Endemic Paragonimus kellicotti infections in animals and humans in USA and Canada: Review and personal perspective

Infections with the lung fluke, Paragonimus kellicotti, have been diagnosed in a variety of domestic and wild animals and humans in USA and Canada. Although there are many species of Paragonimus in other parts of the world; P. kellicotti is the only species definitively diagnosed in USA and Canada. Fresh water snails (several species) and crayfish (mainly Orconectes spp.) are its intermediate hosts. Humans and animals become infected with P. kellicotti only by ingesting metacercariae encysted in the heart of crayfish. After ingestion, the fluke penetrates intestinal wall, enters peritoneal cavity, and reaches pleural cavity by direct penetration of diaphragm, 2–3 weeks post inoculation (p.i.). Young flukes penetrate lungs and become encysted in pulmonary tissue, often in pairs. Time to maturity is around 4–7 weeks p.i. Eggs are coughed up, swallowed, and are excreted in feces. Although the parasite has been known for more than a century, there has been an upsurge of human infections in the USA. Here, I review P. kellicotti infections in naturally infected hosts. Pathogenesis, diagnosis, and treatment in parasite-free cats and dogs experimentally infected P. kellicotti are reviewed to shed light on the pathogenesis of human paragonimiasis. Problems and challenges facing diagnosis of paragonimiasis, especially non-pulmonary infections, are discussed. Fluke stages are deposited in Smithsonian Museum.


Introduction
Paragonimiasis is parasitic infection of animals and humans recognized for more than a century and there are several reviews on this topic (Yokogawa, 1969;Diaz, 2013;Fischer and Weil, 2015;Yoshida et al., 2019;Blair, 2022;Le et al., 2022). There are many species of Paragonimus (Blair, 2022). The disease in the Far East caused mainly by Paragonimus westermanni is well characterized . The recent reports of human paragonimiasis in USA caused by Paragonimus kellicotti infections in North America have aroused the interest of public health authorities and clinicians (reviewed by Coogle et al., 2022). Paragonimus kellicotti is the only species of Paragonimus established as endemic in USA.
Compared to human infections, much more is known concerning P. kellicotti infections in domestic and wild animals in North America. Adopting a One Health approach to aid zoonotic risk assessment and treatment of human infections, I hereby review the body of knowledge derived from natural and experimental studies in animals with the interest that the information might be useful for pathogenesis of infection in humans. This paper exclusively discusses P. kellicotti infections in the USA and Canada.

Table 1
Summary of life cycle stages of Paragonimus kellicotti.
Thus, livestock consumption appears very unlikely to pose any risk to people. Here, I have reviewed these old reports of Paragonimus infections in pigs and a goat in USA.
The objective of the present review is to summarize information on paragonimiasis in animals and humans in the USA, in particular pathogenesis in experimentally infected cats and dogs performed in 1970's. I have attempted to consult and summarize original papers on Paragonimus infections here to clarify misinterpretations. Although there are 66 records of submissions of Paragonimus infections listed in the United States National Parasite Collection (USNPC) (previously at the Animal Parasitic Diseases Laboratory, Beltsville, Maryland, now at the Department of Invertebrate Zoology, Smithsonian Institution, National Museum of Natural History), it is often difficult to match records with their publications. Therefore, I have listed the USNPC number when stated by the authors. Additionally, I now deposit immature and mature specimens of flukes, histologically stained sections of tissues with lesions, and a paraffin block of infected lung in the Smithsonian Museum and provide museum numbers for the benefit of future researchers.
Population biology of P. kellicotti metacercariae has been studied in Ohio and Missouri (Table 3). It is remarkable that although there were some geographical/ habitat variations, in both studies around 60% of crayfish were infected with a similar parasite load, averaging 2-3 metacercariae per crayfish (Table 3). In two habitats (municipal park, woodlot) in Columbus Ohio, prevalence was 41.8% in a municipal park versus 71.7% in the wood lot; this was expected because woodlot will be visited more often by wild definitive hosts (such as mink) than the municipal park. Metacercariae occurred year-round . The metacercariae were identified morphologically and by bioassay in cats and dogs. Metacercariae recruitment in crayfish occurred during summer and autumn, metacercariae lived up to a year, but some died and were mineralized. Prevalence and intensity of infection increased with body weight of crayfish . Microscopic examination of infected crayfish revealed no inflammation.
The survey in Missouri was conducted for a period of six months in 2010 (30 years after the study in Ohio) but with similar prevalence rates (Table 3). Floating streams in three rivers were tested for metacercariae. The metacercariae were identified morphologically and molecularly; 65% of crayfish were infected .
In a survey of intermediate hosts in Kentucky, USA, P. kellicotti cercariae were found in 3 of 18 Pomatiopsis lapidaria and 9 of 22 P. cincinnatiensis freshwater snails and metacercariae were detected in 24 (12%) of 200 Orenectes juvenilis and 1 of 28 Cambarus bartoni crayfish. As many as 32 metacercariae were found in an infected crayfish (Harley, 1972).

Cat
In total, 28 cats were inoculated orally with 14-50 metacercariae and observed for up to 263 days. The dosage of metacercarae used to infect cats was modest considering that up to 32 metacercariae can be present in a single crayfish as stated above (Harley, 1972). Clinically, eight cats were observed for >12 weeks. For blood and biochemical evaluation (total leukocyte counts, differential leukocyte counts, hemoglobin, packed cell volume, and total protein), cats were tested weekly for 12 weeks (Dubey et al., 1978a).
All cats were euthanized at different intervals. Complete necropsies were performed, and their internal organs were studied histologically. Lungs were fixed with airways perfusion with 10% formalin. For migratory pathway and pathogenesis, cats were euthanized 1,3,5,7,10,14,21,23,29,34,39, and 55-263 days later (Table 4). Tissues were embedded in paraffin, cut at 3-5 μm thick, and examined microscopically after staining with hematoxylin and eosin (HE) stain. The following observations were made.  (p.i.). Flukes reached pleural cavity by penetrating diaphragm and were found in pleural cavity as early as day 4 p.i. The migration was not synchronous because some flukes were present in peritoneal cavity on day 14 p.i. and some flukes were free in pleural cavity on day 23 p.i. . As many as 87% reached the lungs; in 1 cat, 13 adults were recovered on day 263 after feeding 15 metacercariae. More flukes were found in caudal lobes of lungs, adjacent to diaphragm than in other lobes. Most growth of the flukes occurred in the lungs. Flukes reaching the lungs were usually <3 mm long; adult flukes were as large as 15 mm. Mature adult flukes weighed ~1 g.
Eggs were first detected in feces of a cat day 34 p.i. the cat was fed 14 metacercariae (Dubey et al., 1978a). Eggs per gram of feces (epg) was monitored daily in six cats, 70-85 days after consuming metacercariae. All feces voided in 24-h were weighed and emulsified in two volumes of water. Because the egg excretion is not continuous, epg was estimated in total daily feces . It was estimated that each fluke excreted 1000-2000 eggs daily. In one cat, egg count was 1350 on day 80, 920 on day 90, 1100 on day 100; thereafter egg counts were stable until the cat was euthanized day 153 (Dubey et al., 1978a). The sedimentation technique was more efficient for the diagnosis of eggs in feces; eggs were detected eight days earlier by the sedimentation technique than by the Fig. 3. Paragonimus kellicotti stages recovered from experimentally infected cats. Flukes were fixed under moderate pressure and stained with Semichon's carmine as described .   . Table 4 Migration, fluke development, and lesions in experimental Paragonimus kellcotti infection in cats (data from Hoover and Dubey, 1978;Dubey et al., 1978a) Table 4. The lesions were primarily found in lungs and the pleural cavity.

Peripheral eosinophilia.
Two peaks of eosinophilia were observed (Dubey et al., 1978a). The first peak of eosinophilia occurred around three weeks p.i. and coincided with penetration of flukes in the lungs. The second occurred around eight weeks p.i., probably related to entrapment of eggs in the lungs and in the mediastinum.

Radiographic changes.
Earliest lesions were detected in caudal lobes of lungs weeks 2-3 p.i. (Dubey et al., 1978a). Early lesions were nodular with 2-4 cm air cavities with chambers divided by septa. By day 65 p.i., well defined cysts were formed. Pneumothorax was seen in four cats, in two of them recurrent. In one cat an entire lobe was consolidated (Dubey et al., 1978a).

Clinical signs and outcome of infection.
In general cats developed only mild disease. Coughing was the predominant sign. One cat had paroxysms of coughing when disturbed but otherwise appeared normal. One cat was euthanized because of dyspnea; pneumothorax was conformed at necropsy examination. One pregnant cat successfully delivered and nursed four kittens; Paragonimus infection was not detected in kittens at necropsy (Dubey et al., 1978a).
4.1.1.6. Chemotherapy. Until 1976, bithionol was the only drug tried to treat natural paragonimasis in cats (Table 6). Bithionol, a phenol derivative, is relatively toxic. Benzimidazole derivative drugs are broad spectrum anthelminthic drugs which were commonly used in 1970's and 1980's. Albendazole was found effective in treating experimentally infected cats (Dubey et al., 1978b). Five cats fed 25 P. kellicotti metacercariae were medicated with albendazole (2 cats-20 mg/kg/daily, two cats 100 mg/kg daily, one cat 50 mg/kg daily) as oral suspension for 14-21 days. Egg excretion was reduced or stopped within one week of dosing drug; at necropsy performed 14-20 days after medication revealed shrunken or dead flukes and resoulation of lesions. (Fig. 9).

Dog
Thirteen dogs were euthanized between days 7 and 70 after feeding 25 or 50 metacercariae and same parameters investigated for cats were investigated for dogs (Dubey et al., 1979a(Dubey et al., , 1979b. The life cycle and lesions observed in dogs were essentially similar to those in cats. Salient features of infections in dogs were: (i). Free flukes were found in pleural cavity up to day 43 p.i. (ii). Eggs were detected as early as day 30 p.i. in a dog.
(iii). Overall clinical disease was more severe in dogs versus cats. Two of five dogs dosed with 35 metacercariae died of paragonimiasis on the 32nd and 35th day p.i. One dog died of dyspnea suddenly on day 32 p.i. The second dog also died despite prompt clinical intervention and died despite being put on a respirator. Granulomatous pneumonia associated with Paragonimus eggs predominated in a dog, 70 days p.i. (Fig. 9B). (iv). Lesions were found on liver day 7 p.i. and immature flukes were found in lesions by histological examination of stained sections. Focal hepatitis persisted until day 35 p.i. Fibrinous deposits were detected on the serosal surfaces of kidneys, spleen, and other visceral organs but flukes were not Found in lesions.

Infections in cats and dogs performed at Cornell University
Seven cats and seven dogs were inoculated with 12-22 metacercariae, and five cats and five dogs were treated with praziquantel (23 mg/kg of body weight, 3 times daily for 3 days), 7 or 14 weeks p.i. (Bowman et al., 1991). None of the dogs or cats developed visible clinical signs. Only five cats developed patent infection and eggs were detected in feces by seven weeks after infection. In dogs, pulmonic lesions were detectable days 21 p.i., and all lesions resolved by two weeks post treatment. Lesions were still detectable in cats by four weeks p.i. In treated dogs necropsied four weeks p.i., no flukes were seen but eggs were detectable in lungs and appeared morphologically normal (Bowman et al., 1991).

Natural hosts of P. kellicotti
Although several carnivores are natural hosts in USA and Canada, mink (Mustela vison) is considered as one of the most important reservoirs of P. kellicotti infection (Table 1). Because there is uncertainty concerning the Paragonimus specimens from livestock (goats, pigs), I have reviewed the original publications.
There is an old record of Paragonimus infection in a goat (Hall, 1925). The goat in question, a year-old female, was slaughtered December 1924 at the National Stock Yards, Illinois and probably came from Mississippi (Hall, 1925). Thirty-six flukes recovered from lung were partly macerated and no spines were detectable on the cuticle; thus, it is unlikely that the fluke was P. kellicotti. This information was presented at a meeting; I could find no evidence that these flukes were subjected to further study.
Whether pigs are a host for P. kellicotti is also uncertain. Stiles and Hassall (1900) first recorded it. An unknown number of flukes collected from hogs (number not stated) were sent to Stiles by a meat inspector in charge of slaughterhouse in Cincinnati, Ohio. Stiles and Hassall considered them as the same fluke from the dog and cat in USA; P. kellicotti had not yet been named. They reviewed the worldwide literature on paragonimiasis known until 1900. Nothing more is known of the flukes recorded in that 1900 report. Ameel (1934) mentioned using P. kellicotti eggs from lungs of a pig for life cycle studies but did not provide details concerning infected pig. Also, there are anecdotal reports of P. kellicotti infection from Georgia, USA summarized by Jordan and Byrd (1958). These flukes were found in sections of lungs of two pigs slaughtered at Atlanta, Georgia; the source of pigs is undetermined. Cooperrider (1952) listed P. kellicotti among the parasites found in Georgia, but no details were provided. Stewart and Jones (1959) found small immature flukes in lungs of a pig from Fitzgerald, Georgia that were considered Paragonimus rudis (=Paragonimus kellicotti, USNPC no. 49428).
Pulmonic lesions associated with P. kellicotti infections were reported in bobcats and other carnivores ( Table 2). Lungs of two of five bobcats from Arkansas contained approximately 1 cm diameter nodules that contained P. kellicotti (Snyder et al., 1991). Ramsden and Presidente (1975) and Presidente and Ramsden, 1975 provided a detailed description of lesions associated with P. kellicotti in several species of carnivores from Canada ( Table 2). The nodular lesions were found in all lobes of mink lungs. Lesions were essentially similar in mink, skunk, and red fox. The nodules in coyotes had thick walls. Although 26 of 323 raccoon lungs had pleuritis including adhesions, flukes were not found.
Paragonimus. kellicotti eggs have been detected rarely in feces of cats and dogs in the USA examined routinely for parasitism (Conboy, 2009;). Data from general population surveys are summarized in Table 5. Most of the animals were stray. The number of animals found infected was an underestimate because P. kellicotti eggs have a higher specific gravity than solutions often used for flotations. Sedimentation technique is more sensitive, but it is time consuming and rarely used for routine surveys (Dubey et al., 1978a).

Clinical P. kellicotti infections in animals
Clinical paragonimiasis associated with P. kellicotti infection has been reported in domestic cats and dogs in USA and Canada   Alden et al. (1980) Missouri, USA 1 Incidental finding in an adult female cat used in laboratory for cytauxzoonosis research. Several dozen P. kellicotti flukes found in bronchioles at necropsy. Stewart et al. (1981) Indiana, USA 2 Paragonimiasis in 2 cats successfully treated with albendazole (25 mg/kg, twice daily for 10 days). Case 1, 3-year-old female, coughing, wheezing, diagnosed by fecal examination and radiographic findings. Case 2, 9-months-old female, hospitalized for persistent cough for 6 weeks, blood eosinophilia, Paragonimus eggs in feces, radiographic density in lung. After treatment, eosinophilia and eggs disappeared, and pulmonic lesions reduced. Johnson et al. (1981) Louisiana, USA 10 Albendazole (50 mg/kg body weight, twice daily for 11-24 days) therapy was successful in 8 of 10 cats with paragonimiasis. Cats, 2-5 years-old, cough for 1-9 months, paragonimiasis confirmed by fecal examination and radiography. Treatment partially successful in a 2-year-old female medicated with albendazole for 23 days, euthanized because of pneumothorax, 16 flukes recovered from nodular lung lesions at necropsy. The other cat with failed therapy, a 2.5-years-old male, treated with albendazole for 24 days, eggs still present its feces, cat not necropsied. After a few days of therapy, cats disliked the drug and were hyper salivating. Hoskins et al. (1981) Oklahoma, USA 1 2-year-old-neutered male developed clinical signs 1 week after surgical removal of testis (orchiectomy). Cat had dyspnea and polydipsia/polyurea. P. kellicotti diagnosed by radiography and fecal testing. Treated successfully with fenbendazole (50 mg/kg body weight) for 14 days. Cat had not travelled outside of Oklahoma. Rochat et al. (1990a) Kentucky, USA 1 8-year-old barn cat died after episodes of coughing and respiratory distress. Necropsy examination revealed nodules, primarily in diaphragmatic lobe. Adult P. kellicotti and eggs were detected histologically.
Swerczek and Lyons (2000) Ontario, Canada 1 This is the most extensive radiographic evaluation of fenbendazole therapy of paragonimiasis in a 16-month-old female cat.
Cat coughing 20-30 times daily, 7 nodules in lungs and P. kellicotti eggs in feces, fenbendazole (28 mg/kg, orally, twice daily for 21 days) given and followed for a year, clinical improvement day 9 post treatment (pt), cough returned on day 49 pt. Thoracic radiographs revealed that cavitated lesions seen initially were smaller, but a solid nodule was not cavitated, and P. kellicotti eggs were still present in feces,treated second time with same dose of fenbendazole as before. On day 94 pt., P. kellicotti eggs not found but nodules still present in lungs. Cat was evaluated clinically on days 135 and 221 pt. and condition was stable. A final examination on day 316 pt. revealed no P. kellicotti eggs in feces and the pulmonic lesions were smaller. The authors discuss the possibility concerning differences among strains of P. kellicotti in different regions of Canada and the USA.

Peregrine et al. (2014)
DOGS Ontario, Canada 2 A 2-year-old coon hound from Waterloo, several attacks of cough since it was a pup, dyspneic, died of suffocation, 16 flukes in cysts in both lungs, and eggs in feces at necropsy. The second dog, littermate of the dog that died, had mild symptoms and eggs in feces. Nielsen (1955) Arkansas, USA 1 Three months-old-pup died of dyspnea of 3 days duration, no eggs in feces, radiography revealed a cyst in lung, died a few hours after radiography. Necropsy revealed 2 (5-7 mm × 3-5 mm) trematodes in a Short and Hendrickson (1960) (continued on next page) Five-month-old Golden Labrador female from London, Ontario was ovariohysterectomized in a clinic and sent home after 4 days. The next morning the dog was dyspneic, running around frantically, and died. Necropsy examination revealed pneumothorax, collapsed lungs, and a ruptured bronchus. The lungs had 3 nodules and 9 flukes. Comfort and Axelson (1962) Iowa, USA 4 Dog 1, 7-year-old male Labrador retriever and a US Army K-9 Corps, examined in 1948 because of convulsions, fecal examination revealed eggs of Ancylostoma caninum and Paragonimus, served in Orient and whether it acquired infection overseas is uncertain. Dog 2, 7-year-old male coon, from Polk County,fecal examination revealed Capillaria sp. A. caninum, and P. kellicotti eggs. Large (1-3 cm diameter) nodules were found in both lungs and contained adult flukes. In 1 lesion the fluke was free in the pulmonary parenchyma with hemorrhage and inflammation. Dog 3 with no other information, examined at the clinic. A discrete abscess containing 2 flukes was surgically removed from 1 lobe of lung. Dog 4, 7-year-old tan hound from Dallas County, admitted to clinic for treatment of dog bite wound, A. caninum and P. kellicotti eggs in feces, treated for hookworms and sent home. Greve et al. (1963Greve et al. ( -1964 Indiana, USA 1 Paragonimus eggs found during fecal examination of a 2-year-old-mongrel female asymptomatic dog used for teaching. Radiographic examination revealed increased density in lung lobes. Thoracotomy of the diaphragmatic lobe revealed a 6 cm diameter nodule with granulomatous reaction. Dog recovered.
Bisgard and Lewis Pennsylvania, USA 1 This case is unusual because it was an incidental finding of P. kellicotti in a Beagle born and raised in a kennel for drug trials. The dog was necropsied at the end of a trial. Necropsy examination revealed a cystic nodule with eggs. Wilson and Lord (1965) Iowa, USA 2 Two cases of paragonimiasis treated successfully with bithionol (20-40 mg /kg, twice daily for-days). Case 1, 3-month-old male Boston terrier with Paragonimus eggs in feces, mild cough, 20 mg /kg of bithionol not effective, therefore dose increased to 40 mg. Increased in eosinophilia after treatment interpreted to indicate reaction to dead flukes. Case 2,year-old male Coonhound, treated with 45 mg/kg body weight, eggs not detected 5 days after treatment. Greve (1969) Ontario, Canada 1 Four-year-old female Collie from Guelph, intermittent cough for 6 months, pneumothorax, and atelectasis of right apical lobe by radiography. Examination of bronchiolar lavage revealed Paragonimus eggs. No treatment was needed.
Gillick (1972) Mississippi, USA 1 Paragonimus kellcotti infection diagnosed in cat (no details provided) by detection of eggs in feces, radiographs, and by necropsy examination (no details).
Majune and Moore (1975) Illinois, USA 1 Two-year-old female Husky, P. kellicotti infection diagnosed based on a routine fecal examination. Radiography revealed mild diffuse interstitial lung density. No respiratory signs were reported. Medication with Bithionol (100 mg/kg mixed in food every other day for 30 days) stopped shedding of P. kellicotti eggs.
Macy and Todd Jr. Pechman (1976) Georgia, USA 1 Two-years-old mongrel male from Atlanta from a shelter had been used for filarial research. The dog was euthanized, examined at necropsy as part of the filarial research. The dog was emaciated, dyspneic, and had intermittent cough. All lobes of the lungs had nodules that contained a total of 59 flukes, up to 4 flukes per nodule. The flukes were considered P. kellicotti, primarily based on the host species. This is the most heavily infection diagnosed in a dog. This dog had extrapulmonary lesions with Paragonimus eggs. Paragonimus eggs were found in granulomatous lesions in scrotum, spermatic cord, liver, and mediastinal lymph nodes. This is only case with extra pulmonic lesions in dogs. The identity of the Paragonimus species is in question. Ah and Chapman Jr. (1976) Illinois, USA 1 An adult Beagle that whelped 6 pups, diagnosed to have Paragonimus eggs in feces and a cyst in lung. Medicated with albendazole (30 mg/kg body weight, mixed in dog food for 12 days), eggs not seen on day 8 after treatment, necropsied because of cystitis, a dead fluke found in the pleural cavity; cysts were not detected in lungs, eggs present in granulomatous pulmonic lesions.
Todd Jr. et al. (1978) Pennsylvania, USA 1 Four-years-old mixed breed male with chronic cough, gagging, occasional hemoptysis, and weight loss. Diagnosis confirmed by presence of P. kellicotti eggs in feces, and radiography. Dog medicated with praziquantel (5 mg/kg body weight) subcutaneously for 2 days. Because P. kellicotti eggs were still present, the dog was medicated with praziquantel (25 mg/kg body weight) orally, 3 times a day for 2 days. Treatment was successful; the dog gained weight and parasite eggs were no longer detectable 2 months later. Kirkpatrick and Shelly (1985) Missouri, USA 2 Paragonimiasis diagnosed in 2 adult University Research Colony dogs, based on radiographs and P. kellicotti eggs in tracheal washings. Both dogs treated successfully with praziquantel (25 mg/kg/ body weight, thrice daily, total doses 2.7 g and 3.0 g). Eggs were detected in feces of 1 dog for 14 days post treatment in 1 dog and day 5 in the other dog. Kern (1991) Wisconsin, USA 2 A 3-years-old beagle female found dead, 2 other beagles in the same household died within3 weeks with clinical signs of coughing. Necropsy of the index case revealed 3-5 cm diameter nodules in lungs. Madden et al. (1999) (continued on next page) (Table 6). Salient features of these reports are indicated in bold. Most cases from Canada were from Ontario province and there were no reports of P. kellicotti infections from western parts of USA and Canada. The youngest infected cat was 3.5-months-old and the youngest dog was 3-months old (Table 6). Most cases were solitary infections, except three beagles in one household dog died of respiratory distress within three weeks; P. kellicotti infection was confirmed in one of these dogs examined at necropsy (Madden et al., 1999). The owner reported that the dogs had eaten crayfish the previous summer (Madden et al., 1999).
Stress might have aggravated or initiated onset of clinical signs in some cases (Table 6). A cat became dyspneic four days after orchiectomy (Rochat et al., 1990a) and a dog became dyspneic four days after ovariohysterectomy (Comfort and Axelson, 1962).
In all but one case, infections were confined to lungs. The exception was a mongrel dog from Atlanta, Georgia. This dog was also the most heavily infected; all lobes of the lungs had nodules that contained a total of 59 flukes, up to four flukes per nodule (Ah and Chapman Jr., 1976). This dog had extrapulmonary lesions with Paragonimus eggs. Paragonimus eggs were found in granulomatous lesions in scrotum, spermatic cord, liver, and mediastinal lymph nodes (Ah and Chapman Jr., 1976). It is uncertain if the dog had P. kellicotti or other species of Paragonimus (Table 6).
Before the development of albendazole and fenbendazole therapy in 1970's (Dubey et al., 1977b;Dubey et al., 1979b), paragonimiasis in cats and dogs was treated with lobectomy (Bisgard and Lewis, 1964;Rendano Jr., 1974;Pechman, 1976) or bithionol (Greve, 1969;Macy and Todd Jr., 1975;Pechman, 1976) and a variety of other drugs (Rochat et al., 1990b). Subsequently cats and dogs were treated with albendazole (Todd Jr. et al., 1978;Hoskins et al., 1981;Johnson et al., 1981), fenbendazole (Rochat et al., 1990b;Madden et al., 1999;Peregrine et al., 2014) or praziquantel (Kirkpatrick and Shelly, 1985;Kern, 1991; Table 6). In most cases responses to therapy could be followed by necropsy examination. Whether there are regional parasite strain differences with respect to chemotherapeutic is a challenging question (Peregrine et al., 2014; see Table 6). For example, albendazole therapy was successful in 8 of 10 cats in Louisiana, USA (Hoskins et al., 1981). In the other two cats, Paragonimus eggs or flukes were still present despite threeweek therapy (Hoskins et al., 1981). There are individual variations in efficacy of chemotherapy. For example, of two dogs treated with praziquantel, eggs were not seen five days after therapy in one dog, but eggs were still present on the 14th day after treatment in another dog (Kern, 1991). Although triclabendazole and other drugs have been used to treat humans and animals infected with P. westeramani in other countries, the present discussion was limited to P. kellicotti infections in the USA and Canada (Liu et al., 1999;Keiser et al., 2005;Richter, 2022.

Human infections with P. kellicotti
Paragonimus kellicotti infections in humans in USA and Canada have been reviewed Fischer and Weil, 2015;Blair, 2022). One report from Canada described paragonimiasis in four patients that were immigrant to Canada (Béland et al., 1969). I have not discussed this report further because of uncertainty of the species of Paragonimus involved. Following are the salient features of human paragonimiasis in USA.

Geographic distribution
Although autochthonous Paragonimus infections were reported from Oklahoma , Michigan (DeFrain and Hooker, 2002), Colorado (Boé and Schwarz, 2007), and Nebraska , 15 of the 20 reports of were from Missouri (Lane et al., 2009Johannesen and Nguyen, 2016;Horn et al., 2016;Bahr et al., 2017). It is most likely that paragonimiasis was recognized more often in Missouri because of the interest of physicians and researchers at the Washington University, St. Louis, Missouri.

Risk factors
The ingestion of infected crayfish is the only confirmed mode of transmission of P. kellicotti and definitive data are available only from patients who went on boat trips in Missouri and ate crayfish; patients were mostly intoxicated by drinking alcohol and had recalled eating raw crayfish. Although an incubation period of two weeks is mentioned (Bahr et al., 2017;Pachucki et al., 1984), three weeks is the minimum time when symptoms of paragonimiasis were observed (Lane et al., 2009;Lane et al., 2012). This three-week period coincides with the time when P. kellicotti successfully enters lung parenchyma (in experimentally infected cats and dogs).

Treatment
Although there are many drugs available to treat paragonimiasis in humans, praziquantel is the most commonly used in the USA (Calvopiña et al., 1998;Keiser et al., 2005;Fischer and Weil, 2015;Richter, 2022). Of 21 cases of P. kellicotti infections in humans in USA, 20 were treated with praziquantel (reviewed in Coogle et al., 2022). The usual dosage is 25 mg/kg/body weight, three times daily for 2-3 days .

Conclusions and perspective
Here, I have reviewed biology of P. kellicotti in animals and humans in USA and Canada. Among many species of wildlife, the mink is likely the most important reservoirs of P. kellicotti infection. The infective stage of the parasite, metacercariae are produced year around and infections are common in crayfish. Thus, people or animals are likely to become infected by ingesting raw crayfish, as has happened in people who were intoxicated with alcohol while on boat trips in fresh waters. Most symptoms are related to pulmonary infection, and death can occur due to pneumothorax resulting from cyst rupture. The pathogenesis of extrapulmonary symptoms in paragonimiasis in humans remains unclear, because these symptoms/signs have not been documented in cats or dogs. Sensitive and simple diagnostic methods, now in development, should aid research and clinical management.

Specimens deposited
The specimens were deposited in the United States National Parasite Collection in the Division of Invertebrate Zoology and National Museum of Natural History, Smithsonian Institution, Museum Support Center, MRC 534, 4210 Silver Hill Road, Suitland, Maryland 20746, USA (Table 8).

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements
I thank Oliver Kwok for bibliography, and J. Mowery for help with illustrations. Generous advice and help of Dr. Peter Fischer are gratefully acknowledged. I also would like to thank Drs. Nathan Bahr, Dwight Bowman, Andrew Peregrine, and Benjamin Rosenthal for