Diphyllobothriasis

Diphyllobothriasis is defined as human intestinal infection with the cestode D latum, D nihonkaiense, or other broad tapeworm species. It is acquired by ingestion of inadequately cooked or unfrozen freshwater, anadromous, or marine fish containing larvae called plerocercoids, either in fish muscle or on serosal surfaces.[1] Most individuals with diphyllobothriasis have minimal or minor gastrointestinal symptoms or present with passage of worm segments (ie, proglottids) in stool.

Adult D latum is the largest human parasite and can grow to a length of greater than 20 meters and live for decades. It is capable of causing vitamin B12 deficiency through dissociation of the vitamin from intrinsic factor and consumption of the vitamin.[13] This is rare today, but low vitamin B12 levels have been reported in up to 40% of patients with D latum[1] infestation and 5% of patients with A pacificus infestation.[2] Clinical anemia and neurological disease is much rarer (< 2%).[1]

Evidence of human A pacificus infestation and D latum infestation dates to at least 6,000 years ago in Peru and Germany, respectively, and D nihonkaiense  to 1,000 years ago in Japan,[14] with the first clinical description in Switzerland in 1592. Diphyllobothriasis’s relationship to fish was first noted by Sporing in 1747. The disease appears to have been particularly widespread in Baltic and Alpine freshwater areas up through the early 20th century.[1]

In the early 1970s, an estimated 9 million people were infested with D latum worldwide, with 5 million in Europe, 4 million in Asia, and the remainder in the Americas.[1]

The disease is notable for its association with temperate climate and rarity in the tropics.With improvement in human sewerage treatment, prevalence has significantly decreased in developed areas; however, some zoonotic infection persists, especially with species other than D latum, owing to nonhuman definitive hosts, including bears, wolves, marine birds, and sea lions.

With the increased popularity of raw seafood as part of ethnic foods, wider and faster food distribution networks, and, possibly, fish aquaculture, diphyllobothriasis seems to be extending its traditional geography and resurging, particularly with species other than D latum.[3, 15]

Fish tapeworms have a complex life cycle, with humans, other fish-eating mammals, and birds as their definitive hosts.

Diphyllobothrium life cycle. This illustration depicts the life cycle of different species of Diphyllobothrium parasitic cestodes, the causal agents of the disease diphyllobothriasis. Courtesy of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/dpdx/diphyllobothriasis/).

Adults are long ribbonlike creatures originally identified based on scolex and egg morphology; increasingly, cytochrome oxidase (COX1) molecular testing has clarified nosology and epidemiology.[15] Except for D latum, and possibly D nihonkaiense, which appears specifically adaptive to humans as the preferential host and are by far the most common species involved in human infection, most other species rely on non-human definitive hosts, and humans are incidentally infected.[15]

A full-grown Diphyllobothrium worm is the longest human tapeworm; it can range from 1-15 m in length and 1-2 cm in width.[16]  It consists of up to 3000-4000 proglottids. The scolex has 2 sucking grooves, also called bothria, that attach to small-intestinal mucosa. Proglottids are typically wider than they are long and contain hermaphroditic sexual parts. Humans and other animals may be infested with multiple worms simultaneously.

In the gravid state, the worms have a distinctive rosettelike uterus in the center. Each adult worm sheds around one million operculated eggs every day. To complete their maturation, the eggs must reach water to be eaten by one of 40 species of crustacean copepods and cyclops, within which the procercoid matures.

Copepods that contain the procercoid are then eaten by small fish that function as the second intermediate host. Here, the procercoid matures into the plerocercoid in fish muscle or, in the case of D dendriticum and A pacificus, a serosal body surface such as the peritoneum or an organ such as the liver.[2, 4]

Fish surveys of infected lakes can be performed, monitoring risk via inspection of fish muscle or organs for encysted plerocercoids.[17]  A study of fish caught in Lake Como, Italy, demonstrated infection rates of D latum in pike (Esox lucius) and perch (Perca fluviatilis) of 84% and 25%, respectively. This prevalence was attributed to the popularity of a local dish and the breakdown of sewerage effectiveness.[18]

Progressively larger fish that are paratenic hosts (hosts in which the larvae do not mature further) consume the infected fish. In this manner, the plerocercoid are passed on until, finally, the fish is consumed by a human, the definitive host. Over the subsequent 2-4 weeks, the plerocercoid larva attaches to the host intestine and matures into an adult that can live for up to 20 years.

Table 1. Prevalence of Diphyllobothriasis Infections (Open Table in a new window)

Plerocercoid larvae infect humans who have ingested infected and inadequately cooked or unfrozen fish. Because of the requirement for intermediate hosts, direct human-to-human transmission does not occur; therefore, no isolation measures are required.

Most humans with diphyllobothriasis (all forms) are asymptomatic, and the most common presentation is passage of worm parts, which can be alarming. Many patients retrospectively report diarrhea or may present with symptoms of obstruction[19] or even appendicitis.[5]  Both vitamin B12 deficiency and iron deficiency anemia have been attributed to infestation with D latum, but not as often with other species.[1] Because of this, infection might be a concern for pregnant women.[20]

Diphyllobothriasis is caused by ingestion of raw, undercooked, or unfrozen infected fish and subsequent intestinal infection. The main causative organisms are D latum and D nihonkaiense, but other Diphyllobothrium and similar species have also been reported as infecting agents, albeit much less frequently. Examples include the following[3] :

• Diphyllobothrium dendriticum
• Adenocephalus pacificus
• Diphyllobothrium balanopterae
• Diphyllobothrium alascense
• Diphyllobothrium cameroni
• Diphyllobothrium cordatum
• Diphyllobothrium dalliae
• Diphyllobothrium elegans
• Diphyllobothrium lanceolatum
• Diphyllobothrium orcini
• Diphyllobothrium scoticum
• Diphyllobothrium stemmacephalum
• Diphyllobothrium ursi (possible synonym of  D dendritum)
• Ligula intestinalis
• Schistocephalus solidus

Diphyllobothriasis has been traditionally considered an endemic disease of specific locations where consumption of uncooked fish is common, such as Finland, Scandinavia, alpine Europe, North American lakes (D latum), northern Japan (D nihonkaiense), and Peru (A pacificus). With improvements in sanitation and understanding of disease pathogenesis, the prevalence of infection in endemic areas appears to have fallen dramatically during the 20th century.[1]  Although Japan has mandated case reporting since 2012, little is known about the current prevalence and incidence of various fish tapeworm infections except for case reports and occasional surveys.[21]

Increasing travel, migration, and popularity of ethnic foods have contributed to a broadening of interest and, possibly, exposure to raw fish delicacies, particularly in Asia,[22] but also elsewhere owing to rapid food transport and fish aquaculture.[23]

Examples of foods responsible for infection include raw and salted or marinated fish filets in Scandinavia, Jewish gefilte fish, Italian carpaccio, French tartare maison (raw salmon) and poisson du lac façon nordique, Japanese sushi (raw fish on rice cakes or balls) and sashimi (sliced raw fish), and ceviche (lightly marinated fish) in Latin America. The quality and type of fish, as well as other animal products in dishes, varies by locale and cost, with the highest risk apparently associated with rural restaurants and street vendors. Types of fish and risk may vary by season. The peak risk for D nihonkaiense is associated with the spring catch of cherry and immature chum salmon in Northern Japan. The peak risk for D balanopterae in Northern Japan is associated with the harvest of anchovies from June to August.[21]

Concerns have been raised regarding salmon and other fish aquaculture, particularly in Chile, because of growing salmon smolt in lakes endemic for D latum and potential contamination and escape of infected fish grown in oceanic pens.[23] Such infection might account for infections with D latum in Brazil[24] and other tropical areas such as Taiwan[25] and South India.[26]  Similarly, infection with A pacificus in Spain might be associated with heavy importation of chilled fish from Chile, Ecuador, and Peru.[2, 27]  Although salmonids are not the preferred intermediate host for D latum in the Northern hemisphere, recent reports of D latum plerocercoid larvae adapting to salmonids are especially alarming in South America and may have important epidemiologic consequences as the consumption of salmonids increases.[28]  Placing fish on ice for transport is inadequate to kill plerocercoids and therefore, adequate freezing of fish and parasitologic screening before exportation may be warranted to prevent the spread of disease.[28]

In addition to human migration and importation of disease, other factors might account for the increased incidence and range of disease. These include, in the case of D dentriticum, migrating birds such as gulls around Lake Baikal and climate change affecting intermediate hosts.[4] In the absence of effective surveillance and reporting, these diseases will primarily be discovered incidentally. Fish surveys show variable positivity, with D latum plerocercoid larvae in 84% of pike in Lake Como in 2013-2014 [18] and 51% of Tokyo chum salmon in 2001[14] to 20% of various species of Peruvian marine fish infested with A pacificus in 2014.[2]

Workers in the fish industry may be at some risk for diphyllobothriasis, particularly for serosal or organ-encysted worms such as D dendriticum and A pacificus, from gutting and either contamination or habits of consumption of roe and fish organs while working.[2, 4]

Diphyllobothriasis has no reported age predilection or sexual predilection. In addition, it has no known racial predilection, except as would be expected based on geographic and cultural factors.

Diphyllobothriasis carries an excellent prognosis. D latum is not invasive, and mortality due to diphyllobothriasis is rare. Patients are often frightened and emotionally upset at the passage of worm parts for a long period of time unless treated. Single-dose therapy is usually effective, although some treatment failures have been reported, and repeat treatment is occasionally needed.

Occasionally, infestation can lead to severe megaloblastic anemia or intestinal obstruction. Although it is well described, macrocytic anemia and neurological disease is extremely rare.Gastrointestinal (GI) obstruction is also rare but may occur, especially when numerous worms are present.

Because reinfection is possible, patients should be advised to modify their dietary habits to minimize the potential for reexposure.

Proper food preparation and hygiene should be encouraged, particularly during travel within endemic areas. Preventive public education has been generally inadequate, and the food and restaurant industry has generally been slow to adopt recommendations for freezing of fish. Simple icing of fish is insufficient to prevent infection.

The US Centers for Disease Control and Prevention (CDC) recommends cooking fish to an internal temperature of 63°C (145°F) or higher, freezing fish to -4°F (-20°C) for 7 days or -31°F (-35°C) or less until solid, and storing at either -31°F (-65°C) or below for 15 hours or -4°F (-20°C) for 24 hours.[29] These precautions kill the plerocercoid larvae. The fish must never be sampled before it is properly prepared.

Most persons with diphyllobothriasis are asymptomatic. The vast majority of patients who are diagnosed present with passage of proglottids.

Among persons with diphyllobothriasis who are symptomatic, the following are the most common symptoms[30] :

• Passage of proglottids
• Indigestion or dyspepsia
• Abdominal discomfort

Other, less common, symptoms include the following:

• Fatigue
• Diarrhea
• Dizziness
• Weakness (rare)
• Numbness of extremities
• Sensation of hunger
• Pruritus ani

Gastrointestinal (GI) obstruction is rare, but when it does occur, it manifests as acute abdominal pain associated with vomiting, distention, or both.[19]

Megaloblastic anemia is also rare. Studies note that about 40% of patients have decreased serum vitamin B12 levels, but fewer than 2% of patients are anemic.[31, 1] Patients with an underlying problem (eg, celiac disease or congenital malabsorption) are at higher risk of developing a symptomatic infection. Anemic patients can present with pallor, breathlessness, and neurologic symptoms such as weakness, numbness, and disturbances in coordination. The symptoms depend on the severity.

D latum has an unusual affinity for vitamin B12, and the presentation of diphyllobothriasis may resemble that of megaloblastic anemia. No typical examination findings are noted, except for those seen in severe cases of anemia. Because significant anemia affects less than 2% of persons infected with D latum, most patients with diphyllobothriasis have no signs of illness.

The following physical findings associated with diphyllobothriasis are rare and are most likely related to underlying nutritional anemia:

• Pallor
• Glossitis
• Dyspnea
• Tachycardia
• Weakness
• Hypoesthesia
• Paresthesias
• Disturbances of movement and coordination, loss of vibratory sense and proprioception (related to degeneration of the posterior columns of the spinal cord)

If the patient presents with obstruction, the following physical findings may be noted:

• Abdominal tenderness
• Abdominal distention
• Peritoneal signs

Rarely, patients with diphyllobothriasis may need surgical relief for obstruction or replacement of vitamin B12 or iron.

Laboratory studies that may be used in the diagnosis of diphyllobothriasis include the following:

• Microscopic stool examination for ova and parasites ^[33] : In Taenia species, stool examination has a poor sensitivity of 51.5 to 68%. For Diphyllobothrium infestation, more data is required to determine whether the sensitivity of microscopy for detection of ova and parasites is higher given that Diphyllobothrium adults produce > 1 million eggs per day compared to 300,000 eggs per day by Taenia species. ^{[34, 35, 36]}
• Complete blood count (CBC) - Eosinophilia may be present
• Hemoglobin level and hematocrit - These may be below or at the lower end of the reference range. The anemia produced by diphyllobothriasis is typically associated with increased free hydrochloric acid in gastric juice, in contrast to the relative achlorhydria invariably observed in true pernicious anemia.
• Mean cell volume - This may be above or at the higher end of the reference range
• Peripheral smear
• Vitamin B-12 level
• Folate level

Diagnosis of D latum infection is based on identification of the ovoid and operculated eggs in the stool with a typical knob on the end opposite the operculum. The stool sample does not require concentration for visualization of the eggs. Usually, this is not difficult, because of the large quantity of eggs (≥1 million) produced each day. Also frequently seen in stool are the trapezoid-shaped mature proglottids, which are wider than long and have a rosette-shaped gravid uterus with a central uterine pore. While species identification on gross morphologic appearance is difficult, it may not have much clinical relevance as treatment of Diphyllobothriasis is the same regardless of the species. Species identification through multiplex PCR studies sequencing the COX1 gene, subsequently helps clarify the intermediate hosts and is important for epidemiological purposes and disease prevention.[37, 38, 39, 40]

Proglottids of Diphyllobothrium latum.

Egg of Diphyllobothrium latum with arrow pointing to operculum.

In general, no imaging studies are required to evaluate diphyllobothriasis, unless they are clinically indicated by other aspects of the patient’s presentation. For example, patients who present with obstruction require appropriate testing, starting with both flat and upright abdominal radiography. Abdominal ultrasonography,  a real-time, non-invasive test might detect the hyperechoic, ribbon-like structure freely floating in the intestinal lumen.[8]

On occasion, cases of diphyllobothriasis have been successfully identified by means of upper endoscopy or capsule endoscopy.[13, 41, 42]

Most patients with diphyllobothriasis, unless they have severe symptoms, can be safely treated on an outpatient basis. Inpatient care is not generally required but may have to be considered in advanced, resistant, or complicated cases.

Diphyllobothriasis is treated by pharmacologic means; surgical treatment is not required unless otherwise indicated (eg, in a patient presenting with intestinal obstruction). Even in the face of decreased vitamin B12 levels, less than 2% of patients with diphyllobothriasis develop anemia. Vitamin supplementation may be required in severe cases. As a rule, no activity limitations or restrictions are necessary.

Treatment of diphyllobothriasis is pharmacologic. Because the parasite’s biochemical pathways are different from those of the human host, drug toxicity is directed toward the parasite, the egg, or the larvae. 

Praziquantel is the drug of choice for Diphyllobothrium infections.[43]  The exact mechanism of action in Diphyllobothrial infections is unclear; however, it has been proposed to lead to a rapid influx of calcium ions into schistosomes, with subsequent muscle contraction and paralysis.[44] Praziquantel is effective against D latum as a single dose of 25 mg/kg . A lower dose of 10 mg/kg has been reported to be effective against D pacificum.

Similarly, whereas a lower praziquantel dose of 5 to 10 mg/kg has been reported to be effective against D nihonkaiense, a single dose of 25 mg/kg is the typical dose administered. Side effects are typically minor and include headache, malaise, dizziness, and, rarely, urticaria. An alternative drug is niclosamide, which has limited availability in many countries and has been proposed to act by uncoupling oxidative phosphorylation.[43, 45]  It is effective as a single oral dose of 2 g in adults and side effects rare.[1]

The neurologic and hematologic manifestations of vitamin B12 deficiency respond well to supplementation. In the case of vitamin B12 deficiency secondary to diphyllobothriasis, the signs and symptoms may resolve with antiparasitic therapy alone.

Note: Gastrografin, an iodine-based contrast agent combining diatrizoate and meglumine, used for diagnostic imaging of the intestine, is also a strong laxative and cathartic. Prior to the discovery of praziquantel, it was found to be effective in the rapid expulsion of the entire worm intact, including the scolex. Its use is limited because it requires delivery through a duodenal tube to maintain high concentration in the vicinity of the worm and fluoroscopy is needed.[1, 46]

Resistant or advanced cases of diphyllobothriasis may require consultation with a gastroenterologist and an infectious disease specialist. Consultation with a hematologist may be considered, depending on the severity of anemia. In the case of suspected obstruction, consultation with a surgeon is indicated.

The patient’s stool should be reexamined 1 to 2 months after therapy to test for cure. If the first course of treatment fails, a second identical course of therapy may be administered.[47, 48]  

Rarely, infection with this parasite can lead to intestinal obstruction, cholangitis, subacute appendicitis and cholecystitis.[1, 5] Although more frequently reported in the past, infestation with Diphyllobothrium, particularly D latum can lead to complications associated with severe B12 deficiency, including megaloblastic anemia, peripheral neuropathy, and optic neuropathy.[1, 49]

Diphyllobothrium infection can be prevented on a population level by appropriate sewage treatment, thus preventing human feces containing the eggs from entering water bodies and subsequent hosts of the parasite life cycle.[50]  Furthermore, parasitic screening of fish prior to exportation and ensuring adequate freezing of fish during exportation are other key processes required to prevent spread of this disease.[18, 28]  Adequate labeling of fish products attesting to the safety of preparation procedures is also a measure that would protect consumers from purchasing potentially contaminated fish.[50]

On an individual level, the US Centers for Disease Control and Prevention (CDC) recommends cooking fish to an internal temperature of 63°C (145°F) or higher, freezing fish to -4°F (-20°C) for 7 days or -31°F (-35°C) or less until solid, and storing at either -31°F (-65°C) or below for 15 hours or -4°F (-20°C) for 24 hours.[29] These precautions kill the plerocercoid larvae. The fish must never be sampled before it is properly prepared.

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Class Summary

Antimicrobial agents are used to eradicate the infecting organism (most often, D latum). Praziquantel is the drug of choice; niclosamide is an alternative.

Praziquantel (Biltricide)

Praziquantel is used in the treatment of several different infestations and is the drug of choice for diphyllobothriasis. It increases cell membrane permeability in susceptible worms, resulting in loss of intracellular calcium, massive contractions, and paralysis of musculature. Tablets should be swallowed with liquid during meals; keeping the tablets in the mouth may result in a bitter taste that can induce nausea or vomiting. It is effective as a single dose of 25 mg/kg. While a lower dose of 10 mg/kg has been reported to be effective against D. pacificum, 25 mg/kg is the typical dose administered for D. latum and D. nihonkaiense.

Niclosamide (Niclocide)

Alternative treatment for diphyllobothrium infections. This drug has limited availability is some countries. It acts by inhibition of mitochondrial oxidative phosphorylation and glucose uptake in the parasite. It is effective as a single oral dose of 2 g in adults and side effects rare.