A review of food poisoning caused by local food in Japan

Abstract Increasingly popular worldwide, Japanese cuisine includes several raw preparations such as sashimi and sushi; however, limited information on food poisoning from Japanese local food is available in English literature. Without appropriate knowledge, physicians may underdiagnose traveler's diarrhea among people returning from Japan. To provide accurate information to primary care physicians worldwide, we conducted a narrative review on food poisoning research published in Japanese and English over the past four years, considering the frequency and clinical importance of various presentations.


| BACKG ROU N D
Japanese food culture is increasingly popular worldwide. Excluding fast food, Italy and Japan are the largest net exporters of local cuisine. 1 The number of tourists entering Japan has also increased rapidly in recent years; annually, 31.88 million people visit to enjoy Japanese food culture. 2 Japanese cuisine includes many examples of raw preparations such as sashimi and sushi; however, few English reports are available on the potential for food poisoning. This lack of knowledge may lead to physicians underdiagnosing traveler's diarrhea in individuals returning from Japan. Therefore, we conducted a review of food poisoning research published in Japanese and English over the past four years. We focused on data of clinical importance, such as case frequency. poisoning) unfamiliar to physicians working outside Japan. Ethical approval was not required, as this study did not involve human subjects.

| RE SULTS
We recorded at least 1000 cases of food poisoning per year in Japan from 2015 to 2018 (Table 1). This number excluded cases of suspected food poisoning. Figure 1 shows a map of Japan with representative types of food poisoning due to local cuisine.  5 Notably, raw meat, such as chicken sashimi and raw liver, is consumed in the unique Japanese food culture and can be a cause of food poisoning. Of note, the consumption of raw beef liver and pork meat is prohibited by law; however, some restaurants still provide these "delicacies." Demographic analysis indicates that Campylobacter poisoning has two peaks, in early childhood (1-4 year old) and in young adults (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) year old). Men are more frequently infected, and adults tend to exhibit stronger symptoms. 6

| Etiology
Chickens harbor Campylobacter spp. in their intestinal tract, and contamination of chicken meat from improper cleaning occurs in meat-processing plants. Therefore, even packed chicken meat at a grocery store may be contaminated. 7,8 Campylobacter spp. can invade human epithelial cells, triggering apoptosis to cause cell damage and diarrhea. 9

| Clinical manifestation
The incubation period for Campylobacter spp. infection is usually 24-72 hours, and sometimes more than 1 week. Major symptoms are watery diarrhea (occasionally frequent and bloody), abdominal pain, and fever. Similar to other parasitic infections such as yersiniosis and salmonellosis, Campylobacter can mimic appendicitis when patients experience right lower abdominal pain. 10

| Prognosis
Almost all patients will recover in a few days, but some may develop late complications such as Guillain-Barré syndrome (GBS) and reactive arthritis in the delayed phase. 14,15 The incidence rate of GBS is estimated at one in 1000 symptomatic patients and can occur even in the context of asymptomatic infections. 16 Besides, the incidence of Campylobacter reactive arthritis is around 1% to 5% of infected patients. 17

| Epidemiology
Anisakis is a genus of nematodes that parasitize marine mammals; fish such as mackerel, horse mackerel, and sardines; and other aquatic organisms such as squid. Japan is among the highest-risk countries for anisakiasis because people frequently consume raw fish. From 2013 to 2015, most cases of Anisakis food poisoning were caused by marinated mackerel fillets called "shimesaba," rather than sashimi (traditional Japanese form of raw fish consumption). 18

| Etiology
Anisakid larvae invade gastric and gut mucosa after ingestion.

| Clinical manifestation
General manifestations of anisakiasis include gastric, intestinal, extraintestinal, and allergic symptoms. In Japan, 95% of anisakiasis is gastric. 19 Gastric anisakiasis causes sudden abdominal pain at 1-12 hours postingestion, along with nausea, vomiting, and slight fever. Intestinal anisakiasis is characterized by intermittent or continuous abdominal pain for 5-7 days after ingestion of larva. Symptoms of extragastric anisakiasis differ depending on parasite location. 20

| Diagnosis and treatment
Patients with acute gastric anisakiasis who consumed raw fish in the previous 12 hours are recommended to undergo gastrointestinal endoscopy. Treatment for gastric anisakiasis involves detection of larva through endoscopy and using biopsy forceps. 21 No therapeutic medication for intestinal anisakiasis currently exists, but albendazole treatment appears to have some therapeutic properties in patients with intestinal obstruction. 22 When a patient has allergic symptoms with or without endoscopic observation of larva, elevation of total or specific immunoglobulin E at 1 month post-allergic reaction can help diagnose gastric allergic anisakiasis. 23

| Prognosis
Vomiting and removal of larva with forceps improve symptoms.
Anisakid larva cannot survive in the human intestine for more than a few days. Therefore, even if endoscopy is not performed, supportive treatment is sufficient in most cases.

| Epidemiology
Japan is one of the few countries that eat pufferfish and among the biggest consumers, so most poisoning cases are from Japan.
Annually, 30-50 casualties (including lethal cases) are reported. This number increases from autumn to winter. 4

| Etiology
Tetrodotoxin (TTX) is the most well-known causative agent of pufferfish poisoning, but the fish also contain other toxins (eg, saxitoxin).
Pufferfish does not directly produce TTX. Instead, Pseudomonas or Vibrio in the ocean synthesize TTX, which then accumulates in the fish's ovary or liver. 24

| Clinical manifestation
Eating pufferfish ovary or liver is prohibited because it almost always contains TTX. The prohibition extends to muscle or skin in some species that contain TTX in those parts. 25

| Diagnosis and treatment
Without commercial tests, almost all cases are diagnosed via clinical reasoning. Definitive diagnosis is made through TXX identification from urinary or blood specimens of patients or from their leftover meals.
Symptoms occur rapidly, minutes to hours after ingestion. Typical clinical manifestations are paresthesia of the face or around the mouth and paralysis of extremities. Some patients develop respiratory muscle paralysis, which can be lethal. There are four grades of severity. 28 As no antidote or specific treatments are known, symptomatic treatment is the mainstay. If poisoning is reported within 1 hour postonset, gastric lavage or activated carbon ingestion are recommended. Extracellular fluid or atropine administration is considered for bradycardia or hypotension. In the event of respiratory failure, artificial ventilation and intubation are used. 28 The known cure is to wait for the patient's body to excrete the toxin.

| Prognosis
Most symptoms occur in 6-8 hours; hence, re-exacerbation after 24 hours is very rare. Prognosis is favorable if the patient survives the first 24 hours and has intensive care.

| Epidemiology
First reported in 2010, Kudoa septempunctata is a novel Myxosporean approximately 10 µm in size, with 6-7 valves and polar capsules. This flower-shaped organism parasitizes as a cyst in olive flounder muscles. 29,30 Initially considered nontoxigenic for humans, K septempunctata has recently been linked to food poisoning. In Japan, the parasite causes approximately 10 cases of foodborne illnesses annually, 31 with most incidents traced back to hatchery flounders from Korea. However, recent research has shown that native fish can also be parasitized. 32

| Etiology
Most patients with Kudoa poisoning develop diarrhea through the following possible manner, although detailed mechanisms are unknown. 29,33 After ingestion, Kudoa releases the sporoplasm, which invades gut epithelial cells. This loosens tight junctions between epithelial cells, causing fluid accumulation in the intestinal lumen and eventually diarrhea.

| Diagnosis and treatment
Diagnosis usually occurs using polymerase chain reaction or microscopic identification of Kudoa in patient samples. 36

| Prognosis
Kudoa poisoning is a self-limited disease with no known fatalities.

| Epidemiology
Japan experiences approximately 30 cases of mushroom poisoning annually, with most cases occurring between September and November. 38-40

| Etiology
Each poisonous mushroom species contains a different toxin, leading to a wide variety of symptoms. In Japan, "tsukiyotake (Lampteromyces japonicus)" and its specific toxin illudin S causes around half the cases.

Some experiments show that illudin S causes cell damage through
reacting to the sulfate of cysteine or glutathione in gastrointestinal epithelial cells. 39 Heating or washing cannot inactivate illudin S. 39

| Clinical manifestation
Although clinical symptoms of mushroom poisoning vary widely, tsukiyotake poisoning causes gastrointestinal symptoms such as nausea, vomiting, and diarrhea within 30 minutes to several hours postingestion.

| Diagnosis and treatment
Detailed history taking and contact with the regional poisoning center should be done. Since the cases caused by commercially available mushrooms are extremely rare, clarifying route of acquisition is essential for diagnosis. 38,40 Specific treatments are unavailable, so only symptomatic treatments are used.

| Prognosis
Serious cases are rare, with reported mortality being about 0.4% be-

| Etiology
Neptunea poisoning is due to tetramine, a chemical produced in the salivary gland of many whelk species. 44 Tetramine exhibits neuromuscular blockade properties, interacts with the autonomous nervous system, and stimulates parasympathetic nerves. 45

| Diagnosis and treatment
Removal of whelk salivary glands is the most effective way to prevent poisoning. Diagnosis requires history taking for whelk consumption without salivary gland removal and the postingestion time course.
Tetramine is a heat-stable substance, and cooking (boiling and slow thawing) can cause diffusion from salivary glands to other tissues. 46 The toxic dose threshold of tetramine is not well established.
Average tetramine concentration per whelk differs across studies, 47 and some studies have even demonstrated between-season differences in a single individual. 48 Thus, the total number of ingested whelks may help determine poisoning, whereas location and season may not inform diagnosis.

| Prognosis
Only supportive treatment is needed, and symptoms tend to resolve in a few hours.

| Epidemiology
The genus Gambierdiscus includes dinoflagellates that produce cigua- The annual number of CFP cases is 15 (including suspected cases). 49

| Etiology
Ciguatoxin lowers the threshold of voltage-gated sodium channels in neural cell membranes and causes depolarization, releasing Gamma-aminobutyric acid and dopamine. Patients then experience a variety of neurological symptoms. 50 Stable under heating or freezing, ciguatoxin cannot be eliminated through cooking, and the only avoidance method is to prevent ingestion of ciguatoxincontaminated fish. 51

| Clinical manifestation
Typical symptoms such as nausea, vomiting, abdominal pain, or diarrhea develop within 6-24 hours after consumption. In some cases, fatigue, headache, and weakness may last for several months. Cardiac symptoms (acute bradycardia and hypotension) are common, with occasional dyspnea. Neurological symptoms include pain or numbness in the extremities, paresthesia (hands, toes, around the mouth), pruritis, myalgia, and arthralgia. The most characterized symptom of ciguatera is temperature-related dysesthesia (so-called "dry ice sensation"), where cold surfaces are perceived as hot. In most cases, this symptom becomes prominent after gastrointestinal symptoms within the first few days. 50 Oh et al 52 have also reported reversible cerebellar dysfunction in CFP.

| Prognosis
In approximately 50% of CFP cases, patients experience persistent neurological symptoms for two weeks or more. 55 Complete recovery from neurological symptoms sometimes requires several months. 49 Mortality is <0.5%. 55 In some reports, alcohol, fish, caffeine, nuts, chicken, and pork can trigger recurrent symptoms. 56

| Epidemiology
Gibier or game in Japan typically comes from wild boar or deer, which are hunted year-round. Recent cases of venison intoxication in Japan have provided important evidence that hepatitis E virus infection (HEVi) is zoonotic and likely a source of food poisoning. 57,58 However, other routes of infection are possible, including uncooked pork, contaminated water, and shellfish. 57,58

| Etiology
Hepatitis E virus (HEV) is a positive-sense single-stranded RNA virus that causes acute hepatitis, but the specific mechanism is unclear. [59][60][61][62][63][64][65] As it is noncytopathic, hepatocyte destruction likely occurs from host immunological reaction. Human HEV has four genotypes. 57 Genotypes 3 and 4 are the causative pathogens of food poisoning in Japan, and genotype 4 is unevenly distributed in Hokkaido prefecture.

| Clinical manifestation
Viral incubation lasts 2-9 weeks. Fever, fatigue, nausea, emesis, abdominal pain, and jaundice are the chief manifestations. In addition to typical hepatitis, neurological dysfunction and renal failure can occur as extrahepatic symptoms. 63 In Japanese clinical settings, most HEVi cases are identified upon medical examination.
Asymptomatic patients are often misdiagnosed with drug-induced hepatitis or not diagnosed at all. Therefore, identifying HEVi as a differential diagnosis is the essential first step. Fulminant hepatitis is very rare, but pregnant or elderly patients are at high risk.
Such high-risk patients should be treated carefully. 59

| Diagnosis and treatment
The IgA-HEV antibody is important for facilitating early diagnosis.
Monitoring the patients' liver function is essential because HEV does not have a specific treatment.

| Prognosis
Most cases of acute HEV are self-limited and have good prognosis.
Transition to chronic hepatitis is rare, but has been reported. 69

| D ISCUSS I ON
When examining patients with acute gastroenteritis, general physicians always consider food poisoning due to Campylobacter, Norovirus, and Anisakis because they account for the majority of cases. However, food poisoning from less common sources occur annually, and awareness of these sources is also necessary. Most food poisoning incidents occur among tourists who enjoy eating local specialties without knowing that they may contain pathogens.
Food poisoning also occurs when consumers eat carelessly, or without knowing that self-collected ingredients might contain natural poisons.
Here, we reviewed causative agents of food poisoning in Japanese local cuisine, with the aim of helping physicians diagnose patients with symptoms specific to food poisoning. We especially wish to highlight that cases involving ciguatera, tetramine poisoning, pufferfish poisoning, HEV, and K septempunctata depend on regional consumption. Thus, even Japanese primary care physicians have not encountered many such cases and may not recognize or suspect the cause of food poisoning.
To the best of our knowledge, this is the first review on food poisoning caused by Japanese local cuisine. Although patients can spontaneously recover after being infected by many of the described causative agents, some sources have neurotoxins that can be lethal. Our survey has several limitations. First, we have only included confirmed food poisoning cases (~1000) from 2015 to 2018 and physicians are not obligated to report Campylobacter enteritis and norovirus infections in Japan; therefore, the exact number of food poisoning cases remains unknown. Second, we omitted general traveler's diarrhea, but we did so because most physicians can provide a differential diagnosis of the aforementioned diseases to travelers with diarrhea returning from Japan. However, here we provided relevant data so that they can include Japanese local food as a potential source of infection.

| CON CLUS ION
Epidemiological reports of Japanese local food poisoning in English are sparse despite an increase in the number of overseas travelers to Japan. Although not an exhaustive list, here we reviewed, for the first time in English, Japanese foodborne illnesses and their causative agents. Our goal was to facilitate food poisoning diagnosis in travelers to Japan who returned with gastroenteritis. We hope that this review will aid further investigation and documentation of Japanese foodborne illnesses.

ACK N OWLED G EM ENTS
The authors would like to thank the Japanese Ministry of Health, Labor and Welfare for providing references, as well as Professor Kazumichi Onigata, Dean of Shimane University Faculty of Medicine, for his careful advice.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article.