Scombroid (histamine) poisoning

INTRODUCTION — Scombroid poisoning is a common seafood-associated disease throughout the world [1,2]. It may also occur after consumption of contaminated Swiss cheese. The most common findings consist of rapid-onset flushing of the face and neck, erythematous and urticarial rash, diarrhea, and headache occurring soon after consumption of the contaminated fish or cheese. Rarely, severe bronchospasm or cardiac effects may occur in patients with predisposing conditions, such as asthma or heart disease. Because of its clinical presentation, it is frequently misdiagnosed as seafood allergy. For most patients, management consists of treatment with H1 or H2 antihistamines. Patients with life-threatening airway edema, bronchospasm, or distributive shock warrant treatment as for anaphylaxis (table 1 and table 2) [3].

This topic will discuss the clinical manifestations, diagnosis, and management of scombroid (histamine) poisoning. Other microbial and marine foodborne diseases are discussed separately:

●(See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings".)

●(See "Ciguatera fish poisoning".)

●(See "Overview of shellfish, pufferfish, and other marine toxin poisoning".)

EPIDEMIOLOGY — Scombroid poisoning occurs throughout the world. It typically presents in clusters after ingestion of contaminated dark-meat fish and is classically associated with consumption of finfish from the Scombridae and Scomberesocidae families, such as tuna, mackerel, skipjack, and bonito [4-7]. Scombroid poisoning may also take place after ingestion of other types of fish, such as mahi-mahi (dolphin fish), bluefish, amberjack, swordfish, marlin, herring, sardines, anchovies, salmon, tilapia, and trout [8-10]; as well as contaminated Swiss cheese [11]. In resource-rich countries, scombroid fish poisoning more commonly follows consumption of recreational fish catches rather than more highly regulated commercial fish harvests [7,12].

In the United States and Europe, scombroid fish poisoning accounts for up to 40 percent of seafood-borne illness outbreaks [4,13]. Between 2000 and 2007, there were 223 outbreaks reported to the United States Foodborne Disease Outbreak Surveillance System, representing 865 affected individuals. The majority of cases occurred in Hawaii, Florida, and California; and no deaths were reported [14]. Population-based estimates range from two to five annual scombroid fish poisoning outbreaks per million people in Denmark, New Zealand, France, and Finland to as high as 31 annual outbreaks per million people in Hawaii [7,13]. However, because symptoms are of short duration and are often confused with other illnesses, many experts believe that scombroid poisoning is significantly underreported.

PATHOGENESIS — Scombroid poisoning arises when fish are improperly stored after being caught (temperatures >4°C [40°F]). Under these conditions, the fish undergo bacterial overgrowth and sustain conversion of histidine, found in dark fish meat, to histamine and other biogenic amines by the bacterial enzyme histidine decarboxylase [7]. Toxic levels of histamine can accumulate within as short a time as two to three hours in fish stored at 20°C (68°F) or higher [4]. The responsible bacteria are most commonly Escherichia coli, halophilic Vibrio species, and Proteus, Klebsiella, Clostridium, Salmonella, and Shigella species [1].

Scombroid poisoning has also occurred following consumption of Swiss cheese due to bacterial contamination of the raw milk prior to processing [11].

Histamine and other toxins are not broken down by cooking, freezing, or subsequent refrigeration [7]. Contaminated fish may smell and appear fresh, although patients with scombroid poisoning may report that the fish tastes "peppery," "spicy," or "bubbly" [15]. In some instances, the fish skin can have a honeycombed appearance. Fish contamination frequently occurs when it is refrigerated inadequately at sea but may also happen if the meat is improperly stored at any time prior to consumption [4,7]. Disease can occur even if the vendor selling the fish to the consumer stored the fish properly.

Although more typically associated with fresh fish, scombroid poisoning can also occur with canned fish if the fish is handled improperly either before canning or after the can is opened; opened cans of tuna should be refrigerated to prevent poisoning [16].

CLINICAL MANIFESTATIONS — Signs and symptoms of scombroid toxicity are consistent with histamine poisoning and usually begin within an hour of eating contaminated fish or cheese [7,11,12].

Typical findings vary in individual patients but include [1,11,12,17,18]:

●Cutaneous flushing of the face and neck with an uncomfortable feeling of intense warmth

●Erythematous and urticarial rash often prominent on the face and upper torso (picture 1)

●Perioral burning, itching, or edema

●Abdominal cramping, nausea, vomiting, and diarrhea

●Headache

●Dizziness

●Tachycardia

●Palpitations

●Chest tightness with shortness of breath

●Peppery or metallic taste to the fish flesh

●Blurry vision

●Hypotension (distributive shock)

●Bronchospasm and respiratory distress (rare)

●Cardiac arrhythmias (rare)

Of these findings, flushing, rash, diarrhea, and headache are most frequently described. The more serious respiratory and cardiac findings have been primarily reported in patients with pre-existing conditions (eg, asthma or heart disease) [19,20]. In outbreaks, the attack rate among persons consuming the contaminated fish ranges from 50 to 100 percent [11].

Scombroid poisoning usually resolves within 12 to 48 hours if untreated and has no long-term sequelae [7,11,12]. However, older adult patients and individuals with pulmonary or underlying cardiovascular disease may have a more complicated course [8,21]. Patients taking isoniazid and monoamine oxidase inhibitors, which inhibit histamine metabolism, may be more vulnerable to scombroid poisoning [22] and have more prolonged or severe physical findings [23,24]. On the other hand, patients taking antihistamines may be protected [11]. The duration of scombroid poisoning also depends upon the amount of contaminated food that was consumed.

DIAGNOSIS — A diagnosis of scombroid poisoning can be made based upon the following clinical findings [7,11,12]:

●Rapid onset of symptoms within an hour of consuming a fish meal, especially a scombroid fish (eg, tuna, mackerel, skipjack, or bonito), or cheese

●Flushing, rash, headache, diarrhea, or other findings consistent with scombroid poisoning (see 'Clinical manifestations' above)

●Similar symptoms among other persons who ate the same fish

●Prompt improvement after antihistamine administration

If available, fish can be examined for histamine levels by a variety of different laboratory methods to confirm the working diagnosis [7]. In the United States, histamine levels greater than 100 mg/100 g of fish tissue are diagnostic of poisoning, while levels greater than 50 mg/100 g of fish are considered potentially toxic [7]. In Europe, critical levels are 100 mg/kg in untreated fish and 200 mg/kg in fish that have undergone enzyme maturation in brine. If specimens are being sent out for analysis, they should be frozen. Local health department officials can be helpful in obtaining fish samples from restaurants, grocery stores, and other commercial vendors when the diagnosis is suspected.

If the fish sample is still available, skin prick testing can be conducted in an allergist's office [25]. Although not routinely performed, plasma histamine levels ranging from two to four times the normal upper limit of 10.8 nmol/L were reported in five patients who presented within four hours after ingesting contaminated fish [26]. The plasma histamine levels normalized at 24 hours.

DIFFERENTIAL DIAGNOSIS — Cutaneous flushing similar to that seen in patients with scombroid poisoning may occur in patients with a variety of other conditions. However, the rapid onset of flushing after ingestion of a fish meal distinguishes scombroid poisoning from most other causes. The approach to flushing in adults is described in detail separately and provided in the algorithm (algorithm 1). (See "Approach to flushing in adults".)

Myocardial infarction, allergic reaction, staphylococcal enterotoxin-induced food poisoning, and other types of marine foodborne poisoning are additional considerations when evaluating a patient for suspected scombroid poisoning.

Myocardial ischemia or infarction — The chest tightness, difficulty breathing, sweating, and nausea sometimes associated with scombroid poisoning can simulate the clinical presentation of myocardial ischemia or infarction in adults. In most cases, serial electrocardiograms and cardiac biomarkers adequately differentiate the etiology of chest pain. However, the etiology may be unclear in rare cases of mildly elevated troponin concentrations from subendocardial ischemia caused by a histamine-induced vasoconstrictive reaction associated with scombroid poisoning [21]. (See "Diagnosis of acute myocardial infarction".)

Allergic reaction — Patients with obstructing upper airway edema, hypotension, or bronchospasm warrant treatment as for anaphylaxis regardless of the underlying etiology. (See 'Management' below.)

Allergic reactions to seafood can mimic scombroid poisoning. However, lack of a history of allergy to fish, clustering of symptoms among patients who ate the same fish, and, if available, documentation of elevated histamine levels in the fish can establish the diagnosis of scombroid fish poisoning [7,11]. If a concern for fish allergy persists, a blood test for immunoglobulin E specific to the fish in question can be obtained or, after resolution of symptoms, the patient may be referred to an allergist for later skin testing and possible challenge to the fish in question. Individuals whose symptoms were due to scombroid, and not allergies, will have negative type I allergy testing [27]. (See "Seafood allergies: Fish and shellfish", section on 'Scombroid poisoning'.)

Staphylococcal enterotoxin-induced food poisoning — Staphylococcus aureus enterotoxin may cause abrupt onset of nausea, vomiting, and abdominal cramps approximately one hour after eating contaminated food. These symptoms may be similar to those patients with scombroid who primarily manifest gastrointestinal symptoms. However, patients with staphylococcal food poisoning may develop a fever, which is not seen in patients with scombroid poisoning. Also, unlike those with staphylococcal enterotoxin food poisoning, patients with scombroid poisoning typically have flushing or a rash. (See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings", section on 'Vomiting'.)

Other marine foodborne poisoning — Symptoms of poisoning caused by other marine species, such as ciguatera poisoning, various types of shellfish poisoning, and pufferfish poisoning, are distinguished by a longer latent period between consumption and onset of symptoms and the presence of findings not typical of scombroid poisoning, including paresthesias and temperature-related dysesthesia (ciguatera and neurotoxic shellfish poisoning), paralysis (paralytic shellfish and pufferfish poisoning), and prolonged diarrhea without a rash. (See "Ciguatera fish poisoning", section on 'Clinical manifestations' and "Overview of shellfish, pufferfish, and other marine toxin poisoning".)

MANAGEMENT — Rarely, scombroid poisoning can present with obstructing upper airway edema, hypotension, or bronchospasm. Patients with these findings warrant treatment as for anaphylaxis as shown in the tables (table 1 and table 2). (See "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)

Based upon case series and case reports, we suggest that patients without respiratory distress or hypotension but with significant discomfort from flushing, burning, rash, itching, or perioral edema receive antihistamines rather than supportive care alone as follows:

●A single dose of an H1 (eg, diphenhydramine or hydroxyzine) antihistamine

●For patients with moderate to severe symptoms or any gastrointestinal symptoms, or those who do not respond promptly to H1 antihistamines, a single dose of an H2 antihistamine should also be given (eg, famotidine or cimetidine)

Parenteral administration is appropriate for patients with moderate to severe symptoms; patients with milder symptoms may receive oral antihistamines. Experience suggests that signs and symptoms of poisoning typically resolve within 30 minutes of antihistamine administration in such patients [11,19,28,29]. H2 antihistamines may also treat symptoms in patients who fail to respond to diphenhydramine [29,30].

Patients with significant fluid losses from vomiting or diarrhea accompanied by signs of dehydration should initially receive fluid resuscitation with isotonic fluids (eg, normal saline or buffered crystalloid) with volume and rate of administration determined by clinical findings; additional fluid therapy is guided by clinical response. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

The clinician should contact the local public health authorities to assist in confirming the diagnosis of scombroid poisoning and to prevent further consumption of contaminated fish by others. (See 'Diagnosis' above.)

DISPOSITION — Patients who have mild symptoms not requiring therapy or whose clinical findings fully resolve after treatment with H1 (eg, diphenhydramine or hydroxyzine) and/or H2 (eg, famotidine or cimetidine) antihistamines may be discharged to home. Although specific evidence is lacking, oral antihistamine administration (eg, loratadine or cetirizine) for one to two days is a reasonable approach to prevent recurrence of symptoms caused by continued toxin absorption from the gastrointestinal tract.

Patients with severe features (eg, obstructing upper airway edema, bronchospasm with severe respiratory distress, or hypotension) warrant observation for several hours or admission to ensure full resolution of toxicity.

Patients receiving intravenous fluids for dehydration should be able to tolerate oral intake and be fully fluid repleted before discharge home.

PREVENTION — Rapid chilling of fish below 4°C (40°F) immediately after catch is an effective measure to prevent the accumulation of histamine, which can occur at ambient or high temperatures [4]. However, fish can become contaminated with scombroid on fishing boats, far from the consumer. In the 1990s, many experts noted that much of the scombroid contaminated fish entering in the United States came from off the coast of Central America, where it was often caught on long lines and improperly refrigerated at sea [9]. More recently, recreational fish catches have become the most common source of contaminated fish for developed countries [7,12].

The US Food and Drug Administration (FDA) has instituted a mandatory Hazard Analysis and Critical Control Point system, under which all United States fish processors and importers must identify the points at which fish contamination may occur and must come up with a plan to prevent contamination [7,9]. The FDA and United States Customs and Border Protection also inspect thousands of seafood shipments annually in an attempt to protect consumers. Private companies offer chemical assays that test fish for histamine levels within an hour [8,9,12].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Scombroid poisoning is a common seafood-associated disease occurring from consumption of improperly stored dark-meat fish (typically tuna, mackerel, skipjack, and bonito) or Swiss cheese. If not promptly refrigerated after being caught, these fish undergo bacterial overgrowth leading to conversion of histidine to histamine and other biogenic amines by the bacterial enzyme histidine decarboxylase. Histamine is not degraded by cooking, freezing, or subsequent refrigeration. Contaminated fish may smell and appear fresh but often taste peppery. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical manifestations – Signs and symptoms of scombroid poisoning usually begin within an hour of eating contaminated fish and commonly include flushing of the face and neck with an uncomfortable feeling of intense warmth, an erythematous and urticarial rash often prominent on the face and upper torso (picture 1), diarrhea, and headache. Perioral burning or itching, dizziness, palpitations, and tachycardia may also be present. Rarely, severe bronchospasm with respiratory distress, hypotension, or cardiac arrhythmias may occur, especially in patients with underlying conditions such as asthma or heart disease. (See 'Clinical manifestations' above.)

●Diagnosis – Scombroid poisoning is a clinical diagnosis in patients who have rapid onset of flushing, rash, headache, or diarrhea shortly after consuming dark-meat fish, such as tuna, mackerel, skipjack, or bonito, especially when other individuals who ate the same fish experience similar symptoms. Rapid improvement in symptoms after antihistamine treatment also supports the diagnosis. Testing (eg, histamine levels) is not necessary to establish the diagnosis, nor is it usually available in the acute care setting. Local health department officials can obtain fish samples for histamine concentration testing. (See 'Diagnosis' above.)

●Differential diagnosis – Allergic reactions to seafood and scombroid poisoning present similarly and are often challenging to distinguish. The lack of a known fish allergy and clustering of symptoms among patients who ate the same fish suggests the diagnosis of scombroid. Cutaneous flushing similar to that seen in patients with scombroid poisoning may occur in patients with a variety of other conditions (algorithm 1). (See 'Differential diagnosis' above.)

●Management – In patients with scombroid poisoning, we suggest treatment with antihistamines in addition to supportive care rather than supportive care alone (Grade 2C). Patients with mild symptoms can be treated with an oral H1 antihistamine (eg, diphenhydramine), while those with gastrointestinal symptoms or significant discomfort from flushing, burning, rash, itching, or perioral edema should receive parenteral H1 antihistamine and then, if not responding, an H2 antihistamine (eg, famotidine). Patients with hypovolemia from vomiting or diarrhea should receive intravenous isotonic fluids (eg, normal saline or buffered crystalloid) with the volume and rate of administration determined by clinical findings. (See 'Management' above and "Treatment of severe hypovolemia or hypovolemic shock in adults".)

The rare patient with obstructing upper airway edema, hypotension, or bronchospasm requires treatment for anaphylaxis (table 1 and table 2). (See 'Management' above and "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)

●Disposition – Patients with mild symptoms or those whose symptoms have resolved and can tolerate oral intake after treatment with antihistamines can be discharged home. Patients with severe symptoms (eg, obstructing upper airway edema, bronchospasm with severe respiratory distress, or hypotension) warrant observation for several hours or admission to ensure full resolution of toxicity. (See 'Disposition' above.)

●Prevention – If scombroid poisoning is suspected, the clinician should contact the local public health authorities to assist in confirming the diagnosis and to prevent further consumption of contaminated fish by others. Local health department officials can be helpful in obtaining fish samples from restaurants, grocery stores, and other commercial vendors. Rapid chilling of fish below 4°C (40°F) immediately after being caught is the single most effective measure to prevent the accumulation of histamine and subsequent scombroid poisoning. (See 'Prevention' above.)