Introduction

Paragonimiasis (PRG) is a food-borne parasitic infection caused by the genus Paragonimus and it mimics pulmonary tuberculosis. This parasite usually requires diagnostic differentiation from the tuberculosis¹ and carcinoma² PRG is often caused by Paragonimus westermani(P.westermani) and they belong to Trematodes and are also called flukes that include the helminths. Gibson and Bray (1994) proposed a systemic classification of trematodes. Trematodes belong to the phylum Platyhelminths, class Trematoda or Dignea. P.westermani is classified as a lung trematode (fluke)³. There are more than 50 distinct species in the genus Paragonimus, and 9 species are known to infect people. Asia’s most common species of human pathogen, P. westermani, is well recognised⁴. PRG poses a risk to more than 293.8 million persons worldwide⁵ and regions of South America, Asia, and Africa are plagued by this disease except Australia and Antarctica⁶.

Multiple  organ system infections have intricated variable clinical presentations. The “tunnel” sign and serpentine deformations in the brain, spleen, liver, and lung are significant imaging signs of the disease⁷. Due to the clinical similarities between PRG and tuberculosis(TB), a differential diagnosis is needed.Lung biopsy can be used in conjunction with microbiological diagnostic methods to confirm PRG diagnosis⁸. Both TB and PRG have been identified in the north-eastern states of India, and multiple endemic foci have been located. The frequency of PRG in the general population varied from 7 to 15% and it was around 50% in TB patients. Nevertheless, PRG is frequently underdiagnosed⁹.

Materials and methods                               

During the review process, electronic databases such as Scopus, Google Scholar, PubMed, Web of Science, and Science Direct were accessed. Search terms for PRG research and review papers included lung fluke, Paragonimus in Northeast India, P. westermani, praziquantel, and triclabendazole.

Discussion

Historical review of Paragonimus 

Paragonimus ova were first discovered in the stool and sputum of a Chinese patient in Mumbai, 1919 and it was believed that the infection may have originated outside India. Singh et al. (1981) reported the first instance of paragonimiasis in Manipur. Epidemiological survey of PRG was first carried in the east district of Manipur, India between 1986 and 1987. In November 1990, Manipur hosted the first Indo-Japan joint research on Paragonimus and paragonimiasis. This research focused on the morphological characterisation, pathobiology, and life cycle of Paragonimus species. This has led to the identification of crustaceans as second intermediate hosts, the structural features of Paragonimus species from Manipur and the detection of endemic paragonimiasis sites⁴. The primary cause of human paragonimiasis in these states has been determined to be P.heterotremus⁶. The clinical manifestations such as  tightness  and pain in the chest, coughing up blood-stained sputum or haemoptysis and dyspnoea, can often misdiagnosed as tuberculosis. The differential diagnosis such as the radiologic findings, Dot-immunogold filtration assay (DIGFA), Intradermal test and  ELISA were used for differential diagnosis of paragonimiasis⁴.

Life Cycle

To complete the life cycle, mammals act as a definitive host for the Paragonimus species where sexual reproduction occurs, snails and crustaceans serve as the intermediate hosts ¹⁰.

First intermediate hosts

The life cycle begins with the generation and release of fertilised, operculate ova from sexually developed adult trematodes that are present in the lungs of the host. The eggs are ingested and subsequently either released or excreted in the stool after being coughed out ¹. The first intermediate host (the snail) is invaded when Paragonimus eggs produced in the sputum or stool of definitive hosts hatch and release ciliated miracidia. In the snail, the miracidium changes into a mother sporocyst⁴. The sporocysts, are simple sac-shaped structures containing germ cells, create the first generation of rediaea larvae phase which develops in the intermediate host asexually. Similar germinal cells are present in both the first and second generations of rediae, which are then responsible for producing the stumpy-tailed cercariae that eventually emerge from the snail ¹⁰. As a result, in the snail, it takes between 9 and 13 weeks for miracidium to grow into cercariae. An appropriate crustacean host is where the cercariae continue to develop⁴.

Second intermediate hosts

The second intermediate host for the cercaria are snails and Crustaceans (Anterior stylet and a stumpy tail) they are infected by ingestion of infected snail or by direct penetration of the cercaria¹⁰. Metacercariae from different Paragonimus species may coexist in a single crab. The cercariae transformed into metacercariae and stayed encysted in the crab host’s skeletal muscles, intestines, gills, liver, and possibly heart. The metacercariae must be ingested by an appropriate final mammalian host in order for the life cycle to continue⁴.

Definitive hosts

The metacercariae excyst larvae, which were ingested by the definitive hosts, penetrate the intestinal wall of the small intestine and travel 3–6 hours to the abdominal cavity. The larvae subsequently migrate into the abdomial cavity through the diaphragm leaving back of hemorrhagic and rusty-brown inflammatory exudates ⁴. Following this, the worms enter the lung parenchyma to develop into matured worms that lay ova. The unembronated ova damage the bronchial wall, causing to cough up sputum that is laden with ova or, if consumed, excreted through stools. Consequently, the life cycle continues ¹.

Route of exposure

PRG is a significant contributor to lung disease on a global scale. When freshwater crabs or crayfish are consumed raw or improperly prepared, humans become infected. An alternate way to contract infection is through the consumption of raw flesh from a paratenic animal host, in which matured worms frequently live in groups in lung cysts and release their eggs through air passages ¹¹. Additionally, the parasite migrates from the gut to the lungs and finally to the brain, skin, and subcutaneous tissues¹².

Clinical Manifestations in humans

Human with paragonimiasis typically experienced symptoms of cough concurrently with the presentation of hemoptysis, chest discomfort, dyspnea with occasional fever and eosinophilia¹. One to two months or more may be needed for incubation. Clinical manifestation of a modest bronchopneumonia, bronchiectasis, pneumonitis, or pleural effusion may also accompany paragonimiasis¹³. Common symptoms of persistent infections include weakness, weight loss, anaemia, and fever. In general, lung infections have a high rate of morbidity and a low rate of fatality, unless they are compounded by infections of important organs like the heart and brain. From a clinical perspective, the three types of paragonimiasis are: pulmonary pleuropulmonary, and extra-pulmonary. Contrarily, Paragonimiasis has been divided into three categories by Procop et al. (2009): Ectopic Paragonimiasis, Chronic Pleuropulmonary Paragonimiasis, and Acute Paragonimiasis⁴. In India’s north-eastern states, paragonimiasis and tuberculosis are widespread and paragonimiasis is infrequently included in the distinctive diagnosis of TB. Due to its similarity to the clinical presentation of TB, diagnosis is typically delayed ¹⁴. Paragonimiasis can be misdiagnosed and neglected and often treated with anti-TB medication when it mimics smear-negative pulmonary TB, especially in high-prevalence countries³⁰.

Laboratory diagnosis

Diagnosis is based on microscopic demonstration of Paragonimus eggs in sputum, pleural fluid, and stool or by serological test.  The presence of distinctive ellipsoidal, golden-brown, operculated paragonimus eggs in body fluids, sputum or faeces allows for the precise diagnosis of paragonimiasis. A mature worm may occasionally be discovered in biopsy samples, autopsies, pleural fluid, or sputum¹⁵.

Sputum

Ziehl-Neelsen (ZN) stain is a popular stain, for identifying Paragonimus eggs in sputum. When conventional Wet film (WF) and ZN stains are compared, the ZN Stain examine is preferred since it completely excludes the possibility of TB transmission during the standard WF examination for paragonimiasis. According to Slesak et al. (2011), the ZNS approach provides potential for paragonimiasis epidemiological research. Hence, sputum is frequently screened for Paragonimus eggs ¹⁶. On the contrary, a direct wet mount fecal test for the parasite egg is ideal for specimens of sputum collected in the early morning. In most cases, blood-stained or the rusty brown sputum have many Paragonimus eggs and Charcot-Leyden crystals ⁴.

Pleural Fluid

Approximately 10% of pleural effusion cases may possibly contain paragonimus eggs in the centrifuged deposit of pleural fluid⁴. Pleural fluid is the most suitable specimen to determining if anti-Paragonimus-specific antibody is present. The fibrous tissue removed during decortication may contain several eggs and they are typically not visible in the pleural fluid.The pleural fluid usually consists of leukocytes, eosinophils, and Charcot-Leyden crystals that are birefringent and easily visualised with plane-polarized ¹⁰. In PRG, pneumothoraxor pleural effusion is a significant finding ¹⁷.

Stool

The formalin-ether sedimentation method uses two to three stool samples taken on consecutive days. In children, the sputum samples likely negative for eggs, stool examination for Paragonimus eggs is often suggested⁴. A single stool test has sensitivity between 11 to 15%, which is lower than sputum test sensitivity. However, the sensitivity increases to 25% when three stool samples are examined¹⁰. In addition, it is also possible to observe ova of Trichuris trichiura and Enterobius vermicularis in stools samples¹⁸.

Biopsy

The ova of PRG are far more likely to be discovered than the adult worm during histological and cytologic processing of respiratory samples¹⁰. However, in a carefully dissected cystic lesion or nodular we may find immature adult helminths. As an alternative, a histological analysis will also reveal eosinophils, inflammatory cells, fibro collagenous tissue, sections of the helminths, and deformed eggs⁴. Following the failure of histological and cytologic procedures, a lung biopsy can be performed to ensure a diagnosis of PRG ¹⁴.

Immunodiagnosis

The most accurate technique of diagnosis is a serological test. Clinical samples from patients with early-onset (asymptomatic), chronic (inactive), or ectopic paragonimiasis may not show eggs. However, serological techniques are unable to distinguish between serum antibodies for previous and present infections, which frequently linger afteranti-helmintic therapy. Different serologic assays have been established, and they differ slightly from one another in terms of their sensitivity and specificity. Most serologic assays are extremely sensitive, frequently surpassing 95% sensitivity¹⁰. Numerous immunological assays have been examined, including, Enzyme-Linked Immunosorbent Assay (ELISA), Indirect Haemagglutination Test (IHA), Complement Fixation Test (CFT),Western blot, Intradermal (ID) test, and Immunodiffusion⁵. Based on these, the immunoserologic enzyme-linked immunosorbent assay test, which detects IgG antibodies specific to paragonimus, is generally regarded as sensitive and precise in the examination of paragonimiasis. IHA is a quick and sensitive test that revealed a sensitivity of 88 per cent in the diagnosis of P.heterotrema. CFT is used to confirm cases of ID positivity and to diagnose current infections. Western Blot is for sero-diagnosis of human P. heterotremaand specific diagnosis of PRG. ID test is used to distinguished pulmonary PRG from pulmonary tuberculosis. Immunodiffusion are accurate test and can be used for speciation by demonstration of specific precipitin bands⁴. The availability of serologic tests is constrained, and given the rarity of the condition, they are frequently used as confirmation testing after pathology has identified the organisms¹⁹. A rapid test kit called dot-immunogold filtration assay (DIGFA), can detect anti PRG antibodies in less than 10 minutes. The kit’s sensitivity and specificity were up to 99 and 92 percent, respectively ²⁰.

X-rays and other imaging technique

The life cycle of PRG through human infection result in a variety of imaging findings that are non-specific and diverse.  Common features include Ground-glass opacity(GGO), migration track, worm cyst, nodule, pleural effusion, pleural thickening on chest CT scans, ring-enhancing lesions on brain MRI. In computerised tomography (CT) scans features like mixed density lesions or patchy low, serpentine lesions or conglomerated small cystic and migration worm cyst and migration track ²¹. Pulmonary parenchymal abnormalities and bilateral effusion in chest radiography we also detected²². In the cerebral cortex, clusters of numerous ring-structure shadows known as “grape cluster,” “soap bubble appearance,” or “isodense lesion” that resemble tuberculomas can be seen on brain scans using and MRI in individuals with cerebral paragonimiasis. In comparison, CT scans was a more effective method for observing lung lesions than unlike the chest X-ray⁴.

Treatment

Early diagnostic and efficient treatment is essential to prevent the onset of paragonimiasis. In pulmonary paragonimiasis, praziquantel (325 mg/kg/d for 3 days) cleared ova from sputum after 90 days medication. Triclabendazole at 5 mg/kg/d is necessary to effectively remove ova from sputum. World Health Organization (2012) recommended PZQ and TCZ medications for treatment of human paragonimiasis (Table: 1). PZQ has also been approved by the American Academy of Paediatrics as the first line of treatment for paragonimiasis. The recommended course is a total of 150 mg/kg administered orally three times per day for three days ²³. However, PZQ has side effect which causes  abdominal pain, headache, dizziness, and diarrhea ²⁶. On the other hand, TCZ  causes side effect such as  biliary colic, which  include abdominal, hypochondrial and epigastric pain, often accompanied by sweating.²⁸. Depending on the clinical and epidemiological setting, so far it has shown that if one medication is ineffective, the other has proven to be effective and vice versa ²⁴.

Table 1: Common medication for Paragonimiasis

Prevention and control

Avoiding non-boiled stream water, raw or undercooked river crabs or crawfish, pickled or liquor-soaked crabs, and non-cooked or undercooked river water, paragonimiasis can be avoided. Patients who exhibit symptoms of suspected paragonimiasis need to receive active ²⁴. Mass drug administration, increased public knowledge, and health education are frequently mentioned in paragonimiasis prevention techniques²⁵. Although vaccination is a possibility, it is unlikely to happen given the more urgent demand against illnesses that are more common and their impact on the economy¹⁰.

Figure 1: Direct wet mount of sputum showing operculated egg of P. westermani at 40X, 19. Click here to view Figure

Figure 2: Charcot-Leyden crystals seen in the pleural fluid1. Click here to view Figure

Figure 3: P. Westermani adult taken from a lung biopsy specimen 3. Click here to view Figure

Conclusion

PRG is a foodborne lung infection common in northeast, India, and it was first documented in Manipur. The cause of paragonimiasis has been associated to be P. heterotremus. PRG resemblance to pulmonary tuberculosis in clinical presentation, Chest radiographs shows definitive role in differentiating one disease from the other, which results  in misdiagnosis. Examination of eggs in sputum and stool is the most routine diagnostic protocol. However, the most accurate diagnostic technique is the immunodiagnostic test. PRG infection can be prevented by avoiding uncooked meals and thoroughly preparing food can help prevent the disease. Praziquantel is the preferred medication for paragonimiasis, while triclabendazole is also an option. PRG infection is most likely to persist until there is increased public knowledge on the effects of consuming uncooked crabs and crayfish, and awareness among medical professionals and governing bodies to implement adequate management measures.

Acknowledgement

The author is grateful to Assam downtown University for the assistance provided during the study.

Conflict of interest

The authors affirm that they have no conflict interests to disclose.

Funding source

There are no funding sources.

 Authors’ contributions 

Vekutolu Resuh: Writing – original draft, Investigation, Methodology,

Avolu Kotso: Data curation

Viswedenu Kera: Data curation

Lipoksenla Walling: Data curation

Ibasiewdor Mawlein: Data curation

Wankupar Wankhar: Conceptualization, Validation, Formal analysis, Writing

review & editing.

Ethics Approval Statement

not applicable

Data Availability Statement

not applicable

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