Case 1
A previously healthy male aged 3 years 9 months was sent to hospital for a 3-day history of fever. At presentation, he was lethargic, laboratory test showed white blood cell(WBC) count of 9.1×109 cells/L, with 90.7% neutrophils, and c-reactive protein(CRP) level of 272mg/L; he had cerebrospinal fluid(CSF) pleocytosis with nucleated cell count of 257×106cells/L(73.2% neutrophils), CSF glucose of 2.93mmol/L, and CSF protein of 430mg/L. Head MRI showed bilateral subdural empyema, hemorrhage on right cerebral cortex, and substantial opacification in the bilateral sphenoidal sinuses, ethmoid sinuses and maxillary sinuses, suggestive of serious sinusitis. He received empiric IV vancomycin and meropenem, however, his clinical condition deteriorated rapidly, on the 1stday of admission, he fell into a coma, suffered frequent seizures, acute kidney injury and shock (streptococcal shock syndrome, STSS), he was intubated and sent to paediatric intensive care unit. On the 3rd day of admission, blood culture grew group A streptococcus. On the 8th day of admission, his consciousness improved, his fever and convulsions subsided, he was extubated, but his physical examination showed muscles weakness (grade 3/5 muscle strength) and hypomyotonia on his left limbs. On the 37th day admission, another head MRI showed subdural abscess near right parietal lobe, subdural effusion near left frontal parietal lobe, abnormal signals on right frontal parietal lobe and opacification on his left maxillary sinus and meningeal enhancement (supplemental Figure); his muscles weakness and hypomyotonia improved gradually after aspiration of subdural abscess. Physical examination showed a grade 4/5 muscle strength on his left limbs when he discharged. The patient was followed up for 9 years, no neurological sequela was found. The GOS-E Peds scores was 1(good recovery) at last follow-up.
Case 2
A previously healthy 8 years old female presented for a 10-day-history of fever and lethargy and 5-day-history of headache and photophoby. Full blood cell count revealed WBC of 11.30×109 cells/L, with 94.1% neutrophils; CRP level was elevated to 62.28mg/L; CSF analysis showed nucleated cell count of 41.00×106cells/L, normal levels of glucose, and protein. Head MRI showed hyperintense signals on surface of right frontal lobe on diffusion-weighted imaging substantial opacification in the bilateral sphenoidal sinuses, ethmoid sinuses and maxillary sinuses. She received empiric IV vancomycin and ceftriaxone, on the 2nd day of admission, blood culture yielded GAS, and antibiotic treatments was narrowed to IV penicillin. On the 15th day of admission, the patient recovered very well with resolution of fever and neurological symptoms. A second head MRI on 30th day of admission showed patchy abnormal signals on right frontal lobe (no enhancement was found in this lesion) and meningeal enhancement (Supplemental Figure). The patient was followed up for 5 years, no neurological sequela was found at discharged. The GOS-E Peds scores was 1(good recovery) at last follow-up.
Case 3
A previously healthy 1year and 6 months old male came to hospital for a 7-day-history of fever, on the day of admission, he suffered a status epilepticus, followed by coma; 8 days before admission (1 day before fever onset), he scalded his right hands with hot liquids. Laboratory test showed increased WBC count of 14.37×109 cells/L(79.8% neutrophils), elevated CRP of >160mg/L and procalcitonin of >100ng/ml; CSF analysis revealed nucleated cell count of 1370×106 cells/L, decreased glucose of 1.0mmol/L, he received empiric IV meropemen. On the 3rd day of admission, CSF culture grew GAS, he had improvement on fever but was still in coma with persistent opisthotonic posture. Head MRI showed subdural effusion and ventricular dilation. Brainstem audiometry showed moderate hearing loss (50dB) right ear. On 22nd day of admission, he suffered fever again because of serious persistent hypermyotonia. On 52nd day of admission, a second MRI showed necrosis on cerebral cortex, subdural effusion and communicating hydrocephalus (Supplemental Figure). On the 66th day of admission he discharged from hospital, he had no improvement in fever, unconciousness and hypermyotonia. He was followed up for 2 years, at the age of 3 years 6 months, he demonstrated serious neurological sequela, including paralysis, mental retardation and mood disorders. The GOS-E Peds scores was 6 (severe disability) at last follow-up.
Case 4
A previously healthy 12 years 8 months old female admitted to hospital for headache and swollen right eyelide for 3 days, fever for 2 days and convulsion one time. She was conscious at presentation. Her full blood cell count showed increased WBC count of 17.6×109 cells/L, with 93.2% neutrophils; CRP level was elevated to>160mg/L; She had CSF pleocytosis with nucleated cell count of 298×106 cells/L, normal CSF glucose level and mildly elevated CSF protein level. Orbital CT and MRI showed right orbital cellulitis, orbital abscess and sinusitis (right sphenoidal sinusitis and maxillary sinusitis), head MRI revealed enhanced leptomeninges in right hemisphere (Supplemental Figure). She received empiric IV vancomycin and ceftriaxone. Blood culture and CSF culture were negitive, metagenomic next generation sequencing(mNGS) with CSF showed GAS (124 reads). Clinical condition improved apprently on the 4th day of admission, with resolution of fever, swollen right eyelid and improvement of neurological symptoms. Antibiotic treatment was going on because of orbital abscess. On the 33rd day of admission, the patient discharged, she was followed up for 4 years, no neurological sequela was found. The GOS-E Peds scores was 1 (good recovery) at last follow-up.
Case 5
A previously healthy 11 years old female was sent to hospital for a 6-day-history of fever and headache. On the 4th day of fever, the patient had a convulsion, followed by a coma. Laboratory test revealed an increase in WBC count to18.6×109 cells/L( 91.5% neutrophils), a CRP of 288mg/L; CSF analysis showed increased nucleated cell count(131×106 cells/L), normal glucose and protein level. Head MRI showed diffused abnormal signals in left frontal, parietal and occipital lobes, subfalcine herniation, subdural abscess; Temporal CT showed left mastoiditis and sinusitis (bilateral sphenoidal sinuses, ethmoid sinuses and maxillary sinuses). She received IV vancomycin and meropenon as empirical treatments. Blood culture and CSF culture showed no growth, but mNGS of CSF revealed GAS (40 reads). On the 6th day of admission, her condition improved with resolution of fever and coma, however, physical examination found her with aphasia and muscle weakness on right limbs (3/5 grade muscle strength), her muscle weakness improved slowly, when she discharged on the 32nd day of admission, muscle weakness recovered to grade 4, another head MRI showed obvious abnormal singles and necrosis on cerebral cortex in left hemisphere (Supplemental Figure). She was followed up for 3 years: 3 months after discharging from hospital, her muscle weakness recovered completely, and she could speak several words but could not speak sentences; 7 months after discharging from hospital, she could speak in sentences slowly; 1.5 years after discharging from hospital, she suffered from symptomatic epilepsy, she was independent in daily life, could communicated with simple sentences but had difficulty in study, therefore she transferred to a special school when her epilepsy was controlled with drugs. The GOS-E Peds scores was 4 (moderate disability) at last follow-up.
Systematic review
We found a total of 57 articles, reporting on 230 cases treated in USA, Canada, Brazil, UK, Netherlands, Germany, Switzerland, Norway, Italy, Turkey, Israel, Saudi Arabia, India, Japan, and Nigeria. Of these studies, 52 studies were case reports[6-57] (including 67 cases, supplemental content 2), the other 5 studies were case series[58-62](including 163 cases).
GAS meningitis was found in all age groups, but children younger than 1 year old had peak incidence, data based on case reports (Table 1) showed that 37.5% of individuals aged <1year; data based on case series(Table 2 ) showed that the proportion of patients aged younger than 1 year old ranged from 22% to 56%, and the median age ranged from 2.3 to 5.8 years.
Risk factors were common in GAS meningitis cases, 81.4%(57/70) of cases reviewed from cases reports and 65.0% (106/163)of cases reviewed from case series had risk factors. Extracranial infectious lesions were the most common risk factors, 60.0% of cases reviewed from cases reports had extracranial infectious lesions(Table 1), Table 3 showed the extracranial infectious foci in different age groups, among children ≥3 years old, ear, sinus and mastoid infection were the most common extracranial infection(17/36, 47.2%); however, among children <1year old, soft tissues infection were the most common extracranial infectious lesions (11/27, 40.7%). Ear, sinus and mastoid infection were also the most common extracranial infection among case series studies, the proportion of cases with ear, sinus and mastoid infection ranged from 21.4% to 62.5% in different case series studies(Table 2).
According to the pathogenesis of GAS meningitis, the most of GAS cases were classified to primary infection cases, however, the rate of parameningeal infection related cases increased with age. Among cases reviewed from case reports, 64.3% of them and 100% of cases < 1year old were primary infection cases, but 47.2% of casesin age group ≥3 years old were classified to parameningeal infection related cases. Among series studies, the proportion of primary infection cases ranged from 37.3% to 78.6% in different case series studies(Table 2). Younger cases had higher proportion of primary infection cases was also found in Link-Gelles’s case series study[5], he retrospectively reviewed 91 cases with intracranial GAS infection (including meningitis, epidural, cerebral and cochlear infection), 13 of 20 cases aged <1year were primary infection.
According data to case reports, the most common complications were brain abscess or cerebromalacia (30.2%) , followed with shock(15.9%), among 5 case series studies we reviewed, only one study described 4 cases with cranial abscess, 3 studies described STSS or shock (5/14, 1/8 and 9/83).
Among cases reviewed from case reports, the overall case fatality rate(CFR) was 14.1%(9/64) (Table 1), but 25.9% in age group < 1 year old, all of deaths were primary infection, 7 of them younger than 1 year old, and 5 of them died of shock or STSS; 33 of 55 survived cases had follow-up description, the duration of follow-up ranged from 2 weeks to 9 years, 16 of survivors had neurological sequela (supplemental digital content 3), including: sensorineural deafness, symptomatic epilepsy, developmental delay, limb movement disorders and visual impairment, one case with hypomyotonia when discharged from hospital recovered completely during the follow-up. Among case series studies, the CFR ranged from 0% to 42.9% (Table 2), in a case series study, the case fatality rate (CFR) was 17% in primary cases, higher than ENT infection related cases(9%)[5]. A total 132 isolates described emm types (Table 1 and Table 3), emm1were most common emm types.