Analysis of Severe COVID-19 among Children in Foshan, China

doi:10.21203/rs.3.rs-3134090/v1

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Analysis of Severe COVID-19 among Children in Foshan, China

https://doi.org/10.21203/rs.3.rs-3134090/v1

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Background

This study aimed to analyze the clinical characteristics, treatments, and prognosis of severe neurological impairment among children infected with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) following the change in epidemic prevention policy in China in December 2022.

Methods

A total of 9 pediatric patients with severe neurological impairment caused by SARS-CoV-2 infection from December 17, 2022 to December 31, 2022 in the First People’s Hospital of Foshan were retrospectively analyzed.

Results

Seven (71.43%) of the nine cases involved patients under the age of three, while the other two cases were older than three and had underlying medical conditions. All patients presented with fever and neurological symptoms such as disorders of consciousness and/or convulsive seizures. Besides, all patients showed sudden aggravation (e.g., fulminant cerebral edema) within 24 hours of fever, without respiratory symptoms (e.g., cough). Interleukin-6 (IL-6), lactate dehydrogenase (LDH) and D-dimer were significantly increased in all nine cases. Except for three patients who survived more than 48 hours after the first rescue treatment, five died within 48 hours after hospitalization, while one died of secondary bacterial infection after seven days of treatment. All patients suffered from shock rapidly after onset, and five patients developed multiple organ failure (respiratory, heart, liver, kidney and skeletal muscle) in a short time. In terms of in-hospital treatments, five cases were treated with glucocorticoids, three with intravenous immunoglobulin (IVIG), and two with blood purification and tocilizumab.

Conclusion

SARS-CoV-2 infection can cause severe neurological damage in pediatric patients. Hyperpyrexia, convulsion, and inflammatory factors could serve as early warning indicators. Administering glucocorticoids immunoglobulin, blood purification and tocilizumab might have some therapeutic effects, but further research is needed to establish their effectiveness.

Children

COVID-19

severe neurological impairment

Since the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory disease coronavirus 2 (SARS-CoV-2) in China, numerous studies have focused on severe cases. However, there is a paucity of case reports or series that document neurological complications, such as seizures and encephalopathy, especially in pediatric patients. Despite the fact that children infected with SARS-CoV-2 typically exhibit mild or no symptoms, serious neurological involvement has been reported[1]. Previous articles suggest that children infected with the Alpha or Delta strains mainly exhibit symptoms such as fever, cough, expectoration, and fatigue [2], while those infected with the Omicron strain were significantly associated with neurological symptoms, especially the rapid onset of acute fulminant cerebral edema. Additionally, some children infected with the Omicron strain have been diagnosed with acute necrotizing encephalopathy (ANEC), which leads to a rapid death or causes serious neurological sequelae

[3]. This study aims to summarize the clinical and laboratory features, as well as the treatment strategies for severe neurological impairment among children infected with SARS-CoV-2 since the change in epidemic prevention policy in China in December 2022.

The institutional review board of the First People’s Hospital of Foshan approved this retrospective study. A total of 9 pediatric patients admitted with severe neurological impairment after SARS-CoV-2 infection from December 17, 2022 to December 31, 2022 were recruited. Eligible patients were unvaccinated and tested positive for COVID-19 antigen rapid test and/or COVID-19 nucleic acid test at the emergency department. Acute fulminant cerebral edema was defined as encephalopathy, followed by rapid progression to diffuse cerebral edema with herniation or herniation with brainstem compression on neuroimaging, with no other recognized causes of cerebral edema (e.g., organic, metabolic, toxic) [4–5]. Data collection included demographics, clinical symptoms, laboratory indicators, neuroimaging results, primary treatments, and outcomes. Descriptive analysis was conducted for clinical characteristics, and results were presented as counts (proportion).

Out of the nine cases, seven (71.43%) were under 3 years of age, ranging from 1 year and 2 months to 2 years and 9 months. The remaining two cases were older than 3 years and had underlying diseases, namely, nephrotic syndrome (6 years old) and cerebral palsy (4 years and 6 months old). All patients presented with fever and neurological symptoms such as disorders of consciousness and/or generalized tonic-clonic (GTC) seizures. Additionally, all children rapidly developed fulminant cerebral edema within 24 hours of fever onset, without any respiratory symptoms such as cough. While three patients survived more than 48 hours after the first rescue treatment, five died within 48 hours of hospitalization, and one died due to secondary bacterial infection after 7 days of treatment. All patients suffered from shock rapidly after onset, and 5 patients developed multiple organ failure (respiratory, heart, liver, kidney and skeletal muscle) and disseminated intravascular coagulation (DIC) following a very short time.

Table 1 summarizes the manifestations of SARS-CoV-2 infection in the nine children and their main treatment regimen. In terms of in-hospital treatments, all cases received assisted mechanical ventilation. Glucocorticoids (i.e., methylprednisolone) were administered in five cases and three cases received intravenous immunoglobulin (IVIG) at a dose of 2g/kg. A lumbar puncture was performed in one patient, and the cerebrospinal fluid (CSF) analysis revealed normal CSF white blood cell count but increased CSF protein level (1 g/L). Polymerase chain reaction (PCR) for SARS-CoV-2 in the CSF was negative. Cranial computed tomography (CT) was conducted in five patients, revealing significant cerebral edema. In all patients, the levels of inflammatory biomarkers, including interleukin-6 (IL-6), serum ferritin, lactate dehydrogenase (LDH), and D-dimer, significantly increased within the first three days of hospitalization.

Table 1

Baseline and clinical characteristics of children with severe neurological complications after COVID-19 infection
Variables		Case1	Case2	Case3	Case4	Case5	Case6	Case7	Case8	Case9
Age		1yr2mon	1yr2mon	2yr9mon	2yr2mon	6 year	1yr4mon	4yr6mon	1yr7mon	2yr
Gender		Male	Male	Female	Female	Male	Male	Female	Female	Male
Medical history						Nephrotic syndrome		Cerebral palsy
Clinical evaluation
	PICS	76	74	64	76	78	92	66	80	72
	PRISM III	23	40	39	39	18	14	38	12	5
Hospital stay		5 hours	19 hours	6 hours	8 hours	6 hours	8 days	2.5 hours	8 days	20 days
Clinical outcome		Death	Death	Death	Death	Death	Clinical improvement	Death	Death	Clinical improvement
Complaints		Fever, perilabial cyanosis, coma	Fever, convulsion	Fever, perilabial cyanosis, coma	Fever, changes of consciousness				Fever, convulsion	Fever, convulsion
Symptoms		Peak body temperature 40℃, coma	Peak body temperature 40℃, multiple GTC, non-projectile vomiting	Fever, dyspnea, coma	Peak body temperature 41–42℃, changes of consciousness				Peak body temperature 40.3℃, non-projectile vomiting, 1 GTC	Peak body temperature 39.2℃, multiple GTC, projectile vomiting
Consciousness		Deep coma	Somnolence	Deep coma	Deep coma	Deep coma	Somnolence	Loss of consciousness	Somnolence	Somnolence
Blood test	WBC	21.01	8.25	13.37	11.18	14.95	8.08	8.06	9.3	6.71
	RBC	5.72	5.56	5.39	5.21	4.14	4.33	6.24	3.32	3.81
	PLT	26	152	35	52	179	110	298	52	112
	CRP	2.03	11.1	1.26	3.67	35.64	11.28		31.4	7.28
	PCT	5.19	38.37	4.75	3.34	2.26	14.22		41.53	25.43
	D-dimer	>56	37.96	6.45	>56	0.98	36.42		2.05	29
	IL-6	>5000	97.7	>5000	>5000	35	11.7		1968	57.5
	LDH	3330.5	981.4	4796.4	1867.8	337.2	75		1004.3	97
	ALT	55	104	845	225	68	250		191	1873
	TBIL	3.7	3.6	8.8	12.2	8.4	7.2		5.5	2.8
CSF	CSF WBC						3		2	5
	CSF protein						4.5		1	3.36
Chest X-ray/Lung CT		Not done	Not done	Normal	Not done	Normal	Not done	Bilateral lung markings slightly thickened	Not done	Normal
Cranial CT		Cerebral edema	Not done	Cerebral edema	Cerebral edema	Not done	Multiple patchy low-density shadows in bilateral lateral ventricle, basal ganglia, thalamus, and brain stem	Not done	Cerebral edema	Reduced density in bilateral deep frontoparietal lobes, basal ganglia, and thalamus, complicated with bilateral thalamic edema
Cranial MRI							Multiple lesions in bilateral centrum semiovale, periventricular white matter of bilateral lateral ventricle, bilateral thalamus, callosum, cerebral peduncle, and dorsal brainstem, complicated with enhancement of leptomeninges			Multiple lesions in bilateral frontoparietal cortex, centrum semiovale, radial crown, basal ganglia area, lateral ventricle, splenium of corpus callosum, thalamus, pons, right cerebral peduncle and bilateral cerebellar hemisphere
Main treatment	MV	YES	YES	YES		YES		YES	YES	YES
	Steroid	YES	YES			YES	YES		YES	YES
	IVIG		YES						YES	YES
	TPE and/or CRRT								YES	YES
	Tocilizumab								YES	YES

According to Hong Kong statistics, approximately 50 children needed to be treated at the pediatric intensive care unit (PICU) at the end of March 2022, accounting for 0.045% of the population under 19 years old. Among them, three deaths were reported from suspected encephalitis (accounting for 0.0027% of patients under 19 years old) [6]. In addition, Taiwan Centers for Disease Control Complex reported that 6 out of 10 SARS-CoV-2 related deaths (60%) in children were attributed to fatal fulminant cerebral edema as of April 2022, with a total mortality rate of 0.0008% for people under 20 years old [3]. Following a change in epidemic policy, a total of 36 children were admitted to the PICU of our hospital, 22 of whom presented with neurological symptoms. Therefore, the nine cases of critical neurological impairment included in this study exhibited a good representation.

It has been reported that patients infected with SARS-CoV-2 can experience various neurological complications, ranging from mild to severe, affecting both the central and peripheral nervous systems.These complications can occur in both asymptomatic and severely affected COVID-19 patients due to different pathophysiological mechanisms, mainly characterized by encephalopathy, delirium and behavioral changes [7], while pulmonary symptoms are mild or absent. Herein, there were no significant changes in chest X-rays or lung CTs in any of the cases, indicating that the impact of the Omicron strain on the nervous system of children may be greater than its impact on the respiratory system.

Among the nine cases collected at our center, two cases were diagnosed with acute necrotizing encephalopathy (ANE) through early CSF testing and subsequent cranial MRI, while the remaining seven cases did not undergo CSF testing because of rapid disease progression. However, given the similarities in symptoms and signs across all cases, it is plausible that ANE was also the underlying cause of death in these cases.

The pathogenesis of ANE remains unclear. The most popular hypothesis is that of cytokinemia, or a cytokine storm, which is a potentially lethal immune response consisting of a positive feedback loop between cytokines and leukocytes. Patients with ANE develop an exaggerated immune response to various viruses, similar to systemic inflammatory response syndrome (SIRS) [8].

Acute fulminant cerebral edema is a rare but severe complication of SARS-CoV-2 infection and a major pathological feature of acute necrotizing encephalopathy (ANE). Therefore, early identification of warning signs and close monitoring of clinical progression are crucial, given the potential for fatal outcomes [9]. A previous study indicated that the SARS-CoV-2 Omicron variant might cause more febrile seizures in children [10]. In our study, all patients exhibited seizures or sudden disorders of consciousness 24 hours prior to the onset of symptoms of fulminant cerebral edema, accompanied by high or ultra-high fever. These findings suggest that the fever may be neurogenic due to hypothalamic damage or paroxysmal sympathetic hyperactivity [11]. Therefore, children with SARS-CoV-2 infection should be closely monitored for acute fulminant cerebral edema if they exhibit early hyperpyrexia and neurological symptoms.

Consistent with our study, previous analyses have shown that elevated D-dimer and LDH levels are associated with encephalopathy and lung tissue injury, serving as potential early warning indicators for severe neurological changes [12]. Our study also found that IL-6 levels significantly increased in patients with severe neurological impairment, consistent with the cytokine storm hypothesis [13], suggesting that using anti-inflammatory therapy to inhibit the cytokine storm may have a certain effect. The two children who survived were treated with gamma globulin and hormone pulse therapy in the early stage of the disease. One showed a rapid decrease in body temperature and an earlier recovery of consciousness after treatment, while the other child was additionally treated with continuous renal replacement therapy and tocilizumab. Both had central nervous system injury and different degrees of sequelae on MRI reexamination, but the former was milder, suggesting that the prognosis may be related to the symptom score at admission, and the role of continuous renal replacement therapy (CRRT) in eliminating inflammatory factors may delay disease progression. In addition, there is a lack of comprehensive data analysis worldwide supporting the definite efficacy of blood purification and tocilizumab. Cheng et al. [14] previously reported a successful case of using therapeutic plasma exchange (TPE) combined with continuous renal replacement therapy (CRRT) to treat a critically ill child with COVID-19. In our study, two pediatric patients also underwent the combined therapy. Although one child died of bacterial infection, IL-6 and other indicators decreased rapidly after early blood purification treatment, indicating that blood purification has a certain positive effect in managing cytokine storms [14]. Teoh et al. analyzed the clinical features and outcomes of 16 children and young adults with severe acute COVID-19 treated with tocilizumab and found that delayed administration after admission to PICU may be an important predictor of poor prognosis [15]. One of our patients died of a severe bacterial infection (Escherichia coli) after blood purification and tocilizumab treatment. A possible reason could be due to secondary infection caused by the immunosuppressive effect of tocilizumab; however, further studies are warranted to determine the side effects of tocilizumab. A case report from Singapore described an 11-year-old boy with acute SARS-CoV-2 infection who presented with ophthalmoplegia, ataxia, and aphasia, highlighting the diverse and potentially severe neurological manifestations of COVID-19 in children.The neuroimaging results confirmed significant edema and signal changes in the bilateral thalamus, brain stem, and cerebellar hemispheres, consistent with childhood ANE. The combination of early steroid therapy, intravenous immunoglobulin (IVIG), and targeted IL-6 blocking therapy clearly improved neurological function. [16]. However, the use of steroids in the treatment of lung injury in COVID-19 has been controversial. Baillie et al.previously suggested that steroids have little impact on mortality in COVID-19 patients with septic shock and are generally not useful in shock management [17]. Cao et al concluded that overwhelming inflammation and cytokine-related lung injury among critically ill patients might lead to rapid progressive pneumonia and recommended the cautious use of glucocorticoids [18]. For the severe neurological impairment caused by SARS-CoV-2, no study with a large sample size has been conducted on the efficacy of corticosteroids. Still, we believe that cytokine storm remains the main pathological mechanism of fulminant cerebral edema. Furthermore, glucocorticoids have a certain effect in inhibiting the inflammatory response, but secondary infection should be carefully monitored.

The COVID-19 pandemic may have subsided, but the lasting neurological damage caused by SARS-CoV-2 in children has provided valuable insights and experiences in treating acute fulminant cerebral edema.

Acknowledgments

With thanks to the all colleagues of Department of Pediatrics for recording detailed clinical data, it provided convenient conditions for clinical experimental exploration.

Authors’ contributions

CXQ was the overall project administrator, analyzed data and wrote the manuscript. LYQ edited and formatted the original manuscript. XQY helped collect the data. JSH obtained grant funding and was responsible for the conception of the present study, interpreting results and revising the manuscript. All authors have read and approved the final manuscript.

Funding

The study was funded by Foshan "14th Five-year plan" Construction for Medical High Level Key Specialty.

Availability of data and materials

Data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the Ethics Commission of First People's Hospital of Foshan. And the ethics committee waived the need for informed consent from all the patients.

Consent for publication

All authors have read the manuscript and agreed to publish it. This manuscript has not been published in other journals and is only considered in BMC Pediatrics.

Competing interests

The authors declare that they have no completing interests.

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No competing interests reported.

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Analysis of Severe COVID-19 among Children in Foshan, China

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Abstract

1. Introduction

2. Methods

3. Results

4. Discussion

Declarations

References

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