Current status of the treatment of paragonimiasis

INTRODUCTION

Paragonimiasis belongs to the family of foodborne trematodiases and is a neglected tropical disease. Paragonimiasis is caused by various species of the genus Paragonimus. Out of the 50 different species isolated from freshwater crabs or crayfish in Asia, Africa and the Americas, a dozen species are known to cause disease in humans^[1].

Human infection occurs through consuming improperly cooked freshwater crustaceans, crabs or crayfish, eating paratenic hosts such as wild boar and deer or by ingesting metacercariae from contaminated hands and cooking utensils^[2,3]. Metacercariae may also be present in raw juice extracted from crabs/crayfish. Traditionally, in Korea and Japan the juice is used as traditional medicine for humans and in some African societies raw crabs are thought to increase fertility^[2].

In subtropical and tropical countries paragonimiasis occurs especially in marginalized populations. In Africa and in the Americas, the disease is frequently associated with a low standard of living and insufficient or irregular food supply, causing people to catch and eat freshwater crabs. In Asia, raw or undercooked crabs are regarded as a delicacy including “drunken crab” in China, “Kung Ten” and “Nam Prik Poo” in Thailand, “Ke Jang” in Korea and “Kinilao” and “Sinugba” in the Philippines^[2].

By consequence, paragonimiasis is expected to occur in settings where people do not have sufficiently to eat and/or where people consider eating raw crabs/crayfish as a delicacy. Other risks to take into account include eating undercooked paratenic host meat and traditional beliefs about eating raw crab meat or juice^[2,3].

Approximately one million people are infected every year. Human infections have been reported from 39 countries and areas, although the major endemic areas are in Asia. More than 20 million persons are infected and 292.8 million persons are at risk^[4,5]. Paragonimiasis has always been a serious medical problem in some countries, such as China, Japan, Korea, the Philippines, Cameroon; Nigeria and Ecuador^[5,6]. The number of patients decreased in Japan and Korea over the last decades. In the meantime, new endemic foci have emerged, raising the necessity for effective treatment^[6,7].

The morbidity associated with paragonimiasis is directly related to the development of ingested metacercariae in the final host. Metacercariae released from ingested crabC flesh develop into juvenile worms which penetrate the intestinal wall and then follow a complex migration route through the peritoneum, the diaphragm and the pleura to finally reach the lung parenchyma. Typically, adult flukes encapsulate within the pleura or in the lung parenchyma. In the former case pleuritis or pleural thickening will develop. In the latter case eggs are released into bronchioles, coughed up, mixed with sputum, and are either expectorated or swallowed for later excretion via feces. The clinical picture (cough, hemophthysis, fever, asthenia, pleura effusions, pulmonary masses, lung cavernae) is very similar to tuberculosis (TB)^[8]. Therefore, paragonimiasis in Vietnam is also called “eosinophilic TB” (Richter 2002, personal observation, unpublished). In endemic areas paragonimiasis may also be associated with TB or it may be confused with lung cancer^[8-10].

Symptoms of pulmonary paragonimiasis are results of pleuritis and pneumonia/bronchitis. Pleuritis is caused by worms present in the pleural cavity inducing pleural effusion with massive eosinophil infiltration^[11].

Extrapulmonary localization occurs in about 1% of all patients, its frequency depending on the Paragonimus species^[1]. The most frequent ectopic localization is in the brain with 30%-60% of all extrapulmonary localizations^[1]. Other ectopic localization are: spinal cord, eyes, subcutaneous tissues, heart muscles, mediastinum, breast, bone marrow, liver, spleen, pleural cavity and pericardial cavity and scrotum^[1]. Globally, the disability weight of paragonimiasis is high^[12].

This review aims to provide an update on how to treat paragonimiasis with either triclabendazole or praziquantel, the two drugs currently available.

SEARCH STRATEGIES AND SELECTION CRITERIA

This study is reported according to the Preferred Reporting Items for Systematic Reviews^[13].

The PUBMED database was searched using a combination of the terms “paragonimiasis” AND “treatment*” OR “therap*” from 01/2000 to 02/2022. Since a tentative search did not show any randomized controlled trial (RCT), in the final search, open clinical trials, case reports, case series and retrospective analyses of hospital records were looked for as well.

Additional searches were undertaken in Google Scholar, and reference lists of included papers were manually searched. After duplicates were removed, the titles and abstracts of the records were screened for relevance and the full-text articles were reviewed for eligibility. Due to the small number of publications on the topic, all publications describing at least one case of paragonimiasis treated with praziquantel or triclabendazole were included regardless of study population, intervention type, outcome measures, and duration of follow-up. The non-RCT studies were analyzed and summarized to provide a comprehensive profile on the treatment of paragonimiasis.

RESULTS

No randomized controlled trials were identified. Therefore, open clinical trials, retrospective analyses of hospital records, cases series and case reports were analyzed. The open trials with praziquantel are summarized in Table 1. All trials were performed between 1981 and 1989, a couple of years after the introduction of praziquantel into the market. The five studies on 487 patients aimed to identify the optimal dosage for paragonimiasis in the lungs. Most studies performed in South Korea and China showed that in 81%-100% of patients treated with 3 × 25 mg/kg/d for three days no eggs were detected in sputum after three months^[14,15]. Lower doses, such as 3 × 20 mg/kg/d for 2 days, were less effective. Radiological findings, such as cavities, nodular opacities, pleural effusion diminished in size, but remained visible after 90 days post-treatment^[15]. According to Rim et al., all patients improved clinically, and radiological findings reversed to normal after one year^[14].

The efficacy of the treatment with praziquantel did not seem to depend on the Paragonimus species.

In three open trials on 226 patients triclabendazole was used [Table 2]. The two studies performed in Ecuador were designed to identify the optimal dosage. 5 mg/kg/day for three days cleared eggs from the sputum more rapidly than 5 mg/kg/d in a single dose. Similarly, 2 × 10 mg/kg on one day cleared eggs from the sputum more rapidly than 10 mg/kg in a single dose [Table 2]^[19,20]. Calvopiña et al. reported a similar efficacy of triclabendazole (5 mg/kg/d for 2 days) and praziquantel (3 × 25 mg/kg/d for 3 days). However, the study was not designed to allow a comparison of the efficacy of both drugs^[19].

Retrospective analyses of hospital records, case series and case reports is shown in Table 3. Of the 558 cases described, 425 were from China, 52 from Ecuador, 33 from South Korea, 24 from Columbia and 12 from the USA. From the remaining countries, only single cases were reported. Since the great majority of patients were from Asia, the dominant parasite species was P. westermani in 160 cases, followed by P. skrjabini (71 cases) and P. heterotremus (9 cases). On the American continent, patients were infected with P. mexicanus (74 cases) or P. kellicotti (12 cases). The great majority of the patients had paragonimiasis of the lungs and/or the pleural cavity. In Chinese patients the brain, the pericardium and the liver were also affected.

544 cases were treated with praziquantel and 14 cases with triclabendazole. Usually, praziquantel was administered in a dose of 3 × 25 mg/kg/d for three days and triclabendazole in a dose of 10 mg/kg/d for one or two days. Since the definition of improvement and cure varied greatly between the studies, a quantitative comparison of the efficacy of the different treatments was not possible. To indicate the outcome of the treatment in a narrative manner, the terms “improvement” and “recovery” were therefore used.

After treatment with praziquantel (3 × 25 mg/kg/d) recovery was reported in 147 cases and improvement in 66 cases. In the 244 cases from the retrospective analysis of hospital records either improvement or recovery were noted. In a substantial number of patients full recovery needed additional treatment courses with praziquantel.

All cases of paragonimiasis caused by P. mexicanus (Ecuador, Columbia) and P. kellicotti (USA) were cured after praziquantel (3 × 25 mg/kg/d) except for a single case with a chronic disease^{[7,10,48,50-52]}. In 9 patients infected with P. skrjabini and treated with triclabendazole recovery was reported^[24].

Since the patients differed regarding to organ manifestation, disease duration, stage and severity, co-morbidity (such as TB) and other host-related factors, no conclusion can be drawn on the efficacy of praziquantel for the treatment of paragonimiasis in general. Particularly, it is impossible to determine the efficacy of praziquantel in the treatment of brain paragonimiasis. Many patients were operated and/or received additional medications such as methylprednisolone or anti-epileptics. Two larger case series with cerebral paragonimiasis from China, however, indicate that the great majority of patients improved^[25,26].

Two case reports merit to be discussed in detail. Qian et al. reported that in some patients with paragonimiasis in the brain multiple courses of praziquantel (3 × 25 mg/kg/d for 3 days) did not result in improvement^[33]. These patients were cured after an additional treatment with 10 mg/kg triclabendazole. In contrast, Kyung et al. observed no effect of triclabendazole as the primary treatment of a patient with lung paragonimiasis. The patient was cured after treatment with praziquantel^[40].

None of the studies was designed to allow the comparison of the efficacy of praziquantel and triclabendazole.

DISCUSSION

Paragonimus species develop in a broad range of specific snail (= first intermediate host) and crab/crayfish species (= second intermediate hosts). The final host encompasses many different species of wild and domestic mammals which consume freshwater crabs/crayfish, such as mink bobcat, raccoon, civet, coyote, fox, dog, skunk, weasel, badger, marten, boar, pig, deer, guinea pig, tiger, leopard, panther, and cat^[1-4]. Since paragonimiasis is a zoonosis with many animal reservoirs it is impossible to eradicate, and new cases will continue to occur as long as people consume fresh/undercooked crab/crayfish. Early diagnosis and effective treatment are therefore the mainstay to avoid the development of debilitating, and in the case of brain paragonimiasis, life-threatening disease.

In the open clinical trials, praziquantel (3 × 25 mg/kg/d for 3 days) cleared eggs from the sputum taken 90 days post-treatment in all patients with pulmonary paragonimiasis^[14,15]. Symptoms and signs disappeared, and radiological findings reversed to normal after one year^[14]. However, it cannot be excluded that the true cure-rate was lower: The sensitivity of the detection of eggs in sputum is not known, the method has never been standardized, and day-to-day-variation of release of eggs into the bronchi may have an impact on the diagnostic precision of the method.

In the open clinical trials with triclabendazole, it was shown that 5 mg/kg/d were needed to rapidly clear eggs from the sputum^[19,20]. None of the studies allowed to compare the efficacy of praziquantel with that of triclabendazole. Of the 558 cases identified in retrospective analyses of hospital records, case series and case reports, 544 were treated with praziquantel and only 14 with triclabendazole. Since 2003 only a few cases treated with triclabendazole have been reported.

After treatment with praziquantel (3 × 25 mg/kg/d) recovery was reported from 147 patients and improvement from 66 patients. In the 244 cases from the retrospective analysis of hospital records either improvement or recovery were noted. Similar results were reported also in case series and case reports on patients published earlier than 2000^[17,53-67] In 9 patients infected with P. skrjabini and treated with triclabendazole and recovery was reported. Since the patients differed with regard to organ manifestation, disease duration, stage and severity, co-morbidity (such as tuberculosis), other therapeutic interventions such as surgery and other host-related factors, no conclusion can be drawn on the efficacy of praziquantel compared to that of triclabendazole. For instance, in areas where tuberculosis and paragonimiasis overlap and patients are treated with antibiotics for long periods, the efficacy of the treatment of paragonimiasis may be impaired^[46]. Rifampicin, for example, induces degrading enzymes and thereby reduces the plasma level of praziquantel to zero^[8].

In 11 patients with cerebral paragonimiasis multiple courses of praziquantel (3 × 25 mg/kg/d for 3 days) did not result in improvementl^[33]. These patients were cured after an additional treatment with 10 mg/kg triclabendazole. In a report of a case with lung paragonimiasis, the treatment with triclabendazole remained without effect. The patient was cured after treatment with praziquantel^[40]. Whether these findings indicate that in the first case praziquantel, and in the second case triclabendazole was not sufficiently absorbed or rapidly degraded, remains to be elucidated. The findings, however, underline that the characteristic pharmacokinetics of praziquantel and triclabendazole have to be understood to guarantee that the medication is effective^[68].

Since schistosomiasis and paragonimiasis overlap in many countries in Africa and Asia, and because praziquantel is administered to school-age children as preventive mass chemotherapy in all schistosomiasis-endemic areas, it has been suggested that the regular treatment with praziquantel may have an additional benefit on the incidence of paragonimiasis in children and adolescents^[69].

However, experimental studies show that a 10-fold higher concentration of praziquantel is required to paralyze the small liver fluke Clonorchis sinensis, another member of the family of food-borne trematodes, than to paralyze Schistosoma mansoni^[4].

On the other hand, in areas endemic for Taenia (T.) solium infection and possible unrecognized cerebral cysticercosis, the activity of praziquantel against T. solium metacestodes and the consequent immune response could possibly cause cerebral edema and epilectic attacks which is not expected for triclabendazole which is apparently not active on cysticerca^[70,71]. Furthermore, TCZ is not only active against small liver flukes but also against the large liver fluke Fasciola hepatica^{[68,21,44,72]}. Although TCZ is a well investigated and safe drug higher daily TCZ dosages and co-medication of PZQ and TCZ of unresponsive cases has apparently never been tried.

CONCLUSION

Both, PZQ and TCZ are usually effective for treating paragonimiasis. In some cases not responding to one of the drugs, the other has proven effective, so far. Either drug has its advantages depending on the clinical and epidemiological context. PZQ is effective against a large range of plathelminthes including schistosomes, small liver flukes and taeniae. This effect can be advantageous in areas where these infections are co-endemic. TCZ has the advantage of requiring lower dosages and fewer treatment courses, being effective also against Fasciola spp. as well as apparently not being active on unrecognized cysticercosis co-infection, which might pose problems in areas where Taenia solium is co-endemic. For comparison of the efficacy of PZQ versus TCZ double blinded, controlled randomized investigations are required. Furthermore, trials are warranted to find out the ideal medication (single dose versus multiple dose-therapy schemes, TCZ-PZQ combination-therapy for a given setting taking into account co-infections and logistic issues.