with paragonimiasis and low parasite burdens and without pneumonia, empyema, or pleurisy may remain relatively asymptomatic for prolonged periods or have recurrent attacks of cough, sputum production, fever, and night sweats, mimicking tuberculosis (1; www.parasitesinhumans.org/paragonimus-westermani-lung-fluke.html).

Nonnative P. westermani paragonimiasis and native P. kellicotti paragonimiasis present with similar clinical manifestations. However, shorter incubation periods of 2 to 12 weeks have been described for P. kellicotti infections, compared to 4 to 16 weeks for P. westermani infections (28). In all cases, paragonimiasis must be differentiated from pulmonary tuberculosis by tuberculin skin testing or gamma interferon release assay and specific microscopic and serological tests. A differential diagnosis of unexplained fever, cough, peripheral eosinophilia, and hemoptysis characteristic of paragonimiasis is presented in Table 4. Although lung flukes prefer to encyst and mate in the pleurae or lungs, infective metacercariae may migrate to extrapulmonary sites and cause ectopic granulomatous nodules, most commonly in the brain (cerebral paragonimiasis) or skin (trematode larval migrans).

Table 4.

A differential diagnosis of unexplained fever, cough, hemoptysis, pleural effusions, and peripheral eosinophilia

Type of disorder	Possible diagnoses
Infectious
Bacterial	Pneumonia (community acquired), lung abscess, tuberculosis
Fungal	Allergic bronchopulmonary aspergillosis
Parasitic	Ascariasis, cysticercosis, filarial tropical pulmonary eosinophilia, paragonimiasis, schistosomiasis, strongyloidiasis, toxocariasis, trichinosis
Inflammatory	Bronchial asthma, bronchitis, bronchiectasis
Vascular	Granulomatous vasculitis
Autoimmune	Churg-Strauss syndrome,a eosinophilic lung disease, acute and chronic eosinophilic pneumonia, idiopathic hypereosinophilic syndrome, lymphomatoid granulomatosis, Wegener's granulomatosis
Neoplastic	Potentially some malignancies

^aChurg-Strauss syndrome is a very rare, noninheritable autoimmune vasculitis, also known as allergic granulomatous angiitis, that affects the medium and small arteries of the lung and other organ systems (cardiac, dermal, gastrointestinal, and renal) and is associated with peripheral eosinophilia.

RADIOLOGICAL MANIFESTATIONS OF PARAGONIMIASIS

In 1992, Im and colleagues in Seoul, South Korea, retrospectively reported the chest X-ray features in 71 patients with P. westermani pleuropulmonary paragonimiasis and noted the following findings on chest radiographs (31). Among the 59 patients with pulmonary lesions, lung findings included patchy air space consolidation with or without cystic changes (n = 37), ring shadows (“ring signs”) (n = 16), and peripheral linear opacities (n = 29), which were more prominent in patients with pleural effusions (31). In the 43 patients (61%) who also had pleural lesions, the most common findings included pleural effusions (n = 12) and pneumothoraces (31). Computerized tomographic (CT) findings provided more detailed information than chest X-rays about worm migration tracks and cysts and included round, cystic lesions either fluid filled (n = 5) or gas filled (n = 5), worm migration tracks, and intracystic worms (31).

In another retrospective review of CT findings in microscopically or serologically confirmed patients with paragonimiasis in South Korea, Kim and coauthors described the classic “ring sign” of P. westermani paragonimiasis as a “subpleural or subfissural nodule about 2 cm in diameter” often containing “a necrotic low attenuation area” and adjacent to areas of focal pleural thickening (32). In 2005, Kuroki and coinvestigators in Japan described high-resolution CT scan findings for radiographic confirmation of P. westermani paragonimiasis that included worm-containing cysts, worm migration tracks, centrilobular nodules or “ring signs,” and focal areas of bronchial wall thickening (33). In 2012, Shim and colleagues described low-attenuated serpentine lesions of the liver on abdominal ultrasound and CT scans, presumably worm migration tracks approaching the pleurae and lungs, as another common and relatively specific radiographic finding for P. westermani paragonimiasis (34).

In a retrospective review of the chest CT findings in 8 patients with P. kellicotti paragonimiasis, Henry and colleagues confirmed many radiographic findings in North American paragonimiasis as consistent with previously reported chest CT findings in Asian paragonimiasis, including pleural effusions, thoracic lymphadenopathy, and peripheral lung nodules of 1.0 to 3.5 cm in diameter with frequent linear tracking to pleural surfaces, likely corresponding to parasite burrow tunnels (35). However, other chest CT findings infrequently reported in Asian paragonimiasis and more common in American paragonimiasis included pericardial involvement in 5 patients and omental inflammation also in 5 patients (35).

In summary, chest radiographic findings may be normal in 10 to 20% of patients with Asian paragonimiasis, many of whom may be relatively asymptomatic and may have more pleural than parenchymal disease. In symptomatic patients with either Asian or American paragonimiasis, chest radiographs are usually abnormal and exhibit a similar spectrum of nonspecific findings, including consolidated lobar infiltrates, coin lesions, calcified nodules, hilar enlargement, pleural thickening, pleural effusions, and pneumothoraces. Pericardial and omental involvement, however, appear to be more common diagnostic imaging findings in cases of North American paragonimiasis (35).

Cerebral neuroimaging findings are also nonspecific in American and Asian paragonimiasis but remain essential in excluding cerebral paragonimiasis in patients presenting with headaches, seizures, meningismus, and loss of visual acuity. As noted, cerebral paragonimiasis has been reported in patients with P. westermani infections, and the first U.S. case of P. kellicotti-caused cerebral paragonimiasis was recently described in a patient with a mass lesion in the right occipital lobe (3). Neuroimaging findings on CT and magnetic resonance imaging (MRI) scans in both Asian and American paragonimiasis are often confined to the temporal and occipital lobes and may include solitary nodular lesions or ring-shaped conglomerated lesions (33).

LABORATORY MANIFESTATIONS OF PARAGONIMIASIS

The laboratory manifestations of paragonimiasis may include the microscopic observation of unembryonated Paragonimus eggs in sputum, feces, bronchoalveolar lavage (BAL) fluid, lung or pleural biopsy specimens, or surgical pleurectomy or lobectomy specimens (Fig. 3 and 4). However, the direct parasitological diagnosis of paragonimiasis by the microscopic observation of unembryonated eggs in specimens may be difficult and have low sensitivities. Repeated sputum examinations are recommended to increase the low sensitivity of single sputum examinations, which ranges from 30% to 40% (27). In addition, eggs may not even be present in sputum, BAL fluid, or stool specimens in patients with predominantly pulmonary parenchymal, pleura-based, or ectopic infections in the brain, mesentery, omentum, or subcutaneous tissue (1, 2, 19). Since patients presenting with fever and hemoptysis may have either tuberculosis or paragonimiasis, portions of specimens should be split and saved for parasitological examinations before processing entire specimens for detecting acid-fast mycobacteria, which could dissolve Paragonimus eggs. Adult parasites are also rarely recovered from processed tissues, including lung biopsy specimens.

Although complement fixation tests have been used in the past to successfully confirm P. westermani infections, they quickly revert to normal as flukes die and are of little use in recrudescent or recurrent infections (18). A variety of more sensitive immunodiagnostic techniques are available from reference laboratories today, including enzyme-linked immunosorbent assays (ELISAs) and immunoblotting developed for the detection of cross-reacting P. westermani antibodies (36). In Chinese reference laboratories, ELISAs using adult fluke and metacercarial stage-specific antigens have proven to be sensitive in confirming parasite-specific IgG antibodies in human cases of P. westermani infections (36). In addition, monoclonal antibody-based antigen detection assays produced in reference laboratories have detected both species-specific and even stage-specific Paragonimus westermani infections in human cases (36).

In 1988, Slemenda and coinvestigators at the CDC reported their experiences using a P. westermani antigen-based immunoblot assay to accurately and rapidly detect human paragonimiasis with a sensitivity of 96% and a specificity of 99% (37). Nevertheless, this assay has not been specifically validated for Paragonimus kellicotti species lung flukes in North American paragonimiasis infections.

In 2011, investigators from Washington University used a new Western blot analysis with P. kellicotti adult worm antigen to detect antibodies to the 36-kDa and the doublet 24/26-kDa bands in 10 patients with CDC Western blot analysis or microscopically confirmed P. kellicotti infections and in 2 patients with suspected, but unconfirmed, P. kellicotti infections (K. C. Curtis, G. J. Weil, S. M. Folk, P. Wilkins, L. Marcos, P. U. Fisher, presented in Poster Session C at the 60th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Philadelphia, PA, 4 to 8 December 2011). The P. kellicotti antigen Western blot test appears to be more sensitive and specific than the CDC P. westermani antigen Western blot test for P. kellicotti infections in the United States and may also prove useful in monitoring the effectiveness of therapy with praziquantel.

Some of the newest diagnostic technologies for the rapid detection of food-borne helminthiases, including paragonimiasis, are loop-mediated isothermal amplification (LAMP) assays, DNA pyrosequencing for PCR amplicons, and multiplex protein microarray assays (38–40). In 2011, Chen and coinvestigators developed and validated a new LAMP assay which identified P. westermani DNA in infected freshwater crabs and crayfish and in human specimens, including sputum and pleural fluid within 45 min (38). The authors concluded that their LAMP assay was a rapid, sensitive, and specific test for the detection of P. westermani adults, eggs, and metacercariae in human and animal samples (38). In 2012, Chen and coinvestigators compared a new multiplex protein microarray assay equipped with archived Paragonimus antigens from 5 separate parasite species causing food-borne helminthiases, including P. westermani, with ELISA in 365 human helminthiasis cases and 85 healthy control patients (39). The specificity of the tests ranged from 97% to 100% in the protein microarray and from 97.7% to 100% in ELISA (39). The sensitivity of the tests varied from 85.7% to 92.1% in the protein microarray and from 82.0% to 92.1% in ELISA (39). This investigation showed that the protein microarray provided a more sensitive and faster technology for laboratory screening for multiple food-borne human helminthiases than ELISA (39). In 2012, Tantrawatpan and colleagues reported their experiences using DNA pyrosequencing for species-level identification of Paragonimus infections in areas of endemicity in Thailand and successfully discriminated among 6 species (40). In summary, new, more sensitive molecular technologies are now being developed to rapidly screen patients for several food-borne parasitic diseases simultaneously with species-level detection and with significant improvement in differential diagnoses compared with conventional technologies, including serological and parasitological methods. The diagnostic and laboratory tests for paragonimiasis are compared by their sensitivities and specificities in Table 5.

Table 5.

Diagnostic laboratory tests for paragonimiasis

Diagnostic test	Species	Sensitivity (%)	Specificity (%)	Reference
Parasitological testsa
Eggs in multiple sputum specimens	P. westermani	54–89	NRb	1
Eggs in single sputum specimen	P. westermani	30–40	NR	27
Eggs in 3 stool specimens	P. westermani	25	NR	1
Eggs in single stool specimen	P. westermani	11–15	NR	1
Immunodiagnostic tests
ELISA	P. westermani	82–93	98–100	39
Immunoblot assay	P. westermani	96	>99	37
Molecular diagnostics
Species DNA pyrosequencing	P. bangkokensis, P. harinasutai, P. heterotremus, P. macrorchis, P. siamensis, P. westermani	NR	NR	40
LAMP assay	P. westermani	100	NR	38
Protein microarray	P. westermani	86–92	97–100	39

^aAll parasitological tests required the microscopic identification of unembryonated eggs in specimens. Adult worms were rarely identified in most specimens but have been identified in tissues, such as lung biopsy specimens.

^bNR, not reported.

MANAGEMENT OF PARAGONIMIASIS

All confirmed cases of human paragonimiasis should be treated, to avoid the complications of extrapulmonary disease, with oral praziquantel at 75 mg/kg/day in 3 divided doses of 25 mg/kg for 2 to 3 days (17). Studies in Japan, which has experienced a paragonimiasis reemergence caused by P. miyazakii following consumption of raw wild boar meat, have now demonstrated “a 71 to 75% cure rate” after 1 day of praziquantel therapy, an 86 to 100% cure rate after 2 days, and a 100% cure rate after 3 days of therapy (41). Oral triclabendazole at 10 mg/kg twice a day for 1 to 2 days has also been used successfully to treat human paragonimiasis in South America, is also effective against intestinal flukes (fascioliasis), and may prove to be an effective alternative to praziquantel therapy for paragonimiasis (42). Triclabendazole is not approved for treating paragonimiasis in the United States but is available from the CDC Drug Service (43). Although now replaced by praziquantel therapy, oral bithionol at 50 mg/kg every other day for 15 days has also been used to successfully treat imported P. westermani cases in the United States in the past and is available by request from the CDC Drug Service (16, 18, 43).

Pulmonary complications of untreated or inadequately treated paragonimiasis may include recurrent pleural effusions, empyema, recurrent pneumothoraces, constrictive pleuritis, and recurrent pneumothoraces, all of which may require surgical intervention for diagnostic biopsies, video-assisted thoracoscopy (VAT), thoracostomy tube drainage, talc pleurodesis, pleurectomy, or segmental lobectomy. Untreated or inadequately treated cerebral paragonimiasis may cause eosinophilic meningoencephalitis, hydrocephalus, increased intracranial pressure, and blindness. Although subclinical, indolent pulmonary infections have occurred in untreated cases of paragonimiasis and may last for decades, all patients with serologically confirmed paragonimiasis should be treated with praziquantel for 2 to 3 days because of the risks of pneumonic sepsis and cerebral paragonimiasis.

CONTROL AND PREVENTION OF PARAGONIMIASIS

Control strategies are ineffective for zoonotic paragonimiasis due to the widespread distribution of competent intermediate hosts throughout large freshwater ecosystems and the variety of domestic and wild animal reservoir hosts consuming infected crustaceans. The control of human paragonimiasis is best accomplished by public health education and by proper food preparation. Proper food preparation strategies include frequent hand washing by food preparers when cleaning crustaceans, avoiding contamination of utensils and serving platters with metacercariae from infected crustaceans, and boiling or cooking crustaceans to reach an internal temperature of 145°F (63°C) before eating (43).

The behavioral factors that led to most cases of P. kellicotti paragonimiasis in the United States included alcohol consumption and intoxication on camping, paddling, and floating trips, dares, and demonstration of wilderness survival skills while outdoors. The CDC and the U.S. Food and Drug Administration now advise cooking or boiling crayfish to reach an internal temperature of 145°F (63°C) before eating (43). The operators of campgrounds and canoe, inner tube, and kayak rental outlets should also be alerted to the necessity of thoroughly boiling or cooking crayfish before eating (28, 43).

CONCLUSIONS AND RECOMMENDATIONS

Clinicians should consider autochthonous paragonimiasis in vacationers and weekenders returning from areas of the United States where P. kellicotti is endemic and should inquire about the ingestion of raw or undercooked crayfish in all patients with unexplained fever, cough, eosinophilia, and pleural effusions, with or without hemoptysis. Diagnosis should be confirmed by histopathological and parasitological identification of distinctive eggs in sputum, BAL or pleural fluid, stool specimens, or pleural, lung, or skin biopsy specimens. Immunodiagnostics will be useful for the confirmation of suspected cases without microscopic evidence of paragonimiasis. Nevertheless, all patients with a positive history of ingestion of raw or undercooked imported Asian freshwater crab or native crayfish and the pathognomonic clinical presentation of paragonimiasis should be evaluated serologically and radiographically and treated with praziquantel on the basis of positive serologies, regardless of negative microscopic findings, in order to avoid pulmonary and cerebral complications.

Biography

James H. Diaz, M.D., M.P.H.&T.M., Dr.P.H., received his formal education at the Tulane University School of Medicine and the Tulane University School of Public Health and Tropical Medicine. From 1980 until 1995, Dr. Diaz served as attending anesthesiologist and intensivist at the Ochsner Clinic in New Orleans. In 1996, Dr. Diaz became Professor and Head of the Department of Public Health and Preventive Medicine at Louisiana State University Health Sciences Center in New Orleans, where he currently serves as Professor and Head of Environmental Health Sciences in the School of Public Health and Professor of Anesthesiology in the School of Medicine. Since 1996, his scientific interests have included autochthonous and imported parasitic infections, food-borne and arthropod-borne infectious diseases, and the impact of climate change on natural disasters and their public health outcomes. Dr. Diaz currently authors the section on ectoparasite-borne infectious diseases in Principles and Practice of Infectious Diseases, now in its eighth edition.