Becker K, Southwick K, Reardon J, Berg R, MacCormack JN. Histamine Poisoning Associated With Eating Tuna Burgers. JAMA. 2001;285(10):1327-1330. doi:10.1001/jama.285.10.1327
Author Affiliations: Centers for Disease Control and Prevention, Raleigh, NC (Drs Becker and Southwick); North Carolina Department of Health and Human Services, Raleigh (Drs Becker, Southwick, and MacCormack); North Carolina Department of Agriculture and Consumer Services, Raleigh (Mr Reardon); and United States Food and Drug Administration, Atlanta, Ga (Ms Berg).
Context Histamine poisoning occurs when persons ingest fish in which bacteria
have converted histidine to histamine, a process that usually can be controlled
by storage at low temperatures. From 1994 to 1997, North Carolina averaged
2 cases annually; however, from July 1998 to February 1999, a total of 22
cases of histamine fish poisoning were reported.
Objectives To examine the increase in histamine case reports, identify risk factors
for poisoning, and develop recommendations for prevention.
Design and Setting Case series evaluated in North Carolina from July 1998 to February 1999.
Subjects Reported case-patients with 2 of the following symptoms within 2 hours
of eating tuna: rash, facial flushing, vomiting, diarrhea, dyspnea, a tight
feeling in the throat, headache, or a metallic or peppery taste in the mouth.
Results Twenty cases occurred during 5 outbreaks, and there were 2 single occurrences.
Of the 22 persons affected, 19 (86%) sought emergency medical care. All case-patients
ate tuna: 18 ate tuna burgers, 2 ate salad containing tuna, and 2 ate filets.
Tuna samples (available from 3 outbreaks) had histamine levels above the Food
and Drug Administration regulatory level of 50 ppm (levels were between 213
and 3245 ppm). In 19 cases, the tuna used to prepare burgers or salads was
frozen and thawed more than once before serving. Violations of recommended
temperature controls were identified in 2 of the 5 restaurants, accounting
for 14 (64%) cases.
Conclusions Tuna burgers, a relatively new menu item in restaurants, were associated
with an increase in histamine poisoning cases in North Carolina. Tuna ground
for burgers can be susceptible to both temperature fluctuations and bacterial
Persons with histamine (or scombroid) poisoning often seek emergency
medical care because of its toxic clinical manifestations. During the period
1998 through 1999, more cases of histamine poisoning were reported to the
North Carolina Department of Health and Human Services than usual. No evidence
existed that reporting practices had changed during the period 1997 through
1998, suggesting an actual increase in reported morbidity. With an increasingly
health-conscious public eating less red meat and more seafood, we wondered
if this increase was from more consumption of fish or from changes in food-handling
practices. We evaluated a case series to describe the increase in histamine
poisoning, identify characteristics associated with case patients, and develop
recommendations for prevention.
For this study, histamine poisoning was defined as an illness occurring
within 2 hours of eating fish in North Carolina for the period from July 1998
through February 1999, with at least 2 of the following symptoms: rash, facial
flushing, vomiting, diarrhea, dyspnea, a tight feeling in the throat, headache,
or a metallic or peppery taste in the mouth. We searched computerized phone
log records from the North Carolina Department of Health and Human Services
for the period 1994 through 1999, including all communications between the
county and state health departments, then reviewed all local health department
records of these cases of histamine poisoning. Records of histamine poisoning
cases at the North Carolina Department of Agriculture were also reviewed.
Once the case series was assembled, we traced shipments of the implicated
fish by interviewing seafood distributors and reviewing restaurant inspection
logs and seafood supply orders. Restaurant chefs or managers were interviewed
for information on where their fish came from, how it was prepared, and when
it was served.
Histamine, putrescine, and cadaverine levels in the implicated fish
samples were tested by the Southeast Regional Laboratory of the US Food and
Drug Administration (FDA) using Association of Official Analytical Chemists
methods.1- 3 A histamine
level greater than 50 ppm is considered evidence of decomposition by the FDA
for regulatory purposes. For industry quality-control purposes, a histamine
level of 20 ppm or greater indicates that some violation of temperature controls
has occurred.4 While there are no established
regulatory action levels for putrescine and cadaverine, they are considered
markers of decomposition and their presence indicates product abuse.
From 1994 through 1997, no more than 4 cases of histamine poisoning
had been reported annually (Figure 1).
During the 8-month period of July 1998 through February 1999, a total of 22
cases of histamine poisoning from fish were reported in North Carolina. Twenty-one
cases were restaurant-associated and involved 4 different establishments,
whereas 1 case-patient cooked and ate the fish at home. The fish prepared
and eaten in the home was transported unfrozen in the trunk of a car for several
hours before consumption. All cases occurred in persons aged 18 years or older.
Four counties were involved; 3 of the outbreaks, involving 15 (68%) cases,
occurred in 1 eastern North Carolina county, whereas the 2 remaining outbreaks
and 2 individual cases occurred in 3 counties in central North Carolina. All
case-patients ate tuna; 18 (82%) ate tuna burgers, and 2 ate salad containing
tuna. The 2 single-event case-patients ate tuna filets. Of the 22 persons
affected, 86% sought medical care. There were no hospitalizations, serious
complications, or deaths.
The tuna shipments containing the implicated fish were all brought into
Miami, Fla, from both local and international waters. Seafood distributors
delivered shipments to North Carolina in refrigerated trucks within 7 to 14
days of arrival in Florida. The tuna for burgers and salads was from the belly
meat of the fish. This meat was saved in freezer bags and stored in both freezers
and coolers for 2 to 4 days until served as salads or burgers. Once the tuna
was ground, patties were formed and stored in the cooler until cooked and
served. Inspection of this process showed several freezing and thawing cycles.
These food-handling practices were common to all restaurants that served the
implicated tuna burgers. Restaurant inspections identified inadequate refrigeration
in 2 of the 5 restaurants, accounting for 14 (64%) cases. In 1 restaurant
that showed violations of storage temperature controls, the grinder used to
make the tuna burgers was not sanitized between uses.
Fourteen representative tuna samples from 3 outbreaks of tuna-associated
illness were available for laboratory testing (Table 1). The highest levels of histamine were measured in samples
collected from tuna burgers left over from the first outbreak (July 1998;
n = 11). For this outbreak, levels of histamine, putrescine, and cadaverine
indicative of decomposition were also detected in samples of tuna that had
not been ground. However, levels were much lower when compared with the ground
tuna patties. For the second outbreak (September 1998; n = 2), all tuna burgers
were consumed before the cases were reported, preventing testing of the implicated
product. Samples collected for analysis from the third outbreak (February
1999; n = 2) included pieces of tuna from the same shipment as the tuna salad
eaten by the 2 case-patients. Detectable levels of histamine and putrescine
were also found in tuna samples taken from that shipment at the market that
provided the fish eaten at the restaurant where the third outbreak occurred.
Histamine poisoning is a chemical intoxication with a short incubation
period, usually ranging from minutes to a few hours after ingestion. Symptoms
include tingling and burning sensations around the mouth, headache, facial
flushing and sweating, rash and itching on the upper body, abdominal cramps,
nausea, vomiting, diarrhea, and heart palpitations.5
In most persons, symptoms are self-limiting, although histamine poisoning
can be life-threatening in persons with conditions such as asthma and heart
disease. Some drugs, such as monoamine oxidase inhibitors, can worsen or prolong
an attack by inhibiting the breakdown of histamine. Antihistamine medication
such as diphenhydramine and cimetidine often relieve symptoms; however, severe
cases of toxicity can require the same aggressive management as acute anaphylaxis.6 Symptoms related to histamine poisoning can also be
similar to those of coronary heart disease, increasing the possibility of
an invasive medical intervention if misdiagnosed.
Histamine poisoning from fish is probably the principal cause of morbidity
from toxic fish consumption worldwide,7 and
it is the only form of fish poisoning caused by bacterial contamination.8 Spoiled fish of the family Scombridae (eg, tuna, mackerel,
and bonito) are commonly implicated, hence the term scombroid
fish poisoning.9 However, other types
of fish are often implicated in histamine poisoning from fish, including mahimahi,
bluefish, salmon, amberjack, herrings, sardines, and anchovies.10- 17
Forty-two percent of all histamine outbreaks reported to the Centers for Disease
Control and Prevention during the period 1978 through 1982 occurred in nonscombroid
fish.18 Because this condition is not specific
to scombroid fish, histamine poisoning is a more appropriate descriptive term
for this food-related illness.
High histamine levels are formed by bacterial proliferation on the surface
of fish that have been improperly refrigerated. These histamine-forming bacteria
usually belong to the Enterobacteriaceae family, which have the enzyme necessary
to decarboxylate histidine to histamine.19,20
Because histamine poisoning has been reported after consumption of fish containing
low levels of histamine, other vasoactive amines present in the fish (eg,
putrescine and cadaverine) might act synergistically with histamine to lower
the toxic dose threshold.21 Putrescine and
cadaverine have been shown to potentiate histamine toxicity through inhibition
of metabolizing enzymes that detoxify histamine.22
Histamine development is more likely to occur in raw, unfrozen fish.
Because the fish might appear and smell normal, the consumer is unlikely to
identify a problem before eating the fish. Once the bacteria have formed the
enzyme histidine decarboxylase, histamine production can continue even if
the bacteria are killed. Although cooking can inactivate both the enzyme and
the bacteria, the toxic factors produced are heat stable and, once formed,
are not destroyed by cooking, smoking, or freezing.
In this investigation, tuna burgers were associated with an increase
in histamine poisoning cases in North Carolina. For histamine to form in the
fish, the tuna had to be mishandled at some point between capture and consumption.
Tuna can be especially vulnerable to temperature fluctuations because their
average body temperature when caught tends to be several degrees warmer than
that of other types of fish.23 Belly meat might
have an increased susceptibility to bacterial contamination during the evisceration
process because of its proximity to the fish gut cavity, where histamine-forming
bacteria reside. Furthermore, thin pieces of fish, such as the belly meat
used for ground tuna and salads, might be more vulnerable to temperature fluctuations
than thicker tuna filets. Violation of storage and temperature controls are
also more likely with tuna used for salads and burgers, because pieces are
stored over a longer period than filets and exposed to multiple thawing and
refreezing cycles. The grinding process used to make tuna burgers also might
contaminate the fish by either mixing histamine-forming bacteria into previously
uncontaminated material or by increasing the temperature of the tuna through
mechanical friction. This hypothesis is supported by evidence that the prepared
tuna burgers contained higher toxic amine levels than unground fish from the
Underreporting was 1 of the limitations of this investigation. Documentation
of histamine poisoning has been inconsistent because of a vague case definition
and insufficient knowledge about it in the medical community. Many mild, self-limiting
histamine-like reactions might not have been linked to an actual episode of
eating fish. When medical attention is sought, physicians might misdiagnose
histamine poisoning cases as a "seafood allergy" or confuse symptoms with
those of other types of seafood toxins. Allergic symptoms and those related
to fish poisoning can be similar, and both are responsive to antihistamine
treatment. Tracing to the origin of contamination was another limitation because
inspection records were only available for the restaurants involved. If problems
were not found at the restaurant, we could not be sure where violations of
temperature controls or mishandling might have occurred. The critical hazard
point could have occurred anywhere from the tuna boat to the restaurant.
Based on the findings of this investigation, we can make several recommendations.
Scientific evidence has shown that rapid chilling of fish on the fishing vessel
and keeping the temperature of the fish lower than 0°C throughout storage
and distribution is the best way to prevent histamine formation.24,25
This is lower than the current FDA recommendation of 5°C. Prospective
studies are needed to determine where the highest risk for violations of temperature
controls occurs in the path from sea to table.
In December 1997, the FDA launched a new program that requires seafood
processors to follow a modern safety system known as Hazard Analysis Critical
Control Point (HACCP).26 This system requires
hazard analysis at all stages of processing, establishment of critical control
points within the food chain continuum, establishment and monitoring of histamine
and temperature limits, and verification that the program is being followed.
To monitor histamine, implicated fish products must be sent to the regional
FDA seafood laboratory for testing.
Although the FDA has regulated seafood for decades, its jurisdiction
is limited to imported (international and interstate) products. Local wholesale
seafood businesses are subject to state government inspection, which includes
enforcement of the new HACCP rules. The feasibility of applying principles
similar to those of HACCP to recreational and commercial fishing vessels,
retail seafood facilities, and restaurants to improve seafood safety should
be tested and evaluated. Following 1 recent reported outbreak, investigators
recommended that regulations be developed and enforced concerning how long
a fish can remain on a fishing line27; however,
further evaluation is needed before policies like this can be considered for
Better recognition of and surveillance for histamine poisoning from
fish are needed, particularly given the increased consumption of fish. Although
all food-borne illnesses are reportable in North Carolina, a specific line
item for histamine poisoning on the reporting card is needed to accurately
document the magnitude of this problem, and identify where food-safety interventions
are needed. Furthermore, the sensitivity of testing for histamine poisoning
would improve if acceptable levels for nonhistamine amines (eg, putrescine
and cadaverine) were standardized. Currently, histamine activity cannot be
readily determined in the commercial environment, and after-the-fact laboratory
testing only confirms that an unsafe product has already been consumed. A
simple and cost-effective test that is sensitive enough to detect contamination
before a health problem occurs is needed. For example, cultures are used to
enforce the zero tolerance policy for Listeria monocytogenes in ready-to-eat processed meats.28
Further research is needed to develop commercially available, rapid field
tests to use for random seafood quality checks or when contamination is suspected.
With these recommendations as guidelines, a comprehensive regulatory approach
at state and local levels, encompassing all phases of preparation leading
up to consumption, will provide a more uniform system of controls for seafood
safety based on the best available evidence.