General information
From December 1, 2022 to January 12, 2023, we encountered nine pediatric cases of COVID-19 with severe CNS injury. Of the nine patients, seven were male (77.78%) and two were female (22.22%). Five children were aged ≥ 10 years, and the other four were 1–2 years old. The latter children were not vaccinated, and six children were previously healthy. One child (10 years old at the time of admission) had a history of asthma before the age of 3 years, one child was diagnosed with acute disseminated encephalomyelitis 1 year earlier, and one child with abnormal genetic test results was diagnosed with severe encephalitis 6 months earlier and treated with oral antiepileptic drugs as maintenance therapy (Table 1).
Table 1
General information of the 9 children with CNS consequences of COVID-19
No. | Gender | Age | Admit date | Survival time | Vaccination | Underlying disease | Max body temp. (°C) | Convulsions | DIC | stroke | Gastrointestinal bleeding | Pneumonia |
1 | M | 10years | 2022/12/23 | 22 hours 55 minutes | Yes | No | 40.0℃ | Yes | No | Yes | No | Yes |
2 | F | 1year | 2022/12/24 | 120 hours 20 minutes | No | ADEM | 38.6℃ | Yes | No | No | No | Yes |
3 | M | 10years | 2022/12/24 | 23 hours 5 minutes | Yes | asthma | 41.0℃ | Yes | Yes | Yes | Yes | Yes |
4 | M | 1year | 2022/12/26 | 98 hours 11 minutes | No | RANBP2NM- 006767.4 | 39.5℃ | Yes | No | No | No | Yes |
5 | M | 10years | 2022/12/25 | 73 hours 33 minutes | Yes | No | 38.6℃ | No | No | No | No | No |
6 | M | 10years | 2022/12/24 | 84 hours 9 minutes | Yes | No | 39.0℃ | Yes | Yes | No | Yes | Yes |
7 | M | 2years | 2022/12/25 | 40 hours 1 minutes | No | No | 41.3℃ | Yes | No | No | Yes | Yes |
8 | M | 1year | 2022/12/26 | Alive | No | No | 41.0℃ | Yes | No | No | No | Yes |
9 | F | 11years | 2022/12/28 | 40 minutes | Yes | No | 40.0℃ | Yes | No | No | No | - |
ADEM,acute disseminated encephalomyelitis;Survival time,Time of presentation to death |
Clinical manifestations
All nine pediatric patients had fever, and five had a body temperature of ≥ 40°C and difficulty during defervescence. Eight patients developed fever and convulsions, and the remaining child developed fever and headache. Seven patients had generalized tonic-clonic seizures, one had an unknown form of convulsions, and four had status convulsivus. All patients experienced varying degrees of coma, ranging from fever to coma between 2 hours and 3 days in duration. Eight patients died, and the length of hospital stay ranged from 30 minutes to 5 days. The only survivor has severe neurological sequelae and is currently undergoing rehabilitation. In addition to neurological symptoms, two patients developed shock, and two others developed diffuse intravascular coagulation. Three patients developed gastrointestinal bleeding, and seven progressed to multiple organ failure involving the nervous, respiratory, circulatory, digestive, and coagulation systems.
Laboratory tests and imaging examinations
One child (case 9) did not undergo any examinations because his vital signs had disappeared at the time of admission. Another child (case 1) died within half a day of admission. On admission, white blood cell counts were normal or low (62.5%). All patients had reduced lymphocyte counts and lymphocyte rates. Most patients had a high neutrophil-to-lymphocyte ratio of > 5.0 (75%). Platelet and hemoglobin levels were decreased in 62.5% of patients. All patients had elevated procalcitonin, and 50% had elevated C-reactive protein. Moreover, all patients tested exhibited elevated lactic acid (n = 8/8), interleukin-6 (n = 7/7), D-dimer (n = 8/8) and myoglobin (n = 3/3). Most patients had high creatine kinase-MB (n = 7/8, 87.5%), cardiac troponin I (n = 6/7, 85.7%), creatine kinase (n = 5/7, 71.4%), lactate dehydrogenase (n = 6/7, 85.7%), alanine aminotransferase (n = 7/8, 87.5%), aspartate aminotransferase (n = 7/8, 87.5%), and immunoglobulin E (n = 3/4, 75%) levels. We observed a decrease in albumin levels in seven of eight patients (87.5%). The plasma ammonia levels of most children were within the normal range (n = 5/6, 83.33%) (Table 2).
Table 2 Abnormal laboratory data categorized from the normal range
|
Normal range
|
available laboratory measurement,n
|
abnormal laboratory value,n (%)
|
Elevated white blood cell, ×109/ L
|
1~<2years,5.1~14.1
2~<6years,4.4~11.9
6~<13years,4.3~11.3
|
8
|
3(37.5)
|
Elevated Neutrophil count, ×109/L
|
1~<2years,0.8~5.8
2~<6years,1.2~7.0
6~<13years,1.6~7.8
|
8
|
4(50)
|
Elevated Neutrophil count, %
|
1~<2years,13~54
2~<6years,22~65
6~<13years,31~70
|
8
|
8(100)
|
Low Lymphocyte count, × 109/L
|
1~<2years,2.7~9.1
2~<6years,1.8~6.3
6~<13years,1.5~4.6
|
8
|
8(100)
|
Low Lymphocyte count, %
|
1~<2years,33~77
2~<6years,23~69
6~<13years,23~59
|
8
|
8(100)
|
Elevated Neutrophil-to-lymphocyte ratio, %
|
≤5
|
8
|
6(75)
|
Low Platelet count,×109/ L
|
1~<2years,190~524
2~<6years,188~472
6~<12years,167~453
|
8
|
5(62.5)
|
Low hemoglobin,g/L
|
1~<2years,107~141
2~<6years,112~149
6~<13years,118~156
|
8
|
5(62.5)
|
Elevated C-reactive protein level, U/L
|
0-6
|
8
|
4(50.0)
|
Elevated Procalcitonin, ng/ml
|
0-0.05
|
7
|
7(100)
|
Elevated D-dimer, mg/L
|
0-0.5
|
8
|
8(100)
|
Elevated Creatine kinase-MB, ng/ml
|
0-5
|
8
|
7(87.5)
|
Elevated Cardiac troponin I, pg/ml
|
0-0.175
|
7
|
6(85.7)
|
Elevated Myoglobin, μg/L
|
1.5-70
|
3
|
3(100)
|
Elevated Creatine kinase, U/L
|
50-310
|
7
|
5(71.4)
|
Elevated Lactate dehydrogenase, U/L
|
120-250
|
7
|
6(85.7)
|
Elevated Creatinine, μmol/L
|
28days~<2years,13~33
2~<6years,19~44
6~<13years,27~66
|
8
|
5(62.5)
|
Elevated Blood urea nitrogen, mmol/L
|
1~<2years,2.3~6.7
2~18years
2.7~7.0(male)
2.5~6.5(female)
|
8
|
2(25)
|
Elevated Alanine aminotransferase, U/L
|
1~<2years,8~42
2~<13years,7~30
|
8
|
7(87.5)
|
Elevated Aspartate aminotransferase, U/L
|
1~<2years,11~47
2~<13years,8~30
|
8
|
7(87.5)
|
Low Albumin, g/L
|
6months~<13years,
39~54
|
8
|
7(87.5)
|
Elevated NT-pro B-type natriuretic peptide, pg/ml
|
0-100
|
7
|
3(42.9)
|
Elevated lactic acid, mmol/L
|
0.5-1.8
|
8
|
8(100)
|
Elevated ferritin, ng/mL
|
Male,21.81 - 274.66
Famale,4.63 - 204.00
|
3
|
1(33.3)
|
Elevated,plasma ammonia, umol/L
|
9-33
|
6
|
1(16.7)
|
Elevated Interleukin-6, pg/ml
|
0-3.4
|
7
|
7(100)
|
Elevated Immunoglobulin E, IU/mL
|
1~5years,< 60
10~15years,< 200
|
4
|
3(75)
|
Low Immunoglobulin A, g/L
|
0.7-4
|
6
|
3(50)
|
Low Immunoglobulin M, g/L
|
0.4-2.3
|
6
|
0(0)
|
Low Immunoglobulin G, g/L
|
7-16
|
6
|
2(33.3)
|
Chest imaging showed that seven patients were complicated with pneumonia. However, the imaging also showed that it was not typical viral pneumonia; rather, it was considered to be hypostatic pneumonia caused by convulsive coma. Moreover, one child had bronchitis. Six patients underwent cardiac ultrasound, two of whom had decreased left heart function (ejection fraction < 40%). Two patients were complicated with myocarditis, and one child had arrhythmia.
Five patients underwent lumbar puncture, and the cerebrospinal fluid (CSF) white blood cell count was in the normal range. Four patients exhibited CSF protein-cell separation, with the CSF protein content being increased by 80%. The lactate dehydrogenase level in the CSF of three patients was increased by 60%. The protein and lactate dehydrogenase levels in the CSF of the surviving child were normal (Table 3).
Table 3
The CSF and neuroimaging results of children
No. | CSF protein, g/L | CSF white blood cells, × 106/ L | CSF Lactate dehydrogenase, U/L | CT of the brain | MRI of the brain | encephlogram |
1 | 1.84 | 10 | 657 | plain scanning, no obvious abnormalities | - | - |
2 | 1.52 | 3 | 157 | - | multiple abnormal signals in the brain, infectious disease likely, acute disseminated encephalomyelitis possible | Broad persistent low voltage pattern |
3 | - | - | - | 1. Subarachnoid hemorrhage, diffuse cerebral edema, 2. Bilateral globus pallidus, caudate nucleus head symmetrical high-density shadow | - | - |
4 | 2.18 | 12 | 37 | - | multiple symmetric abnormal signals in bilateral basal ganglia-thalamus, corpus callosum, pons, and cerebral cortex | Broad persistent low voltage pattern |
5 | - | - | - | Plain scanning, no obvious abnormalities | - | - |
6 | - | - | - | 1. Bilateral thalamic-midbrain and pontine swelling, ring cistern and fourth ventricle unclear 2. Minor subarachnoid hemorrhage. | - | - |
7 | 6.25 | 2 | 188 | - | - | - |
8 | 0.27 | 6 | 28 | - | Abnormal signal foci on the left side of the corpus callosum pressure | A small amount of multi-focal discharge in waking period, slow background rhythm;Sleep is highly arrhythmic |
CSF protein, Normal range 0-0.4g/L.CSF white blood cells, Normal range 0–15 ×106/ L.CSF Lactate dehydrogenase, Normal range 3-40U/L. |
Seven patients underwent cranial imaging, two of whom had no obvious abnormalities on cranial CT examination. One child (case 6) had a bilateral thalamus lesion on cranial CT on the second day after illness, along with swelling of the midbrain and pons (Fig. 1). One child (case 8) showed abnormal MRI signals in the corpus callosum, and the encephalogram showed a small amount of multifocal discharge during waking hours and a slow background rhythm; sleep was highly arrhythmic. Cranial MRI of one child (case 2) showed multiple abnormal signals in the brain, considered indicative of infectious lesions, and the encephalogram showed persistent and widespread low voltage. Another child (case 4) showed abnormal signals in the bilateral basal ganglia, thalamus, corpus callosum, pons, and multiple areas under the cerebral cortex, and encephalogram showed persistent and widespread low voltage. Finally, diffuse cerebral edema was seen in one child (case 3).
Treatment regimen and prognosis
One child who presented to the emergency department with respiratory and cardiac arrest died despite treatment with active chest compression, positive pressure ventilation, and vasoactive drugs. The remaining eight patients were admitted to the PICU and received comprehensive anti-infection, intracranial pressure reduction, and mechanical ventilation treatments. In the PICU, all eight of these patients were given glucocorticoids (pulse methylprednisolone, 20 mg/kg/day [maximum = 1 g/day]) and intravenous human immunoglobulin (2 g/kg [maximum dose = 80 g). To address inflammatory factors, two patients underwent plasmapheresis and three underwent hemodialysis. Because of abnormal coagulation function, plasma transfusion was given to seven patients and cryoprecipitate was given to three patients. Because of varying degrees of anemia, three patients underwent “suspended” red blood cell infusion to enhance blood oxygen carrying capacity. Because of severe shock or multiorgan failure, seven patients died 12 hours to 5 days after onset, and no cases were autopsied. We followed one child (case 8) receiving antiepileptic and rehabilitation therapy for 6 months and noted frequent nodding spasms after startle and infection. This patient had severe motor and neurodevelopmental delay; now aged 2 years and 7 months, the child is still unable to sit or stand.