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Systemic inflammatory response syndrome and prolonged hypoperfusion lesions in an infant with respiratory syncytial virus encephalopathy.
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PMID:  23354937     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Respiratory syncytial virus (RSV) is a cause of neurological complications in infants. We report a rare case of RSV encephalopathy in an infant who presented with poor sucking and hypothermia at 17 days of age after suffering from rhinorrhea and a cough for several days. After hospitalization, the patient presented with stupor and hypotonia lasting for at least 24 h, and was intubated, sedated, and ventilated for treatment of pneumonia. These symptoms led to diagnosis of pediatric systemic inflammatory response syndrome (SIRS) caused by RSV infection. High-dose steroid therapy was combined with artificial ventilation because the initial ventilation therapy was ineffective. Interleukin (IL)-6 levels in spinal fluid were markedly increased upon admission, and serum IL-6 and IL-8 levels showed even greater elevation. The patient was diagnosed with RSV encephalopathy. On day 5, high signal intensity in the bilateral hippocampus was observed on diffusion-weighted magnetic resonance imaging (MRI). On day 14, the patient presented with delayed partial seizure and an electroencephalogram showed occasional unilateral spikes in the parietal area, but the hippocampal abnormality had improved to normal on MRI. (99m)Tc-labeled ethylcysteinate dimer single-photon emission computed tomography (SPECT) on day 18 showed hypoperfusion of the bilateral frontal and parietal regions and the unilateral temporal region. SPECT at 3 months after onset still showed hypoperfusion of the bilateral frontal region and unilateral temporal region, but hypoperfusion of the bilateral parietal region had improved. The patient has no neurological deficit at 6 months. These findings suggest that RSV encephalopathy with cytokine storm induces several symptoms and complications, including SIRS and prolonged brain hypoperfusion on SPECT.
Authors:
Kenji Miyamoto; Masahide Fujisawa; Hajime Hozumi; Tatsuo Tsuboi; Shigeko Kuwashima; Jun-Ichi Hirao; Kenichi Sugita; Osamu Arisaka
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-26
Journal Detail:
Title:  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy     Volume:  -     ISSN:  1437-7780     ISO Abbreviation:  J. Infect. Chemother.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9608375     Medline TA:  J Infect Chemother     Country:  -    
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Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pediatrics, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga, Tochigi, 321-0293, Japan, kenmimi@dokkyomed.ac.jp.
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Journal Information
Journal ID (nlm-ta): J Infect Chemother
Journal ID (iso-abbrev): J. Infect. Chemother
ISSN: 1341-321X
ISSN: 1437-7780
Publisher: Springer Japan, Tokyo
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© The Author(s) 2013
OpenAccess:
Received Day: 17 Month: 8 Year: 2012
Accepted Day: 9 Month: 1 Year: 2013
Electronic publication date: Day: 26 Month: 1 Year: 2013
pmc-release publication date: Day: 26 Month: 1 Year: 2013
Print publication date: Year: 2013
Volume: 19First Page: 978 Last Page: 982
PubMed Id: 23354937
ID: 3824296
Publisher Id: 558
DOI: 10.1007/s10156-013-0558-0

Systemic inflammatory response syndrome and prolonged hypoperfusion lesions in an infant with respiratory syncytial virus encephalopathy
Kenji MiyamotoAff1 Address: kenmimi@dokkyomed.ac.jp
Masahide FujisawaAff1
Hajime HozumiAff3
Tatsuo TsuboiAff1
Shigeko KuwashimaAff2
Jun-ichi HiraoAff1
Kenichi SugitaAff1
Osamu ArisakaAff1
Department of Pediatrics, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga, Tochigi, 321-0293 Japan
Department of Radiology, Dokkyo Medical University, Tochigi, Japan
Clinical Training Center, Dokkyo Medical University, Tochigi, Japan

Introduction

Infection with respiratory syncytial virus (RSV) causes bronchitis, bronchiolitis, and pneumonia, and leads to neurological complications in 1.8 % of cases [1]. These neurological complications include RSV encephalopathy [2, 3], the cause of which remains unclear. Kawashima et al. [4] defined three pathogenic types of RSV encephalopathy characterized by metabolic error, excitotoxicity, and cytokine storm. Here, we describe a rare case of a neonate with RSV encephalopathy of the cytokine storm type, which involved development of pediatric systemic inflammatory response syndrome (SIRS) and prolonged hypoperfusion lesions on brain single-photon emission computed tomography (SPECT) without neurological sequelae.


Case report

The patient was a male infant born at 39 weeks gestation (birth weight, 3,562 g). At this time, his brother and cousin both had a cold, and the patient presented with rhinorrhea and cough after several days. At 17 days of age, his parents brought him to the emergency department because of poor sucking for more than half a day and hypothermia (33.0 °C). The patient was in a continuous stupor with hypotonia and did not respond to pain. He presented with cyanosis, and percutaneous oxygen saturation was 86 %. The desaturation was reversed by oxygenation. After hospitalization, a physical examination showed wheezes and hepatomegaly. Respiratory therapy with nasal continuous positive airway pressure was started, but apnea persisted.

Laboratory findings upon admission showed increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactase dehydrogenase (LDH), creatine phosphokinase (CPK), and carbon dioxide (PaCO2) (Table 1). AST, ALT, LDH, and CPK levels in serum increased progressively until day 2. RSV antigen was detected in a nasopharyngeal swab. The results of several cultures were negative. Chest radiography and computed tomography scans showed bilateral pulmonary infiltrative shadow, atelectasis, and severe air trapping. A diagnosis of pediatric SIRS caused by RSV infection was made based on the published criteria for this condition [5].

The patient was intubated and ventilated immediately. Profound sedation was used because high-pressure mechanical ventilation was required. Immunomodulatory therapy with high-dose steroids (methylprednisolone 30 mg/kg/day for 3 days) was also initiated because the respiratory therapies were ineffective. On day 5, there were no significant abnormalities on T1-weighted, T2-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging (MRI), but the bilateral hippocampus showed a high signal intensity in diffusion-weighted imaging (DWI) MRI with reduction of the apparent diffusion coefficient (ADC) (Fig. 1 a, b). An electroencephalogram (EEG) was normal on day 5. The patient was extubated on day 7.

On day 14, the hippocampal abnormality and ADC were improved on DWI MRI. However, on the same day, the patient presented with trembling of the upper limbs from side to side, and an EEG showed occasional unilateral spikes in the parietal area. Therefore, anticonvulsant therapy with phenobarbital was started. Serological tests for rubella, measles, cytomegalovirus, Epstein–Barr virus, herpes simplex virus, and autoantibodies associated with limbic encephalitis (antibodies against the glutamate receptor Gluε2, voltage-gated potassium channel, and NR1/NR2 subunits of the N-methyl-D-aspartate receptor) were negative during the acute phase. RSV antibody in serum was positive (NT ×16) on day 3. His mother had no ovarian teratoma during pregnancy.

At admission, interleukin (IL)-6 was increased markedly in the spinal fluid, and IL-6 serum levels were even more elevated compared with the spinal fluid [2, 3]. In the acute phase, serum IL-8 was significantly and markedly increased, but IL-1β, IL-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α levels were only slightly increased or not significantly altered (Table 1). Therefore, the patient was diagnosed with encephalopathy caused by RSV infection, as suggested by a prior study showing stupor and hypotonia lasting for at least 24 h and seizure [6]. 99mTc-labeled ethylcysteinate dimer (ECD) SPECT on hospital day 18 showed hypoperfusion of the bilateral frontal and parietal regions and the unilateral temporal region with some predominance on the left side (Fig. 1c, d).

Follow-up EEG, MRI, and SPECT were performed 3 months after onset. EEG was normal and phenobarbital treatment was ended. MRI did not show any signs of atrophy. 99mTc-labeled ECD SPECT at 3 months still showed hypoperfusion of the bilateral frontal region and unilateral temporal region with some predominance on the left side. Hypoperfusion on SPECT had improved in the bilateral parietal lobes but persisted in the frontal and temporal regions (Fig. 1e, f). The patient has no neurological deficit at 6 months of age.


Discussion

The present case was diagnosed as RSV encephalopathy accompanied by markedly increased levels of serum IL-6. These findings are consistent with alteration of cytokine levels in influenza virus-associated encephalopathy, because previous studies have shown marked increases of IL-6 in serum and spinal fluid in this disease [7, 8]. In particular, the serum IL-6 level has been suggested to be a useful indicator for the diagnosis and clinical severity of viral encephalopathy [7]. In our case, spinal fluid IL-6 was increased significantly and serum IL-6 showed an even greater increase. However, we also note that some studies have not found increased serum IL-6 in RSV encephalopathy [24].

Our observations in this case indicate that RSV encephalopathy can occur during SIRS. The cause of SIRS is essentially overproduction of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [9]. Thus, SIRS associated with RSV infection may be characterized by progression of severe pneumonia caused by hematogenous actions of elevated IL-6 on the lung and encephalopathy of the cytokine storm type resulting from similar actions of IL-6 on the brain. This suggestion is supported by the marked increase in serum IL-8, which is similar to the cytokine storm that can occur in influenza virus-associated encephalopathy [10]. The elevated IL-6 levels in the spinal fluid and serum and elevated IL-8 levels in the serum suggest that cytokine storm may be involved in the pathogenesis of RSV encephalopathy. However, the etiology of RSV encephalopathy is unclear. Specifically, it is uncertain whether direct impairment of the central nervous system is primarily responsible for the cerebral involvement in RSV disease, or if this is caused by increased production of one or more cytokines in cerebrospinal fluid during the acute phase [11, 12].

The characteristics of brain imaging findings in RSV encephalopathy are also unclear. A recent report showed that these findings often include unilateral brain hemisphere abnormalities on CT, MRI, and SPECT [3, 11, 13]. Our case exhibited hypoperfusion of the bilateral hippocampal regions and the unilateral temporal region on SPECT. In general, limbic encephalitis associated with infection is most commonly caused by herpes simplex virus, but a test for herpes simplex virus IgM antibody was negative on day 12. Most cases of autoimmune limbic encephalitis are indicated by autoantibodies, but in this case these autoantibodies were negative or normal in the acute phase [14]. Förster et al. showed that hippocampal DWI hyperintensities and a reduction of ADC on MRI were caused by limbic encephalitis with viral infection. These infections included human herpesvirus 6 and herpes simplex virus, but not RSV [15]. Therefore, this patient was diagnosed with RSV encephalopathy without limbic encephalitis.

After 3 months, hypoperfusion on SPECT had improved in the bilateral parietal lobes, but persisted in the frontal and temporal regions without neurological sequelae. Similarly, Hirayama et al. [16] found that residual cerebellar abnormalities on SPECT persisted 1 year after onset in RSV encephalitis with mild ataxia. Thus, RSV encephalopathy may be associated with prolonged cerebral hypoperfusion. Our case suggests that detection of severe RSV infection should lead to consideration of an early diagnosis of encephalopathy associated with SIRS.


We thank Dr. Osamu Watanabe, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, for measurement of antibodies to the voltage-gated potassium channel; Dr. Yukitoshi Takahashi, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, for measurement of antibodies to the glutamate receptor Gluε2; Dr. Keiko Tanaka, Department of Neurology, Kanazawa Medical University, for measurement of antibodies to the NR1/NR2 subunits of N-methyl-D-aspartate receptor; and Dr. Hidemitsu Kurosawa, Department of Pediatrics, Dokkyo Medical University, for his helpful comments on the therapy.

Conflict of interest

The authors declare no conflicts of interest.


References
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2.. Morichi S,Kawashima H,Ioi H,Yamanaka G,Kashiwagi Y,Hoshika A,et al. Classification of acute encephalopathy in respiratory syncytial virus infectionJ Infect ChemotherYear: 20111777678110.1007/s10156-011-0259-521647570
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6.. Antonucci R,Chiappe S,Porcella A,Rosatelli D,Fanos V. Bronchiolitis-associated encephalopathy in critically-ill infants: an underestimated complication?J Matern Fetal Neonatal MedYear: 20102343143610.3109/1476705090318418119701864
7.. Aiba H,Mochizuki M,Kimura M,Hojo H. Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathyNeurologyYear: 20015729529910.1212/WNL.57.2.29511468315
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Figures

[Figure ID: Fig1]
Fig. 1 

Magnetic resonance imaging (MRI) on day 6. Diffusion-weighted imaging (DWI) (a) revealed bilateral high-intensity regions in the hippocampus, and the apparent diffusion coefficient (ADC) (b) was low in the same regions. cf99mTc- ethylcysteinate dimer (ECD) single-photon emission computed tomography (SPECT). Axial views through the parietal lobes (c, e) and through the cerebral cortex, white matter, and basal ganglia (d, f). Upper row (c, d): At 18 days after onset (hospital day 18), SPECT showed hypoperfusion of the bilateral frontal and parietal lobes and the unilateral temporal lobe with some predominance on the left side. Lower row (e, f): At 3 months after onset, hypoperfusion of the bilateral parietal lobes on SPECT had improved, but hypoperfusion of the unilateral temporal lobe with some predominance on the left side was exacerbated



Tables
[TableWrap ID: Tab1] Table 1 

Laboratory data at admission


Peripheral blood Arterial blood gas analysis (FiO2 0.30–0.45)
 WBC 20,200/μl  pH 7.228
  Nt 31 %  PaCO2 69.4 Torr
  Ly 47 %  PaO2 72.7 Torr
  Mo 10 %  HCO3 27.9 mmol/l
  Eo 2 %  BE −0.1 mEq/l
  Ba 0 % Serology
 RBC 305 × 104/μl  CRP 3.87 mg/dl
  Hb 10.1 g/dl  Procalcitonin 0.77 ng/ml
  Ht 32.4 %  IgG 853 mg/dl
  Plt 52.7 × 104/μl  IgM 32 mg/dl
Biochemistry  IgA 5 mg/dl
 TP 6.7 g/dl  Ferritin 8163 ng/ml
 Alb 4.1 g/dl  IL-6 (<4 pg/ml)a 304 pg/ml
 AST 192 U/l Serology during hospitalization
 ALT 160 U/l  IL-1β (<10 pg/ml)a <200 pg/ml
 T-bil 1.3 mg/dl  IL-8 (<2 pg/ml)a 115 pg/ml
 LDH 1359 U/l  IL-10 (<5 pg/ml)a <20 pg/ml
 CK 439 U/l  MCP-1 (200–722 pg/ml)a <625 pg/ml
 BUN 12 mg/dl  TNF-α (0.6–2.8 pg/ml)a <5 pg/ml
 Cre 0.24 mg/dl Cerebral spinal fluid
 Na 122 mEq/l  IL-6 (<0.4 pg/ml)a 102 pg/ml
 K 5.8 mEq/l  Viral culture (–)
 Cl 89 mEq/l  Protein 88 mg/dl
 Glucose 55 g/dl  Cell count 2/μl
Culture
 Blood (–)
 Spinal fluid (–)
 Nasal Haemophilus influenzae

aNormal value or range. IL-6 was measured using Human IL-6 CLEIA (Fujirebio, Japan). IL-1β, IL-8, and IL-10 were measured using BIOSOURCE IL-1β, IL-8, and IL-10 ELISA kits (BioSource Europe, Nivelles, Belgium). MCP-1 and TNF-α were measured using Human MCP-1 and TNF-α Immunoassay kits (R&D Systems, Minneapolis, MN, USA)



Article Categories:
  • Case Report

Keywords: Keywords Respiratory syncytial virus, Encephalopathy, Cytokine, Infant, Single-photon emission computed tomography.

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