Determining the Clinical Characteristics, Treatment Strategy and Prognostic Factors of Mycoplasma Pneumoniae Encephalitis in Children: A Multicenter Study from China

doi:10.21203/rs.3.rs-1094490/v1

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Determining the Clinical Characteristics, Treatment Strategy and Prognostic Factors of Mycoplasma Pneumoniae Encephalitis in Children: A Multicenter Study from China

https://doi.org/10.21203/rs.3.rs-1094490/v1

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Background Most of the knowledge on Mycoplasma pneumoniae encephalitis (MPE) in children is based on case reports or small case series.This study aimed to describe the clinical features, the efficacy of azithromycin with or without immunomodulatory therapy ,and prognostic factors of MPE .

Methods The Medical data of eighty-seven MPE patients from three medical centers in southwestern China over a 7-years period were reviewed.

Results MPE was noted in children of all ages except for neonates.The most common neurological manifestations include consciousness disturbance(90%) and headache(87.4%),the most common extra-neurological presentations include fever (96.5%)and respiratory system involvement(94.3%) ,multi-system involvement(98.2%) and elevated C-reactive protein(CRP) (90.8%)were also prominent.M. pneumoniae detection in CSF was less than in blood and respiratory tract secretions.Azithromycin with intravenous immunoglobulin (IVIG) or/and corticosteroids treatment can shorten the hospitalization duration and length of clinical improvement. Multivariate analysis revealed that onset during teenage years and high lactate dehydrogenase (LDH) and CSF protein levels were identified as independent prognostic factors for poor outcome.

Conclusions In children having acute encephalitis with multi-system involvement, especially in those with respiratory tract manifestations, accompanied with prominently elevated CRP,M. pneumoniae should be given preference.Higher age,marked CSF protein and blood LDH were correlated with unfavorable outcomes. Multiplicity mechanisms ,especially immune-mediated inflammation involved in the pathogenesis. Immunomodulating therapies should be recommended regardless of the duration of prodromal period.

Mycoplasma pneumoniaeencephalitis

Childhood

Clinical characterization

Prognostic factor

Azithromycin

Intravenousimmunoglobulin

Corticosteroid

Mycoplasma pneumoniae is a common cause of respiratory tract illness in children. One of the extrapulmonary manifestations is nervous system involvement in the form of conditions including encephalitis, meningoencephalitis, cerebellitis, cerebral infarction, acute disseminated encephalomyelitis,etc[1–4].M. pneumoniae is considered as one of the major causes of encephalitis in children, accounts for 5–10% of the cases of childhood encephalitis.Mycoplasma pneumoniae encephalitis(MPE) caused by direct invasion of the brain, immune-mediated inflammatory response, neurotoxin-mediated damage, or a thromboembolic phenomenon[2, 5–8]. According to the duration of prodromal symptoms (defined as any illness that precedes neurologic symptoms), MPE is divided into early-onset form (prodromal symptoms for 7 or fewer days) and late-onset form (more prolonged prodromal symptoms). The early-onset form is mainly related to the direct invasion of the central nervous system (CNS) by M. pneumoniae, while the late-onset form is usually characterized by an autoimmune of CNS disease principally[1, 9].The multiplicity of possible mechanisms suggests that a range of therapeutic approaches should be considered. It is widely accepted that antibiotics play a key role in the management of all children with suspected MPE[1]. However, the role of immunomodulating medications such as corticosteroids and intravenous immunoglobulin (IVIG) has not been studied extensively[1, 10–11]. Furthermore, few studies have evaluated the prognostic factors associated with MPE[12]. The purpose of this retrospective study was to evaluate patients with MPE at three medical centers in southwestern China,describe the clinical features,determine differences in the efficacy of azithromycin and immunomodulatory therapy and prognostic factors for outcomes associated with the disease.

Diagnosis and definition of MPE

MPE was diagnosed based on the presence of a consistent clinical neurological syndrome, cerebrospinal fluid (CSF) positive for IgM or/and PCR positive for M. pneumoniae, and exclusion of other probable causes[5]. Patients with underlying neuropsychiatric disorders and alternative diagnoses were excluded.

Study Population And Data Collection

This retrospective study included patients with a confirmed diagnosis of MPE between January 1, 2013, and December 31, 2019, who were admitted in three medical centers in southwestern China, including the Chongqing Ninth People's Hospital, Children's Hospital of Chongqing Medical University, and Maternal and Child Health Hospital in Chongqing Fuling District. A total of 87 patients were included in this study during the 7-year study period. A detailed review of medical data was performed, including clinical characteristics, laboratory data of blood and CSF, cranial MRI, electroencephalogram (EEG), treatments with antiviral agents or immunomodulating medications such as corticosteroids and IVIG. The patients were followed up for at least 6 months after discharge. The Glasgow outcome scale (GOS) was used to evaluate the prognosis. Patients with GOS scores of 4-5 grade and 1-3 grade at the main clinical evaluation time point of 6 months after discharge were included in the good outcome (GO) and poor outcome (PO) group, respectively. According to the duration of prodromal symptoms, patients which prodromal symptoms for 7 or fewer days were classified into the early-onset group, and more than 7 days were included in the late-onset group.

Statistical analysis

The data for different parameters are expressed as median values (ranges) or numbers (percentages). For further analyses and comparisons, the patients were divided into two sub-groups according to the outcome(GO/PO group)and the duration of prodromal period༈early/late onset group༉. Statistical differences between different groups were analyzed using the Pearson chi-square test, Fisher’s exact test, or univariate logistic regression according to the nature of the variables. In multivariate analysis, binary logistic regression using backward strategies was used for independent factor analysis. All statistical analyses were performed using IBM SPSS Statistics for Windows version 22.0 (Armonk, NY); the significance level was set at a two-tailed p-value of <0.05.

Demographic and clinical characteristics of the patients

During the study period,87 patients were finally included.The demographic and clinical characteristics of these patients are shown in Table 1.

Table 1. Demographic and clinical characteristics of the study population with a comparison between different sub-groups.

Characteristics (n = 87)			n (%) or median (range)	Prognosis		Onset-type
Characteristics (n = 87)			n (%) or median (range)	Good outcome (n = 72)	Poor outcome (n = 15)	early-onset (n = 49)	late-onset (n = 38)
Male			49（56.3）	40 (55.6)	9 (60)	29（59.2）	20（52.6）
Median age (months)			62（8-176）	59 (8-148)	74.3 (11-176)	55.1（8-176）	82.3（11-148）
Age group	Newborn (0-1 month)		0（0）	0 (0)	0 (0)	0 (0)	0 (0)
	Infanthood (1–12 months)		3（3.3）	3 (4.2)	0 (0)	3（6.1）	0 (0)
	Early childhood (1–5 years)		25(28.7)	21 (29.2)	4 (26.7)	21（42.9）	4（10.5）*
	Late childhood (6–10 years)		43(49.4)	39 (54.2)	4 (26.7)	28（57.1）	15（39.5%）
	Adolescence (11–18 years)		16(18.4)	9 (12.5)	7 (46.7)*	10（20.4）	6（15.8）
Living area	Urban		56(64.4)	53 (73.6)	3 (20)*	32（65.7）	24(63.2)
	Rural		31(35.6)	19 (26.4)	12 (80)*	17(34.7)	14(36.8)
Prodromal symptom	None or for ≤7 days		49（56.3）	40 (55.6)	9 (60)	-	-
Prodromal symptom	For >7 days		38（43.7）	32 (44.4)	6 (40)	-	-
Clinical presentation	Neurological presentation		87(100)	72 (100)	15 (100)	49（100）	38（100）
Clinical presentation	Body temperature change		87(100)	72 (100)	15 (100)	49(100)	38(100)
		Fever	84（96.5）	72 (100)	12 (80)	47(95.9)	37(97.4)
		Hypothermia	3（3.5）	0 (0)	3 (20)*	2(4.1)	1(2.6)
	Respiratory involvement		82(94.3)	72 (100)	10 (66.7)	47(95.2)	35(92.1)
	Gastrointestinal involvement		59(67.8)	48 (66.7)	11 (73.3)	36(73.5)	23(60.5)
	Myocarditis		21（24.1）	16 (22.2)	5 (33.3)	8(16.3)	13(34.2)
	Rash		19(21.8)	14 (19.4)	5 (33.3)	12(24.5)	7(18.4)
	Renal involvement		5（5.7）	4 (5.6)	1 (6.7)	2(4.1)	3(7.9)
Hospitalization duration			11.2（7-29）	8.4 (7-21)	15.2 (12-29)	12.9 (7-29)	9.7 (12-21)
ICU admission			4（4.6）	3 (4.2)	1 (6.7)	2(4.1)	2(5.3)
Death			0（0）	0 (0)	0 (0)	0 (0)	0 (0)
Days from symptom onset to admission			3.8（1-12）	2.3 (1-10)	6.1 (3-12)*	1.7(1-10)	8.2(1-12)
Days from symptom onset to neurological symptom onset			4.9(0-11)	5.1 (0-11)	4.4 (0-9)	2.9(0-11)	9.5(0-11)
Prognosis	Good outcome		72（82.8）			38(77.6)	34(89.5)
	Poor outcome		15（17.2）			7(14.3)	8(21.1)
Management	Azithromycin		87(100)	72 (100)	15 (100)	49(100)	38(100)
	IVIG use		37（42.5）	35(48.7)	2 (13.3)	4(8.2)	33(86.8)
	Steroid use		12（13.8）	9 (12.5)	3 (20.0)	2(4.1)	10(26.3)
	IVIG + steroid use		6（6.9）	2 (2.8)	4 (26.7)*	0(0)	6(15.8)

*P<0.05

Overall,56.3% were male and the median patient age was 5.3 years. The disease can affect children of any ages except for neonates,most patients (49.4%) were in the 6-10 years age group.City residents (64.4%) were the majority.

No specific clinical features were represented in our cohort. All patients had abnormal body temperature, with most of them had fever (96.5%) ,few of them (3.5%) had hypothermia.The reported most frequently neurological manifestations were disturbance of consciousness (90.0%), positive pyramidal tract sign (89.7%),headache (87.4%) and seizures(75.9%).Varying extra-neurological abnomality was found in 96.5% patients,most frequently on respiratory system(94.3%) followed by gastrointestinal system(73%). Furthermore, a small number of patients had myocardial damage (24.1%), skin rash (21.8%), and urinary damage (5.7%).（Fig.1.）

Laboratory and image findings

Abnormality was found most frequently on EEG(90.8%),followed by CSF(pleocytosis in 73.6%),then MRI(44.8%).Diffuse/focal slow waves was the most common finding in EEG(62/79, 78.5%), and epileptiform discharge waves also being seen (25/79; 31.6%).CSF finding were presented with mild lymphocytosis and elevated CSF protein.In terms of neuroimaging,cortical involvement was the most common (28.7%).Interestingly,five patients (5.7%) showed reversible lesions involving the splenium of the corpus callosum, which were categorized as reversible splenial lesion syndrome (RESLES).(Table.2.)In general,all of these lab findings were compatible with common viral encephalitis.Interestingly,unlike the commonly expected hemogram in patients affected by viral diseases usually with leukopenia and normal CRP,62.1% patients were found to have leukocytosis and 90.8% patients had elevated CRP.（Table.3.）

Table 2. Involved anatomical areas detected on magnetic resonance imaging for the overall population with a comparison between different sub-groups

Neuroimaging presentations	n(%)	Prognosis		Onset-type
Neuroimaging presentations	n(%)	Good outcome (n=72)	Poor outcome (n=15)	early-onset form (n = 49)	late-onset form (n = 38)
Gray matter involvement	25(28.7)	18(25)	7(46.7)	11(22.4)	14(36.8)
Corpus callosum involvement	5(5.7)	5(6.9)	0(0)	4(8.2)	1(2.6)
Basal ganglia involvement	6(6.8)	4(5.6)	2(13.3)*	4(8.2)	2(5.3)
Thalamus involvement	4(5.7)	3(4.2)	1(6.7)	2(4.1)	2(5.3)
Brainstem involvement	2(2.3)	2(2.8）	0(0)	0(0)	2(5.3)
Cerebellar involvement	3(3.4)	3(4.2)	0(0)	1(2)	2(5.3)

*P<0.05

Table 3 Laboratory data of the study population with a comparison between different sub-groups

			N (%) or median (range)	Prognosis		Onset-type
			N (%) or median (range)	Good outcome (n = 72)	Poor outcome (n = 15)	early-onset form (n = 49)	late-onset form (n = 38)
Blood (n = 87)	WBC(*109/l)		14.3（2.7-28.1）	15.6（4.9-28.1）	13.1（2.7-21.5）	11.4（4.9-28.1）	17.8（2.7-21.5）
Blood (n = 87)	Leukocytosis		54（62.1）	45（62.5）	9（60）	26(53.1)	28(73.7)
	CRP elevation		79(90.8)	68(94.4)	11(73.3)	46(93.9)	33(86.8)
	LDH elevation		35（40.2）	23（31.9）	12（80）*	18(36.7)	17(34.7)
	Alb decrease		17（19.5）	7（9.7）	10（66.7）*	10(20.4)	7(18.4)
	Hb decrease		18（20.7）	14（19.4）	4（26.7）	8(16.3)	10(26.3)
	Serum M. pneumoniae IgM	Positive number	73（83.9）	67（93）	6（40）	40(81.6)	33(86.8)
	Serum M. pneumoniae IgM	Titer	1：283 （1:160-1:640）	1：280 （1:160-1:640）	1：352 （1:160-1:640）	1：260 （1:160-1:640）	1：380 （1:160-1:640）
CSF (n = 87)	WBC(*106/l)		182（0-610）	161（0-610）	196（0-597）	75（0-610）	210（0-597）
CSF (n = 87)	Leukocytosis		64（73.6）	52(72.2)	12（80）	35(71.4)	29(76.3)
	Lymphocytosis		53(60.9)	47(65.3)	6（40）	31(63.3)	22(57.9)
	Protein		0.806 (0.48-1.35)	0.735 (0.48-1.29)	0.956 (0.57-1.35)	1.223 (0.57-1.35)	0.594 (0.48-1.29)
	Protein elevation		48(55.17)	37（51.4）	11(73.3)*	27(55.1)	21(55.3)
	CSF/Serum glucose ratio<0.4		5（5.7）	4（5.6）	1（6.7）	3(6.1)	2(5.3)
	M. pneumoniae IgM	Positive number	70（80.5）	61（84.7）	9（60）	33(67.3)	37(97.4)
	M. pneumoniae IgM	Titer	1:277.3 （1:160-1:480）	1:276 （1:160-1:480）	1:280 （1:160-1:480）	1:180 （1:160-1:480）	1:320 （1:160-1:480）
	M. pneumoniae PCR	Positive number	25（28.7）	19（26.4）	6（40）	22(44.9)	3(7.9)*
	M. pneumoniae PCR	copy number	99.3 (1.5×10⁴-3.40×10⁶)	113.3 (1.6×10⁴-3.40×10⁶)	74.9 (1.5×10⁴-2.87×10⁶)	168 (1.6×10⁴-3.40×10⁶)	45.7 (1.5×10⁴-2.87×10⁶)
Throat swabs M. pneumoniae PCR (n = 58)		Positive number	58（66.7）	51（70.8）	7（46.7）	28(57.1)	30(78.9)
Throat swabs M. pneumoniae PCR (n = 58)		copy number	920.3×10⁴ (1×10⁴-6.59×10⁷)	969.8×10⁴ (3×10⁴-6.59×10⁷)	831.2×10⁴ (1×10⁴-3.6×10⁷)	742.5×10⁴ (3×10⁴-3.6×10⁷)	1180.2×10⁴ (1×10⁴-6.59×10⁷)

*P<0.05

Treatment

Azithromycin was administered to all 87 patients, of which 80 patients (91.9%) received intravenous (i.v.) followed by oral azithromycin treatment. The azithromycin regimen consisted of 10 mg·kg^-1·d^-1 given i.v. daily for 5 to 7 days, followed by 10 mg·kg^-1·d^-1 given orally once daily for 3 days, stopped for 4 days repeatedly for 1 week, while 7 patients received only oral azithromycin treatment (10 mg/kg of body weight once per day for 3 days, stopped for 4 days repeatedly for 1 week). 55 patients(63.2%) received immunomodulating therapy,including thirty-seven patients (42.5%) received IVIG treatment (400 mg·kg^-1·d^-1 for 5 days or 1 g·kg^-1·d^-1 for 2 days), 12 (13.8%) patients received corticosteroids (methylprednisolonei.v. 2 mg·kg^-1·d^-1for 5-7 days or methylprednisolone 20 mg·kg^-1·d^-1i.v. for 3 daysfollowed by oral prednisone acetate 1 mg·kg^-1·d^-1for 10~ 14 days, withdrawn gradually)and 6 patients(6.9%) received both IVIG and corticosteroid administration. Supportive care, including mannitol, anticonvulsant, and cooling methods were given.

The mean duration of improvement in clinical and laboratory signs and duration of hospitalization were significantly shorter for azithromycin plus immunomodulatory therapy than for azithromycin alone, especially for the IVIG group. Interestingly, the group that received azithromycin combined with IVIG and corticosteroids did not show this advantage.Moreover,therewas no significant difference in efficacy between early-onset and late onset group. (Table. 4).

Table 4. Clinical data with a comparison of different management regimes

		Defervescence time (days)	Time of disappearance of convulsion (days)	Time of consciousness normalization (days)	ICU duration stay (days)	Hospital duration (days)
Azithromycin monotherapy	Total（n=32）	9.76±1.17	15.39±2.84	10.21±1.95	12.32±5.20	14.66±5.39
	early-onset form(n=24)	7.39±1.92	18.25±3.75	8.75±3.28	14.65±1.98	17.89±2.43
	Late-onset form(n=8)	9.98±3.86	13.58±1.92	11.56±2.34	9.88±4.17	12.67±4.73
Azithromycin + IVIG use	Total（n=37）	4.61±2.30*	8.82±4.26*	6.34±3.56*	10.83±1.97	9.32±1.48*
	early-onset form(n=21)	2.89±2.94	5.79±3.82	7.21±4.79	8.48±3.25	12.74±2.35
	Late-onset form(n=16)	5.61±3.29	9.28±1.93	6.01±4.32	14.23±3.08	7.66±1.93
Azithromycin + Steroid use	Total（n=12）	4.28±1.45*	9.47±3.71*	7.69±2.48	3.57±3.91*	10.49±3.01
	early-onset form(n=2)	2.57±1.09	7.89±2.63	5.99±2.71	2.82±1.03	8.35±2.47
	Late-onset form(n=10)	5.92±2.34	12.45±4.21	9.38±3.06	6.75±3.22	11.20±4.38
Azithromycin + IVIG + steroid use	Total（n=6）	5.07±2.34	12.53±4.11	11.72±3.92	15.72±4.65	12.56±2.37
	early-onset form(n=1)	7.92±3.26	10.65±2.73	8.89±2.04	18.32±4.21	15.98±5.36
	Late-onset form(n=5)	5.77±1.53	15.29±4.84	12.11±4.57	14.72±2.58	10.87±2.78

*P<0.05

Clinical course, outcomes, and prognostic factors

The median hospitalization duration was 11.2 days; 4 patients (4.6%) were admitted to the intensive care unit (ICU) due to status convulsion or respiratory failure. There were no mortality. At the main clinical prognosis assessment (6 months after discharge),72 patients (82.8%) were classified in the GO group, while 15 patients (17.2%) were categorized in the PO group. According to the duration of prodromal symptoms，there were 49 patients （56.3%）presented with early-onset form and 38 patients（43.7%）presented with late-onset form.

All clinical features and laboratory data were compared between the GO/PO and early/late-onset groups.The results revealed the early onset form were more likely to be seen in younger children,moreover,Mycoplasma pneumoniae copy were more easily detected in cerebrospinal fluid of this type,therewas no significant difference in other clinical and lab findings between the early-onset and late-onset group(Table1-3). In univariate analysis, the significant factors associated with the PO group were onset in adolescence (p < 0.001), origin from rural areas (p = 0.042), hypothermia (p = 0.002), convulsion status (p = 0.037), involuntary movement (p = 0.028), increased LDH level (p < 0.001), elevated CSF protein level (p = 0.004), and basal ganglia involvement (p = 0.023)(Table 1-3). In multivariate analysis, the prognostic factors associated with PO were onset in adolescence (p = 0.001), increased LDH level (p = 0.041), and elevated CSF protein level (p = 0.012) (Table.5).

Table 5. Prognostic factors associated with poor outcomes

Variables	Univariate analysis		Multivariate analysis
	OR (95% CI)	p-value	OR (95% CI)	p-value
Juvenile onset	18.934(3.089-93.382)	＜0.001*	20.743(6.398-91.467)	0.001*
Rural area	3.215(0.843-12.561)	0.042*	4.290(1.046-7.931)	0.158
Hypothermia	6.742(2.598-23.237)	0.002*	5.397(0.834-17.365)	0.083
Status seizure	1.276(1.182-1.593)	0.037*	1.692(0.217-5.341)	0.062
Pleural effusion	1.387(0.115-14.131)	0.826	-	-
Involuntary movement	4.226(0.917-13.264)	0.028*	-	-
Days from symptom onset to admission	9.889(1.324-36.879)	0.071	-	-
IVIG + steroid use	1.093(0.836-6.254)	0.092	-	-
LDH elevation	4.826(3.451-29.756)	＜0.001*	13.250(5.729-46.512)	0.041*
Albumin decrease	0.595(0.327-0.892)	0.058	-	-
CSF protein elevation	12.749(6.932-37.698)	0.004*	10.572(3.994-21.380)	0.012*
Basal ganglia involvement	3.278(2.175-12.573)	0.023*	4.197(1.348-8.216)	0.675

*P<0.05

This is a multicenter retrospective study about the clinical features, differences in the efficacy of azithromycin and immunomodulatory therapy and prognosis of MPE in Chinese children.To our knowledge, this is the largest multicenter cohort of children with MPE that has been assessed.

In this cohort,most patients presented with fever, disturbance of consciousness, headache ,mild lymphocytosis and elevated protein in CSF, diffuse slow waves in EEG, or cortical involvements in neuroimaging. The clinical manifestations as well as the lab abnormalities are indistinguishable from those seen in viral encephalitis. Moreover, compared with common viral encephalitis ,which 40-80% patients accompanied by extraneurological involvements(Lima-D.,et al.,2016),in our series,varying multi-system involvement was found in 96.5% patients.most frequently on respiratory tract lesions.The presence of respiratory symptoms also suggests the neurological disease is caused by immunologic mechanisms rather than direct invasion[2, 5–7].In addition,our study revealed other clues,including a significant increased CRP,the presence of RESLES in neuroimaging, also should be considered the possibility of M. pneumoniae infection, consistent with a previous study[13, 14]. M. pneumoniae infections are assumed to be unusual in children aged younger than 5 year[1, 5, 15].In our study, the disease can affect children of any age except for neonates,the most common onset age were 6-10 years, our cohort also had a considerable proportion of patients who younger than 5 year,moreover,younger children were likely presented with shorter prodromal period ,should be explained by the blood-brain barrier (BBB)of young children is not well developed and is prone to the direct invasion of M. pneumoniae .In addition,our cohort also had 5% patients who lacked a clear presentation of respiratory tract manifestations. Therefore, while the value of respiratory tract manifestations is undeniable, the diagnosis of MPE cannot be ruled out in patients who do not show these manifestations.Taken together, these findings suggest that M. pneumoniae should be considered as a potential culprit in all children with acute encephalitis, irrespective of age, presence or absence of respiratory symptoms, and neurological manifestations, especially in patients with multi-system involvement or respiratory tract manifestations that are accompanied by pronounced elevated CRP or those with RESLES.

Detection of M. pneumoniae in blood, CSF, and respiratory secretions by serological and PCR examinations is a critical step for confirming the diagnosis[1, 5, 16]. In this cohort, all patients tested positive for CSF M. pneumoniae-IgM or/and showed positive results in M. pneumoniae-PCR testing. The number of M. pneumoniae-IgM-positive patients was more than M. pneumoniae-PCR-positive patients. The patients with M. pneumoniae-PCR-positive for respiratory tract secretions were more than those for CSF.Moreover,the copy number of M. pneumoniae in CSF was much lower than that in respiratory secretions. The difference in the copy number between the two samples due to respiratory tract rather than CSF are more suitable for the growth of M. pneumoniae[5]. These results also suggested that, in our cohort, direct invasion was not the most common cause. In addition, M. pneumoniae copy were more easily detected in CSF of early-onset form patients, which also supported this hypothesis that the early-onset form is mainly related to the direct invasion of CNS by M. pneumoniae.

Due to the limitation of detection technology,400 copies/mL was the lower detection limit of our study, so those below 400/mL may be missed, which should be account for the low M. pneumoniae -PCR positive rate in CSF.

The study by Daxboeck revealed the mortality associated with MPE was 7.3%-9%, and that 14.6%-34% of the surviving patients had neurological sequelae. The study also found that a high CSF cell count, CSF protein elevation, and higher age were associated with an unfavorable outcome[11]. In our cohort, there was no deaths, although nearly 20% of the patients showed poor prognosis. Our univariate and further multivariate analysis revealed that onset in adolescence, increased CSF protein level, and LDH elevation were independent predictors of PO. The autoimmune response induced by infection in older children is usually stronger than that in younger children, and cerebral plasticity after injury in younger children is also better than that in older children maybe the reasonable explanation for older age group are more likely to have neurological sequelae[17]. Elevated CSF protein levels may imply the abnormality in intrathecal protein synthesis or the BBB properties ,which correlated with the clinical neurological symptoms of encephalitis and poor outcome[18–21].Recent studies revealed that LDH is related to the formation of mucus thrombi by affecting biomembrane permeability,the mucus thrombi is related to the refractory M. pneumoniae pneumonia and extrapulmonary injury[22, 23]. Our study found that LDH elevation was related to a poor prognosis of MPE, suggesting that LDH elevation may affect the permeability of the blood–brain barrier and aggravating the neurological damage caused by MPE.

Antibiotic therapy has been generally considered for all children with suspected MPE and is associated with clinical improvement in most patients with MPE[1, 5, 24]. Because of its good CNS penetration, relatively fewer adverse effects and some anti-inflammatory effect, azithromycin is considered to be a first-line agent for most pediatric MPE patients[25, 26]. In our cohort, all patients received azithromycin treatment,this therapy can avoid subsequent CNS invasion and activation of the immune system[1]. However,the role of immune-modulating therapies, such as corticosteroids, IVIG, or plasmapharesis, in the management of MPE remains undefined because of the lack of conclusive evidence from controlled studies in favor of such therapies, with most studies being case reports. The common assumption is that immune modulating therapies should be considered in those with immune-mediated syndromes such as acute disseminated encephalomyelitis or in those with prodromal symptoms[5, 9]. Some research suggested that corticosteroids should be used in patients diagnosed with M. pneumoniae who also show severe extrapulmonary complications, and methylprednisolone should take precedence as first recommendation[27–29]. A single-center cohort study by Mebratu Daba et. al showed that early administration of IVIG should be considered in patients with suspected MPE, particularly in those with prodromal symptoms of infection for approximately a week or longer and no response to other therapies[9]. In our cohort, the higher presence of prodromal respiratory symptoms and relatively lower detection of M. pneumoniae in CSF suggested immunologically mediated infection rather than direct invasion was the most common cause, so,the immune modulatory therapy should be considered.Our study also found that azithromycin combined with IVIG or corticosteroid therapy was correlated with shorter lengths of stay and symptom control than the azithromycin group alone, especially in the IVIG-combined group. However, in our study, the length of prodromal symptoms did not affect the efficacy, which is in contrast to Daba’s study[9],and should be explained by multiple mechanisms involved in the pathogenesis of MPE.Interestingly, the group that received IVIG and corticosteroids with azithromycin did not show this advantage, which may be related to more critically ill cases in this group.

This study has some limitations. First, this was a retrospective study, data loss was inevitable. Second. this study has a referral bias, as it was conducted in a tertiary care referral center, where high proportion of critically ill patients and those with advanced illness are referred. In addition, it is not nationally representative.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Chongqing Ninth People's Hospital, the Children's Hospital of Chongqing Medical University and Maternal and Child Health Hospital in Fuling District . In this study, personal identifiers, such as name, address, and telephone number, were not disclosed to maintain patient confidentiality. All patients’medical information was analyzed anonymously.

Informed consent obtained from legal guardians / parents of all participants in the manuscript.

All procedures were performed in accordance with the Declaration of Helsinki and relevant guidelines

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article

Competing interests

The authors declare no conflict of interest.

Funding

This work was supported by grant from the National Natural Science Function of China(81701277)

Authors' contributions

GQ Fang contributed to the data collection,writing.JZ Li contributed to the data analysis.FJTang,MChen,SLiao,J Wang contributed to the data collection. YGuo contributed to the study design, data collection.All authors read and approved the final manuscript.

Acknowledgements

We would like to thank physicians and nurses in the Pediatrics Department of Chongqing Ninth People's Hospital, the Children's Hospital of Chongqing Medical University, and Maternal and Child Health Hospital in Fuling District in completing the diagnosis, CSF collection, and treatment of the MPE cases.

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No competing interests reported.

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Determining the Clinical Characteristics, Treatment Strategy and Prognostic Factors of Mycoplasma Pneumoniae Encephalitis in Children: A Multicenter Study from China

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