A case report of Salmonella meningitis in three Chinese children and a literature review

Background: Salmonella is a common pathogen for gastroenteritis, but it rarely causes intracranial infection in China. To improve the understanding of pediatric Salmonella meningitis, we report three cases of Salmonella meningitis in Chinese children. Case presentation: The patients were aged from 1 day to 14 months. Fever was the �rst symptom in two patients, while loose stool with a little mucus occurred in one patient during the course of disease. Peripheral white blood cell count, neutrophils count, and C-reactive protein were 20.08 - 25.2 *10 9 /L, 15.4 - 19.7 *10 9 /L, and 1.6 - >160 mg/L, respectively. CSF analysis showed that white blood cell count, glucose, and protein were 70 - 1473 *10 6 /L, 0.18 - 3.19 mmol/L, and 598.1 - 6639.0 mg/L, respectively. Three isolates of Salmonella were detected in cerebrospinal �uid cultures, including Salmonella newport, Salmonella paratyphi, and Salmonella typhimurium (one case per each). All strains were sensitive to ceftriaxone, ceftazidime, cefoperazone / sulbactam, meropenem, and imipenem, while one strain was resistant to ampicillin. The blood cultures were all negative. All patients were treated with carbapenems after failed therapies of cefotaxime or ceftriaxone, for a total duration of 3 - 5 weeks. One patient died, and subdural effusion occurred in one of the two survivors. Conclusions: Salmonella meningitis was rare, but the clinical conditions were serious. Carbapenems might be the �rst choice for treating Salmonella meningitis.


Background
As a common zoonotic disease, Salmonella infection is mainly transmitted by the fecal-oral route through contaminated food or water and causes acute gastroenteritis, typhoid, paratyphoid, bacteremia, and sepsis [1, 2] , but rarely meningitis.Reports on Salmonella meningitis are mainly in developing countries, especially in Africa [3][4][5][6] , but few in China.As a result, there is not enough clinical experience in the diagnosis and treatment of Salmonella meningitis in Chinese children.Therefore, we conducted this study to improve the condition.In our study, three cases were found to be Salmonella-positive in cerebrospinal uid (CSF) cultures obtained from 2007 to 2019 according to the records in the laboratory information system of our hospital.The clinical characteristics and hospital course of these patients were collected from the medical records retrospectively and reported as follows.Additionally, relevant literatures were reviewed as well.

Case Presentation
Case 1 A 1 day-old premature infant, diagnosed as neonatal asphyxia and low birth weight, was admitted on November 6, 2018 for 4 hours after the asphyxia rescue.She was delivered by cesarean section in a local hospital at the gestational age of 33 weeks, with a birth weight of 1.55 kg and an Apgar score of 6-9 points / 1-5 minutes.After birth, she was treated with oxygen inhalation, sputum suction, and intravenous administration of penicillin and cefotaxime (the details were unknown).Her mother was a healthy rural woman who denied the history of unclean diet, diarrhea, or vomiting.On admission, physical examination and routine blood test revealed no abnormality except hypotonia.She was fed with formula milk after admission.Continuous fever occurred on the 8th day.CSF culture was performed on the 11th day and Salmonella typhimurium, a strain sensitive to ceftriaxone, ceftazidime, cefoperazone/sulbactam, and meropenem, but resistant to ampicillin, was isolated 5 days later.No gastrointestinal symptoms or neurological signs were noted during the hospitalization.The stool routine test was normal.The blood culture was negative while stool culture was not performed.The hospital course is shown in Fig. 1.The cerebral magnetic resonance image (MRI) is shown in Fig. 2.She was discharged after 32 days of hospitalization.No neurological sequelae had occurred up to July, 2020.

Case 2
A 44 day-old rural female infant was admitted on September 27, 2016 with the presentation of recurrent fever for 10 days.She was previously admitted to a local hospital for neonatal hypoglycemia, hyperbilirubinemia, and anemia, where she was bottle-fed, treated with piperacillin/tazobactam (the details were unknown), and discharged in stable condition after one month of hospitalization.On September 17, 2016, two days after discharge, she developed a fever (the temperature was not measured).On the next day, she was taken to a local hospital, where she was diagnosed with purulent meningitis, sepsis, septic shock, metabolic acidosis, liver dysfunction, and anemia, and was successively treated with cefotaxime, penicillin, ceftriaxone, meropenem, and vancomycin for a week (the details were unknown).However, the symptom improved while fever persisted, and then the parents took her home by abandoning therapy.Three days before admission to our hospital, she presented less eating, less crying, and less movement.One day prior to admission, she had a generalized tonic-clonic seizure that lasted for about 10 minutes and recovered spontaneously.History of unclean diet was denied, and no diarrhea or vomiting occurred during the course of disease.On admission, she was conscious, but her mental state was poor.The anterior fontanel was at, and the neck was supple.Brudzinski's and Kernig's signs were negative, while Babinski's sign was positive.Stool routine test was normal.Blood culture was negative.Cultures of both CSF and stool specimens yielded Salmonella paratyphi of the same antibiogram which was sensitive to ampicillin, ceftriaxone, ceftazidime, cefoperazone/sulbactam, and meropenem.After admission, she had recurrent fever and convulsions, mild neck stiffness, and bulging anterior fontanel along with gradually deteriorated condition.Sudden cardiac and respiratory arrest occurred on the 15th day after admission, and the parents decided to give up all treatment and took her home.The hospital course is shown in Fig. 3. Follow-up by telephone con rmed her death.The cerebral MRI is shown in Fig. 4.

Case 3
A previously healthy 14-month-old urban girl was admitted on June 10, 2008 with a history of recurrent fever and sleepiness for half a month.The fever was continuous and high-grade up to 39.4 ℃ even after 10 days' treatments of intravenous penicillin, cefotaxime, and azithromycin administration in another hospital (the details were unknown).Neither the child nor any family members had a history of unclean diet, diarrhea, or vomiting, but she had loose stool with a little mucus during the hospitalization.On admission, she was conscious, irritable, the anterior fontanel was bulging, the neck was mild stiff, Brudzinski's and Kernig's signs were negative, and Babinski's sign was positive.Routine tests of the stool samples were all normal.Salmonella newport, which was sensitive to ampicillin, ceftriaxone, ceftazidime, cefoperazone/sulbactam, and meropenem, was found to be positive in CSF culture.Blood culture was negative.Stool culture was not performed.Considering the poor effect of antibiotic therapy and the presence of subdural effusion on computerized tomography (CT) scans, she was then treated with surgical drainage on the 9th day of hospitalization.During the operation, xanthochromic and slightly cloudy CSF was observed.She defervesced on the 12th day of hospital stay.The subdural drainage tubes were removed successively when her condition improved.She was discharged after 21 days of hospitalization.However, She was lost to follow-up after discharge.The hospital course is shown in Fig. 5.The cerebral CT images before and after the operation are shown in Fig. 6.

Discussion And Conclusions
Salmonella meningitis is a relatively rare clinical entity.Only three cases of Salmonella meningitis were diagnosed in our hospital in the recent 13 years.Consistent with the previous reports [1,[7][8] , the patients were all young children.Salmonella is mainly transmitted by the fecal-oral route and contaminated food or carriers are the common sources of infection.Therefore, the gastrointestinal tract is often the rst site of infection [9] .In this study, two cases were infants who were both bottle-fed in the neonatal period due to hospitalization.It was unclear that whether contaminated milk or bottles were the sources of infection, because no outbreak occurred among the hospitalized neonates during the same period in the hospital.Stool culture revealed the presence of Salmonella in one case who had no diarrhea, suggesting that Salmonella could cause invasive infection without obvious gastrointestinal symptoms in young infants [10]   .Generally, Salmonella meningitis follows invasion of the bloodstream by Salmonella that passes through the intestinal mucosal and lymphatic barrier [9] .Negative results of blood culture might be related to the use of antibiotics before specimen collection, while the bacteria in bloodstream were easier to be killed and eliminated than those in the central nervous system.
No speci c features are found in the routine and biochemical tests of CSF in Salmonella meningitis, neither do the symptoms nor signs.The younger the children, the more atypical their clinical manifestations.Therefore, the diagnosis of Salmonella meningitis mainly depends on CSF culture, while cultures of blood, stool, bone marrow, and other specimens are valuable for facilitating its diagnosis.
Since the gastrointestinal tract is always the rst site of Salmonella infection, stool culture is recommended for patients with suspected invasive infections caused by Salmonella.Unfortunately, two cases failed to perform stool culture in our study.So far, over 2700 serotypes of Salmonella have been described worldwide.The three serotypes detected in our study were newport, paratyphoid, and typhimurium, which were among the most common serotypes that cause invasive infections [11][12][13] .Cerebral CT images of case 3

Figure 1 The hospital course of case 1 Page 11 / 15
Figure 1

Figure 2 Cerebral MRI images of case 1 Page 12 / 15
Figure 2

Figure 3 The hospital course of case 2 Page 13 / 15
Figure 3

Figure 4 Cerebral MRI images of case 2 Figure 6
Figure 4