Update on the Situation

The National Reference Center (NRC) for Salmonella (Institut Pasteur, Paris) receives Salmonella strains isolated by approximately 1,200 clinical and hospital laboratories for serotyping. By late November 2017, the NRC had received and identified an unusual number of Salmonella Agona serotype strains isolated from young children. The identification of 8 strains in 8 days triggered an alert, and epidemiological investigations began on December 1 among the parents of the affected infants.

The epidemiological investigation is being conducted by Santé publique France in collaboration with the CNR, the Directorate General for Competition, Consumer Affairs, and Fraud Control (DGCCRF), and the Directorate General for Health (DGS). Santé publique France is interviewing the families of the cases, particularly regarding the onset of the illness (onset of symptoms, clinical signs, care received, etc.) and the foods consumed during the 3 days prior to the onset of symptoms.

To date, the investigation has identified 38 infants (16 boys and 22 girls; median age 4 months, min: 2.5 weeks, max: 9 months) with Salmonella Agona serotype salmonellosis, which occurred between mid-August and December 2, 2017. All these strains belong to the same epidemic clon. Figure 1 shows the distribution of cases by week of diagnosis by the CNR, which triggers the alert. Note that one of the cases was identified retrospectively by the CNR and developed symptoms in late April 2017.

^a1 strain is currently being confirmed. Nevertheless, they possess the biochemical characteristic identified for the strain responsible for the outbreak: no production of H2S or gas within 18 hours on Kligler-Hajna medium.

Figure 1 - Distribution of S. Agona (epidemic clone) infection cases by week of diagnosis at the CNR, France, April–December 2017 (n=38)

Figure 2 reconstructs the outbreak based on the onset dates of cases obtained through interviews with patients’ families. It allows for an assessment of the impact of control measures on the occurrence of new cases. It shows that after the initial control measures were implemented in week 48, no new cases were identified (no cases with an onset date after week 48).

Figure 2 - Distribution of S. Agona (epidemic clone) infection cases by week of symptom onset, France, April–December 2017 (n=37)

The 38 infants reside in 10 different regions (10 in Auvergne-Rhône-Alpes, 6 in Île-de-France, 5 in Bourgogne-Franche-Comté, 3 in Pays de la Loire, 3 in Occitanie, 3 in Nouvelle-Aquitaine, 2 in Provence-Alpes-Côte d’Azur, 3 in Centre-Val-de-Loire, 2 in Hauts-de-France, 1 in Normandy) (Figure 2).

To date, the families of 37 infants have been interviewed. Among them, 18 were hospitalized due to salmonellosis; all have been discharged from the hospital. During telephone interviews, parents reported that their babies were doing well.

Of these 37 infants, 36 had consumed, within the 3 days preceding the onset of their symptoms, the following brands of infant formula: Pepti Junior by Picot (27 infants), Milumel Bio 1 palm oil-free (5 infants), Picot Rice (2 infants), Picot SL (1 infant), and Picot Anti-Colic (1 infant); these 5 formulas are manufactured at the same production site. The mother of one infant reported exclusive breastfeeding.

Figure 3 - Geographic distribution of the 38 infants with Salmonella Agona serotype salmonellosis (e^pidemic clone ^b), France, April–December 2017

^bOr not producing H2S or gas on Kligler-Hajna medium.

The results of the investigation strongly suggest that the milk formulas Pepti Junior by Picot, Picot SL, Picot Rice, Picot Anti-Colic, and Milumel Bio 1 without palm oil, all produced at the same site, are the source of these Salmonella Agona infections.

The cases identified during this investigation involve infants who experienced diarrhea following consumption of these formulas, who underwent medical consultation and stool culture (stool analysis), and from whom laboratories isolated a strain of Salmonella transmitted to the CNR. It is possible that some cases were not identified. Nevertheless, these unreported cases are generally less severe, and their number is likely limited due to more systematic medical care for infants and for severe infections.

Microbiological investigations

Based on genomic analysis of the strains, the CNR identified an epidemic clone among the S. Agona strains received in 2017.

Given the international distribution of these milk products, the CNR has published the sequence of the epidemic strain on EBI-ENA under the number ERR2219379. The national reference centers and focal points in the affected countries have been informed so that they can compare their S. Agona strain sequences with that of the French outbreak.

The epidemic strain has specific biochemical characteristics recognizable by laboratory biologists: it produces neither H2S nor gas on Kligler-Hajna medium, which is unusual for non-typhoid Salmonella.

Furthermore, this strain does not exhibit any particular antibiotic resistance.

The CNR also retrospectively analyzed S. Agona strains isolated from infants since 2000 using a new technique (genome sequencing) that has been routinely used since 2017 to identify epidemic strains. Without this genome sequencing, it is not possible to distinguish epidemic S. Agona strains from those isolated from sporadic cases.

The epidemic profile identified for the 2017 cases is the same as that of the strains isolated during the 2004–2005 outbreak linked to the consumption of infant formula produced at the same factory. Furthermore, the CNR has identified 27 cases of S. Agona with an epidemic profile to date over the 2006–2016 period, exclusively in infants (Figure 4). This epidemic profile is not found in any strains isolated from older children or adults for which genome sequencing was performed. Finally, these 27 retrospectively identified cases occurred over several years, with no clustering of cases over time or in a specific region.

Figure 4 - Salmonella Agona strains received at the CNR between 2006 and 2017, all ages, indicating strains belonging to the "Agona4" epidemic cluster, by month of collection

Management Measures

Several consecutive measures involving the withdrawal and recall of a wide range of milk products manufactured by the same company have been implemented since December 2, 2017. The list of these products is available on the DGCCRF website.

The DGS set up a toll-free hotline from December 10 to 24, 2017. This call center was designed to answer parents’ questions and provide appropriate health recommendations.

The manufacturer has also made a toll-free number available to parents—0800 120 120 (open from 9:00 a.m. to 8:00 p.m.). This hotline is designed to answer parents’ questions about the recalled products.

International Investigations

In addition to the alert issued in France and the measures taken, on December 6, 2017, Santé publique France alerted its counterparts in national public health agencies and institutes, as well as microbiologists at the European Union’s national reference laboratories, via the Epidemic Intelligence System (EPIS) of the European Centre for Disease Prevention and Control (ECDC). The World Health Organization (WHO) also transmitted the alert via its Infosan network to the national focal points of all potentially affected countries.

Information on the products to be withdrawn from sale was disseminated internationally via the European Rapid Alert System for Food and Feed (RASFF) and the WHO’s Infosan network.

To date, three cases of Salmonella Agona infection in infants who consumed milk from the list of implicated products have been identified outside of France: two children in Spain (one infected with a strain belonging to the epidemic clone, the second with confirmation of the strain’s affiliation with the epidemic clone pending) and one child in Greece (confirmation of the strain’s affiliation with the epidemic clone pending).

The ECDC and the European Food Safety Authority (EFSA), in close collaboration with French health authorities and Santé publique France, conducted a rapid risk assessment of this event. The report of this assessment has been available on the ECDC website since January 17, 2018.

Santé publique France also informed healthcare professionals at the European level through the publication on January 11, 2018, of an article in the scientific journal Eurosurveillance¹.

Reminder of advice for parents - Recommendations from the French Society of Pediatrics

Parents using a can of infant formula affected by this recall must switch to a different formula immediately. The French Society of Pediatrics (SFP) has issued recommendations for possible substitutes, which are also published on the website of the Ministry of Solidarity and Health.

These recommendations have also been shared with general practitioners, pediatricians, midwives, and pharmacists.

Santé publique France reminds the public of the hygiene guidelines to follow when preparing baby bottles:

• hands must be washed thoroughly with soap and water before each step;

• bottles should not be prepared in advance;

• bottles must be cleaned immediately after use.

Reminders about the disease

Salmonella infections generally occur within 3 days of ingestion and cause symptoms of gastroenteritis, including vomiting, diarrhea (which may be bloody), and fever in most cases. If these symptoms appear in an infant, families should consult a doctor immediately.

Salmonella Agona is one of approximately 2,000 Salmonella serotypes that are pathogenic to humans. From 2012 to 2016, the National Reference Center for Salmonella identified approximately 65 strains of Salmonella Agona per year across all age groups. Like most other Salmonella serotypes, Salmonella Agona is found in France in various animal reservoirs, including poultry, cattle, pigs, and animal feed.

Several outbreaks of Salmonella Agona salmonellosis have been reported in the past, notably an outbreak attributed to the consumption of powdered milk by infants in France in 2005, an outbreak among infants in Germany attributed to the consumption of fennel- and anise-based herbal teas³, and outbreaks attributed to the consumption of peanut snacks⁴ or oat-based cereals⁵.

References¹Jourdan-da Silva N, Fabre L, Robinson E, Fournet N, Nisavanh A, Bruyand M, Mailles A, Serre E, Ravel M, Guibert V, Issenhuth-Jeanjean S, Renaudat C, Tourdjman M, Septfons A, de Valk H, Le Hello S. Ongoing nationwide outbreak of Salmonella Agona associated with internationally distributed infant milk products, France, December 2017. Euro Surveill. 2018;23(2):pii=17-00852.²Brouard C, Espie E, Weill FX, Brisabois A, Kerouanton A, Michard J, Hulaud D, Forgues AM, Vaillant V, de Valk H. Salmonellosis outbreak caused by Salmonella enterica serotype Agona linked to the consumption of infant formula, France, January–May 2005. Bull Epidemiol Hebd 2006;(33):248–50. ³Koch J, Schrauder A, Werber D, Alpers K, Rabsch W, Prager R, Broll S, Frank C, Roggentin P, Tschäpe H, Ammon A, and Stark K. A nationwide outbreak of Salmonella Agona in infants due to aniseed in herbal tea, Germany, October 2002–July 2003. 5th World Congress, Foodborne Infections and Intoxications, June 7–11, 2004, Berlin, Germany.⁴Killalea D, Ward LR, Roberts D, et al. International epidemiological and microbiological study of an outbreak of Salmonella Agona infection from a ready-to-eat savory snack — I: England and Wales and the United States. BMJ 1996;311-13.⁵From the Centers for Disease Control and Prevention. Multistate outbreak of Salmonella serotype Agona infections linked to toasted oats cereal—United States, April–May 1998. JAMA. 1998 Aug 5;280(5):411.