To assess the actual/valid occurrences of histamine poisoning from foods.

To assess histamine mean concentration in food involved in actual/valid occurrences of histamine poisoning.

To assess relevant concomitant conditions as "risk factors" in actual/valid occurrences of histamine poisoning from foods.

The search strategies will be focused to detect all reports of histamine poisonings from foods that meet the inclusion criteria, so will be optimized accordingly to this purpose. A main form of search strategy will be designed and could be modified to meet settings of databases consulted. The strategy adopted and database on which it was performed will be recorded. Main key-words will be: "histamine", "scombroid syndrome", "histamine poisoning", food, seafood, “meat products”, fish, cheese, beer, wine, “biogenic amines”. To improve the effectiveness of key-words in the search strategy a preliminary thesaurus study will be performed.

Replicated reports of the same data will be detected and only one report will be considered for inclusion in this review; reasons for the choice will be given and recorded.

Electronic searches:

• General bibliographic databases:

Databases to be searched: Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, EMBASE, FSTA, GOOGLE SCHOLAR, LILACS (LATIN AMERICAN CARIBBEAN HEALTH SCIENCES LITERATURE ), MEDLINE, PubMed, SCIFINDER, SCIRUS, SCOPUS, WEB OF SCIENCE

Electronic databases searched (their names and [their default time intervals or the intervals of interest for this review] )will be recorded.

• Regional/National bibliographic databases:

Regional/National information will be retrieved mainly by appropriate regional electronic databases (example: indexmedicus.afro.who.int/) identified by information expert aid. Other electronic and non-electronic sources could be identified by information expert aid; all sources used will be recorded.

• Subject-specific bibliographic databases:

Subject-specific information will be retrieved mainly by appropriate subject-specific databases (example: International health/Global Health

www.cabi.org/datapage.asp?iDocID=169) identified by information expert aid. Other electronic and non-electronic sources could be identified by information expert aid; all sources used will be recorded.

• Citation indexes:

No citation indexes will be searched.

• Dissertations and theses databases:

Dissertations and theses information will be retrieved by appropriate electronic databases (examples: UK theses, www.theses.com;

German dissertations, www.dissonline.de/) identified by information expert aid; other electronic and non-electronic sources could be identified by information expert aid; all sources used will be recorded.

• Grey literature databases:

Generic grey literature will be retrieved mainly by appropriate electronic databases such as "Open Grey" System database (Formerly "openSIGLE"). Other electronic and non-electronic sources will be identified by information expert aid; all sources used will be recorded.

• Full text journals available electronically:

In general , the electronic full text of eligible articles will be retrieved based on abstracts found by bibliographic database searches. It will be recorded ; If the full-text article was found independently form database searches and the form of retrieved article (electronic, print or both).

• Table of Contents:

It will be recorded if an abstract or full-text article has been considered for eligibility/inclusion by an alert from a "Table of contents" or similar service.

• Conference abstracts or proceedings:

Conference abstracts or proceedings will be searched mainly by appropriate electronic databases identified by information expert aid; Other electronic and non-electronic sources will be identified by information expert aid; all sources used will be recorded.

• Other reviews, guidelines and reference lists as sources of studies:

Specific searches will be done to detect (systematic reviews) having the same or similar topic of this systematic review. The following sources will be searched for this purpose: The Cochrane library, MEDLINE (using publication type term "review" or "meta-analysis"), EMBASE (using "systematic review" as a Thesaurus term). Guidelines will not be considered as a source for information searches.

• WEB searching:

In general WEB searching will not be performed; if from other information or in particular cases WEB sources had been detected they will be searched and recorded. Electronic databases searched (their names and [their default time intervals or the intervals of interest for this review]) will be recorded. Full search strategies for each database will be recorded ( listed in an appendix to this review).

Searching other resources:

• Grey literature:

In general grey literature sources other than those retrieved from electronic databases (see "electronic searches" section) will not be searched; if from other information or in particular cases such sources had been detected they will be searched and recorded.

• Handsearching:

In general there are no sources to be handsearched; if from other information or in particular cases, such sources had been detected they will be searched and recorded.

• Reference lists:

Bibliographic references of reports eligible for inclusion in this systematic review will be checked to find other potentially relevant reports; CB and PC personal reference lists will be checked for reports eligible for inclusion.

• Correspondence:

When it is necessary to retrieve data not included in reports we will attempt to get the data from authors of reports by correspondence and this will be recorded.

• Unpublished and ongoing studies:

If it is likely that any author or colleague could provide useful data, such as unpublished or ongoing studies, the author will be asked to provide such data; data provided will be recorded.

Time interval for considering studies: 1959-2012. The first application of fluorimetric assay of histamine in tissues (Shore 1959); the bioassay method applied before, based on the biological activity of histamine was not specific and accurate.

Reports (abstract and full text) written in English, Italian, French, German, Portuguese and Spanish will be considered; considering a full text in other languages will be decided case-by case based on the potential relevance for this review assessed from its English abstract.

In general, all report types that present histamine poisoning from food will be considered for inclusion in the review.

All types of studies and report will be considered, if a report is considered to be an experimental comparative study (e.g. experimental group versus control group) only data for the group where poisoning events from food occurred will be considered.

Scombroid syndrome/histamine poisoning occurs worldwide and it is considered one of, if not the, most common form of toxicity caused by fish consumption (Dalgaard 2008). The number of cases is increasing in spite of the improving knowledge on seafood safety due to a change in the way in which seafood, (mainly tuna), is eaten, that is preparations raw or cooked like steaks or hamburger (Becker 2001), or as preparations of canned tuna (sandwiches, salads, pizza) (McLauchlin 2005; Cattaneo and Stella, 2001). Less is known about foods other than seafood and it is of the utmost importance to assess the contribution of all the foods on this syndrome to implement specific prevention measures.

People involved in histamine poisoning reports must not belong to excluded categories.

No food allergic patients or other very sensitive people due to serious illness or anomalous physical or psychic conditions. No newborn babies or very old (>80 years old ) people.

The report will be eligible for inclusion if the numeric majority of people poisoned belong to non-excluded categories; this situation will be recorded.

If nothing is said about the people involved in histamine poisoning they will be considered as belonging to a non-excluded category; the health status will be recorded; if not given the health status value will be recorded as “unknown”.

Food intake is considered as exposure for scombroid syndrome when there is evidence of (high) histamine content; every such food for human consumption will be eligible for inclusion in this systematic review; no non-food sources will be considered as histamine poisoning exposure.

Due to the nature of the review there is no actual comparator/control; subgroup analyses could be a surrogate of comparative statistical analyses showing outcome variations between food subgroups.

Reports that present histamine poisonings from non-food sources (as experimental studies with histamine administration) will not be considered for inclusion in the review.

Only reports that present histamine determination with chemical and ELISA methods will be included. Bioassay methods will be not considered for inclusion in the review.

Report must describe a histamine poisoning outbreak or must be a study of histamine food poisoning in people; also reports of single, or few cases must be considered for inclusion in the systematic review.

Report must contain the number of patients involved in histamine poisoning.

Report must contain a "histamine poisoning" or a "scombroid syndrome" diagnosis made by a medical doctor. Alternatively, the author of the report should present the disease as "histamine poisoning" or "scombroid syndrome".

Report must include a value, and its measured unit, of the histamine content of the food involved.

Histamine content measurement method must be declared.

Report must clearly contain the type of food involved in histamine poisoning.

Spatial interval for considering studies: worldwide.

Primary outcomes

Number of histamine poisoning samples, histamine concentration in poisoning sample.

Log-mean of histamine concentration in sample.

Secondary outcomes

Concomitant conditions ("risk factors") relevant to histamine poisoning: female sex, previous medication (Muscle relaxants, Narcotics, Analgesics, Nonsteroidal antiinflammatory drugs, Local anesthetics, Antihypotonics, Antihypertensive drugs, Antiarrhythmics, Diuretics, Drugs influencing gut motility, Antibiotics, Mucolytics, Broncholytics, H2-receptor antagonists, Cytostatics, Antidepressants), food description in poisoning (fish species, food preparation), consumption of alcohol during the meal; consumption of Foods with suggested histamine-releasing capacities (Plant-derived: Citrus fruit, Papaya, Strawberries, Pineapple, Nuts, Peanuts,Tomatoes, Spinach, Chocolate. Animal-derived: Pork, Fish, Crustaceans, Egg white. Other: Additives, Spices, Liquorice). Pathologies (renal failure, viral hepatitis, gut failure, endotoxemia in patients with liver cirrhosis, chronic urticaria) (Mainz & Novak, 2007).

The literature search will be conducted by two investigator/s (EC, FC) with the aid of an information specialist and eventually by consulting with CB and PC. Two authors (CB and FC) independently will select potentially eligible studies for inclusion. Disagreements between reviewers will be resolved by consensus; if no agreement could be reached, a third author (PC) will decide. The full text of all eligible citations will be examined in more detail. A data extraction sheet will be developed and pilot-tested on a randomly-selected subgroup of included studies, and if needed, the data sheet will be refined accordingly. One author (CB) will extract data from extraction sheet; data extracted will be checked by a second author (FC). Disagreements will be resolved by discussion between the two review authors; if no agreement could be reached, a third author will decide (PC). A unique identifier of the report will be included in the report characteristics recorded.

All quantitative measures of histamine content and measures of their variability will be recorded. The method of analysis used to determine food histamine content will be recorded. If no method is mentioned the recording value will be "unknown".

Foods involved in histamine poisoning must be recorded.

Primary and secondary outcome values (number of histamine poisoning samples, histamine concentration in poisoning sample, concomitant conditions ("risk factors") relevant to histamine poisoning) will be recorded.

The country or other identifier of geographic locations of histamine poisoning samples will be recorded.

People (health) category will be recorded: i.e. if participants belong to an excluded category and which is this category; if participants don't belong to the above categories the status of "normal" will be recorded.

When a report refers to more food types being associated with a single histamine mean value, the foods involved will be categorized as "heterogeneous food" and recorded.

Report characteristics, other than those declared in this section of the protocol, that, before or during the data collection process, are pointed out as useful to improve quality of information, will be recorded.

A quality score for reports included in review based on additional relevant details other than inclusion criteria will be produced; the score will be the sum of the number of the following additional relevant variables whose values are given in the report (Murphy, 2009). Variability estimate of histamine concentration, source of medical diagnosis (e.g. hospital m.d., family m.d...) or reasons given for presenting data as "histamine poisoning /scombroid syndrome", age, sex, health status, source of food involved in poisoning ( restaurant, supermarket...) Otherwise any element that could arouse suspicion of bias will be recorded.

No selective reporting bias will be assessed for non-experimental reports; If any experimental studies were included in systematic review and there were indications of selective reporting, the authors will be contacted asking about other results or outcomes not reported. If this issue is not resolved a decision will be made (and reasons recorded) about excluding such reports. Decision will be kept independently by CB and FC; if disagreement occurrs PC will keep final decision. Whatever the decision, the bias clues detected will be recorded.

Log-mean of histamine concentration in sample. In this review for “log- mean” is meant “the value of the estimate of the mean of the logarithms of the raw data”. It is likely that this log- mean value will not be given in almost all reports, so it will almost always be calculated/inferred as below.

Values of histamine content in food samples will be elaborated with documented methods to yield a log-mean and its standard error.

The "histamine concentration in poisoning sample" outcome will be meta-analyzed with the random effect model (DerSimonian and Laird ,1986); the "number of histamine poisonings" outcome will be summarized as the overall sum of histamine poisoning samples; the "concomitant conditions ("risk factors") relevant to histamine poisoning" outcome will be summarized as a contingency table of the declared risk factors versus the number of their occurrences.

The degree of heterogeneity will be assessed by the I-squared statistic (Higgins, 2003).

Subgroup: country or other identifier of geographic locations of histamine poisoning samples.

Subgroup:

1)fresh seafood,

2) frozen seafood,

3) canned seafood,

4) fermented seafood,

5) seafood other than 1,2,3,4;

6) cheese and dairy;

7) other foods.

Aim: - scientific and cultural impact of the results on the scientific community, on food business operators, on graduate students in Veterinary Medicine and Animal production; post-graduate students in Veterinary Medicine.

How: publication on scientific paper at international and national level meetings at local level, with company operators and managers, public veterinary inspectors,

- meeting of the Food Hygiene Field by means of posters, communications, round tables,

- seminars for students attending Veterinary Medicine courses and post-graduate Specialization School in Inspection of Food of animal origin.

Fabio Colombo

Via Annibale Grasselli 7

20137 Milano (Italy)

fabio.colombo@unimi.it

Università degli Studi di Milano

www.unimi.it

Dr Fabio Colombo, Università degli Studi di Milano
Professor Patrizia Cattaneo, Università degli Studi di Milano
Dr Enrica Confalonieri, Università degli Studi di Milano
Dr Cristian Bernardi, Università degli Studi di Milano

01 October 2012

28 June 2013

Università degli Studi di Milano.

Generali Conserve.

This systematic review is a phase of a research commissioned from a food industry.

English

Italy

Subject indexing assigned by CRD

Disease Outbreaks; Fish Products; Foodborne Diseases; Histamine; Humans

18 July 2012

18 July 2012