Salmonella Durban meningitis : case report and genomics study

doi:10.21203/rs.3.rs-2598298/v1

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Case Report

Salmonella Durban meningitis : case report and genomics study

https://doi.org/10.21203/rs.3.rs-2598298/v1

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Journal Publication

published 20 May, 2023

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Background

Bacterial meningitis caused by non-typhoid Salmonella can be a fatal condition which is more common in developing countries than in developed ones.

Case presentation

We report the case of a Salmonella meningitis in a Belgian six-month old male infant. The first clinical examination was reassuring but after a few hours his general state was deteriorating which led to a blood test and a lumbar puncture. The cerebrospinal fluid analysis was compatible with a bacterial meningitis which was later identified by the NRC (National Reference Center) as Salmonella enterica serovar Durban.

Conclusions

This serovar of Salmonella is extremely uncommon. An extended genomic analysis showed relatedness to historical cases with a connection to Guinea. In this paper, we describe the clinical presentation, the genomic typing and probable sources of infection.

Meningitis

non-typhoid salmonella

paediatrics

bacterial infection

Salmonella Durban

Salmonella is gram-negative bacillus belonging the Enterobacteriaceae family. The most recent classification of Salmonella includes two species: Salmonella enterica and Salmonella bongori within whom over 2500 different serovars have been identified based on somatic antigenic factors O, flagellar H and capsular Vi as explained by the World Health Organization (1).

Salmonellosis is a global public health problem; it is an infection acquired orally causing usually a mild gastrointestinal infection which rarely requires antibiotic treatment (2). But between 1% and 5.7% of patients may develop bacteremia, which is mostly benign, although osteoarticular or meningeal secondary involvement may occur (3). Invasive infection occurs due to the distortion of local enteric immunity and is particularly seen in the young or the elderly or in individuals with predisposing conditions, particularly in immunosuppressed patients.

In developed countries, Salmonella meningitis represents less than 1% of cases of bacterial meningitis confirmed in infants and children (4). In contrast, the incidence reported in developing countries can reach up to 13% (5). It has very rapid clinical deterioration and clinical manifestations indistinguishable from any other bacterial meningitis. It is associated with a high incidence of complications, neurological disorders, high mortality, and a high percentage of relapses (6). The prognosis is poor, especially, due to complications inherent to the infection, so early diagnosis is crucial to achieve a favorable outcome.

The surveillance of human salmonellosis in Belgium is dependent on the voluntary referral of human Salmonella isolates to the National Reference Center (NRC) which ensures national epidemiological surveillance of human Salmonella infections by identifying outbreaks and by following the long-term spatial and temporal trends.

This paper aims to present the clinical case of an infant with recurrent Salmonellosis and meningitis caused by a Salmonella serovar Durban, to describe the genomics analysis of this isolate and discuss the possible source of infection.

A 6-month-old patient was admitted in the pediatric emergency department of CHC MontLégia Hospital (Liège, Belgium) with symptoms of fever and vomiting. The mother described a clinical picture with coughing and a runny nose. Medical history revealed that the patient was born in Belgium and vaccinated following the national scheme (7), having no previous serious infection. Two weeks prior to the emergency consultation, the patient was hospitalized in another pediatric hospital also for fever and vomiting, which lead to intravenous rehydration during 72 hours. During this time, a stool analysis came back positive for S. enterica serovar Durban so they started an oral antibiotic treatment with amoxicillin for seven days.

He was admitted in good general condition, no fever and normal vital signs ranges.

Physical examination was normal including a normal fontanel tone and consciousness. The preclinical explorations are detailed in Table 1.

Blood count, complete biochemical analysis, acute-phase proteins determination, blood culture were taken. Laboratory findings showed increased inflammatory markers (platelets and CRP). Electrolytes, glucose, creatinine, liver enzymes, and bilirubin were within normal ranges.

Table 1

Paraclinical results at admission
PARACLINICAL		RESULTS	UNITS	RANGE
Hemogram	Hemoglobin	11,7	g/dL	10,4–12,5
	Hematocrit	34,7%	%	30,5–36,4
	Platelets	582	x10³/mm³	185–399
	Leucocytes	24,180	x10³/mm³	7,70 − 13,10
	Neutrophils	17,26	x10³/mm³	2,50 − 6,4
	Lymphocytes	5,710	x10³/mm³	2,30 − 5,50
Biochemistry	C reactive protein	178,4	mg/L	< 5
	Glycemia	131	mg/dL	60–100
	Urea	32,7	mg/dL	11–36
	Creatinine	0,32	mg/dL	0,20 − 0,40
	Glomerular Filtration Rate	87,2	mL/min/1,73 m²	> 60
	Sodium	140	mmol/L	139–146
	Potassium	4,2	mmol/L	4,1–5,3
	Chloride	103	mmol/L	100–111
Veinous Blood Gas		Normal
Chest X Ray		Normal
Abdominal Ultrasound		Normal

Based on these results, the patient was kept on a close clinical watch with monitoring.

During this time, his clinical state deteriorated with a decreased level of activity and developing of meningeal signs such as neck stiffness. Due to this evolution, a lumbar puncture for cellular and microbiological study was quickly performed and the results are in Table 2.

Table 2. Cerebrospinal fluid analysis

Color

Trouble

		RESULTS	UNITS	RANGE
Biochemistry	Proteins	2,349	g/L	0,100-0,450
	Glucose	< 4	mg/dL	60-80
	Acide lactique	10.880	mmol/L	1,1-2,8
Cell counts	Red cells counts	110	mm³	0-4
	White cells counts	6 406/mm3	mm³	0-5
	Neutrophils	76	%
	Lymphocytes	9	%

PCR Test for Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, Cytomégalovirus, Entérovirus , Herpès simplex virus 1, Herpès simplex virus 2, Human herpesvirus 6, Human parechovirus, Varicella zoster virus, Cryptococcus neoformans/gattii	Negative
Microbial culture	Positive for Salmonella (D group)

Due to the clinical deterioration, an empirical antibiotic treatment with intravenous cefotaxime was initiated at a dose of 200 mg/kg/day and the patient was admitted in the pediatric intensive care unit. The blood cultures collected at admission came back negatives.

Both CSF and stool cultures came back positives for Salmonella (group O9) after 24 hours of incubation. The isolated strain was sent for classification and further analysis to the NRC for Salmonella. The strain was typed as S. enterica serovar Durban and it was susceptible to all antibiotics tested (including amoxicillin and cefotaxim).

This serovar is rarely observed in Belgium (0–6 cases annually in the period 2014–2021) and in the EU/EEA (11–33 cases annually in the period 2014–2020) (9).

The relatedness of the isolates was investigated by whole genome sequencing and confirmed to be genetically indistinguishable (0 allele differences, cgMLST scheme Enterobase). Further genetic comparison with all other S. enterica serovar Durban cases isolated in Belgium during the period 2014–2021 (N = 22, Table 4) revealed a tight cluster with 8 other isolates (0–6 allele differences) (Fig. 2).

Table 3

Immunologic blood test
	RESULTS	UNITS	RANGE
CD3	58	%	51,8–74,2
CD3	2802	/mm³	2284–4476
CD4	39	%	34,9–53,1
CD4	1884	/mm³	1523–3472
CD8	17	%	12,8–27,1
CD8	821	/mm³	524–1583
CD4/CD8 ratio	2,3	ratio	1,5 − 3,8
CD19	36	%	17–37,2
CD19	1739	/mm³	776–2238
CD16 CD56	4	%	4–15,1
CD16 CD56	193	/mm³	230–801
Total proteins	64,4	g/L	44–76
IgG	8,37	g/L	2,20 − 9
IgA	0,76	g/L	0,08 − 0,80
IgM	0,90	g/L	0,35 − 1,25
Complement C3	1,92	g/L	0,70 − 1,40
Complement C4	0,28	g/L	0,12 − 0,36
CH50	> 95	U/mL	41,7–95,1

Table 4

Historical *S. enterica* serovar Durban cases isolated in Belgium during the period 2014–2021
Sample Id	Patient Age	Specimen	Clinical Info	Travel	Country
S14BD00872	1	Blood	Septicemia	Y	Guinea
S14BD03902	UNK	Faeces	UNK	UNK
S15BD03255	11	Faeces	Gastroenteritis	N
S15BD04152	6	Faeces	Gastroenteritis	N
S15BD05605	19	Faeces	Gastroenteritis	N
S15BD10068	30	Faeces	UNK	N
S15BD10166	67	Faeces	UNK	N
S16BD05097	2	Blood	Gastroenteritis	N
S16BD06646	9	Faeces	Malaria + Gastroenteritis	Y	Guinea
S17BD05858	2	Faeces	UNK	N
S17BD07615	0	Faeces	UNK	N
S18BD06055	1	Faeces	UNK	N
S18BD08552	24	Faeces	UNK	N
S19BD02073	2	Faeces	UNK	UNK
S19BD06302	1	Faeces	UNK	N
S19BD06559	1	Blood	cervical adenopathy	Y	Guinea
S19BD06638	3	Faeces	UNK	UNK
S19BD08525	0	Faeces	bronchitis	UNK
S19BD09248	0	Faeces	UNK	UNK
S21BD04961	2	Faeces	UNK	Y	Guinea
S21BD05077	5	Faeces	UNK	UNK
S21BD05152	57	Faeces	UNK	UNK

Because of the very rare clinical presentation, an immunologic workup for the evaluation of patients suspected of having immunodeficiency was done (Table 3).

A complementary exploration was done with an EEG showing a normal awake brain activity and an MRI which showed purulent suffusion in the lateral ventricles consistent with clinical finding of acute meningitis and pyogenic ventriculitis. No brain abscess or extra-axial empyema were shown (Fig. 1). A month later, cerebral MRI showed a persistent frontal purulent suffusion of 5 mm diameter. No brain abscess or extra-axial empyema. Cerebral MRI showed a progressive reduction of the frontal purulent material.

The clinical evolution was good and the patient was discharged after 28 days of parenteral antibiotherapy with cefotaxime.

To this day, he has no neurological sequelae.

When a Salmonella infection is suspected, it is very important to send the Salmonella isolates to the NRC so they can confirm the identification and further characterize the isolate.

There are numerous Salmonella serotypes and the most frequently associated with meningitis are Salmonella serovar Typhimurium (75–88%), followed by Salmonella serovar Enteritidis (8–16%) and less frequently Salmonella serovar Typhi (1–4%) (8). Other serovar very rarely caused meningitis.

Salmonella causes its effects in the gastrointestinal tract and, for immunocompetent patient, is eliminated by the immune response. Children have an immature immune system and are more likely to develop complications like meningitis as described in our case.

When a Salmonella infection is suspected or found, it is very important to send the Salmonella isolates to the NRC so they can confirm the identification and realize further analysis.

The presented case first developed a rather mild episode of salmonellosis with gastrointestinal symptoms which at first appeared to be successfully treated by antibiotics (amoxicillin), yet one month later the patient had a relapse with a more severe clinical presentation of bacterial meningitis.

The isolates of both infectious episodes were further typed by the NRC and confirmed to be S. enterica serovar Durban and were genetically indistinguishable. Further genetic comparison with historical S. enterica serovar Durban cases isolated in Belgium revealed a tight cluster with 8 other isolates.

Epidemiological investigations revealed that no family members had a history of fever or diarrhea. The mother reported no pets or contact with farm animals. The family is originally from Guinea but have not travelled there for two years, neither had contact with people who had recently travelled. It’s interesting to know that 4/8 related historical Belgian cases of S. enterica serovar Durban reported recent travel to Guinea at their time of illness. It’s also known that Salmonella can cause chronic infections which can persist for years, and although infected individuals are highly contagious, they are typically asymptomatic, making the identification of carriers very difficult. The situation is further complicated by the fact that approximately 1 out of 4 carriers experience no clinical manifestations during the acute phase of the disease (10). Carrier identification is not automatically done because it could require multiple stool samples because of the intermittent shedding over a long period of time which would be difficult to achieve.

Finding a link with Guinea in our patient and in light of our investigations, a fecal culture was collected from his parents which turned out positive with a genetically indistinguishable S. enterica serovar Durban strain from the father. The parents being totally asymptomatic as previously stated, transmission from the healthy father as carrier seems therefore the most plausible route of infection.

We described a case of Salmonella infection in an immunocompetent patient living in an industrialized country. The infant developed meningitis as complication of systemic infection probably due to his young age.

According to our experience, an early diagnosis based on recognition of acute neurological signs and laboratory findings associated to a prompt and appropriate antibiotic therapy for at least four to six weeks can improve the outcome of the patient and reduce the risk of neurological sequelae.

In our case, further typing and WGS comparison of the strain hinted at the epidemiological link. We investigated the origin of the family which led to the confirmation of the carrier state of one of the parents. This highlights the added value of enhanced molecular surveillance to investigate the possible source of infection and might help in investigation of outbreaks.

Ethics approval and consent to participate

Not applicable

Consent for publication

Written informed consent was obtained from the legal representants of the patient for the publication of any potentially identifiable images or data included in this article.

Availability of data and materials

All relevant data are in the paper

Competing interests

The authors declare that they have no competing interests

Funding

The authors received no specific funding for this work, but the Belgian reference center for Salmonella is partially supported by the Belgian Ministry of Social Affairs through a fund within the Health Insurance SystemAuthors' contributions

Author contribution

Experiment and data analysis: WM

Redaction manuscript: CN, WM, PJC, AV, MM, SD, OB

Acknowledgements

We would like to thank all the technicians of the National Reference Center for Salmonella and Shigella, for their expertise in serotyping by slide agglutination and their participation to this analysis. Gene sequencing of the Belgian strains was performed at the Platform Biotechnology and Molecular Biology at Sciensano.

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No competing interests reported.

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You are reading this latest preprint version

Salmonella Durban meningitis : case report and genomics study

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Journal Publication

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Abstract

Background

Case presentation

Conclusions

Figures

Background

Case Presentation

Discussion And Conclusions

Declarations

References

Additional Declarations

Status:

Journal Publication

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