Shao-Hsuan Hsia

Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system

Enterovirus 71 (EV71) infection can lead to devastating clinical outcomes. An appreciation of the scientific relationship between cytokine response and patient mortality may help limit the risks posed by this deadly illness. We present the results of a study that compared the cerebrospinal fluid (CSF) and serum levels of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in 24 patients with EV71 infection. Cases in this study involved diverse manifestations or complications, including encephalitis, poliomyelitis-like syndrome, meningitis, and pulmonary edema. CSF levels of IL-6 in study patients were found to be consistently higher during the first 2 days of central nervous system (CNS) involvement than afterward. Compared with patients who did not have pulmonary edema, patients who experienced pulmonary edema had dramatically varied blood values, including IL-6, white blood cell counts, and glucose levels. Our findings suggest that the combination of CNS and systemic inflammatory response may trigger EV71-related cardiopulmonary collapse.

The 1998 Enterovirus 71 Outbreak in Taiwan: Pathogenesis and Management

The most recently discovered enterovirus, enterovirus 71 (EV71), is neurotropic and may cause severe disease and sudden death in children. In 1998, a large outbreak of enterovirus infection occurred in Taiwan that resulted in 405 severe cases in children and 78 deaths. Of the 78 children who died, 71 (91%) were <5 years old. EV71 was the primary agent in fatal cases of infection. Most of these patients died within 1-2 days of admission to the hospital. We hypothesize that EV71 directly attacks the central nervous system and causes neurogenic pulmonary edema and cardiac decompensation through the mechanism of sympathetic hyperactivity and inflammatory responses. Early recognition of risk factors and intensive care are crucial to successful treatment of this fulminant infection. After poliovirus is eradicated, EV71 will become the most important enterovirus that affects children, and development of a vaccine may be the only effective measure against it.

Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002

Background. Enterovirus 71 (EV71) infection may progress through four stages, one of which is cardiopulmonary failure. In Taiwan in 1998 almost all the EV71 patients with cardiopulmonary failure died. To improve clinical outcome of EV71 patients, we developed a stage-based management program in 2000. Methods. The medical records of 196 EV71 patients who did not have stage-based management (1998 to 1999) and of 331 EV71 patients who did (2000 to 2002) at Chang Gung Children’s Hospital were reviewed for demographic characteristics, clinical syndromes, case-fatality rates and sequelae. We compared and analyzed the results for the 2 groups. Results. Of the patients who did not receive stage-based management, 83% (15 of 18) of cases with both central nervous system (CNS) involvement and cardiopulmonary failure died during the acute stage of the infection. Two patients died at convalescence, and 1 had sequelae of dysphagia and limb weakness. By contrast of the patients who received stage-based management, 33% (12 of 36) of patients with CNS and cardiopulmonary failure died during the acute stage, 8% (3 of 36) died at convalescence, 14% (5 of 36) recovered and 43% (16 of 36) had severe sequelae of central hypoventilation, dysphagia and limb weakness (P < 0.001). For cases with CNS and cardiopulmonary failure, multivariate analysis showed that age older than 2 years and cerebro-spinal fluid white blood cell count >100/μl were associated with a increase in acute mortality [95% confidence interval (CI) 1.9 to 105.3, P = 0.001; 95% CI 1.1 to 66.6, P = 0.04, respectively], but stage-based management was significantly associated with a reduction in acute mortality (95% CI 0.007 to 0.24; P = 0.0004). Stage-based management did not affect the outcome of cases with CNS involvement alone. Conclusions. Stage-based management reduced the case fatality rate of EV71-related cardiopulmonary failure, but two-thirds of the survivors had severe sequelae.

Clinical and radiographic spectrum of septic pulmonary embolism

Aims: To review the clinical presentation, radiographic findings, and outcome of therapy in children with septic pulmonary embolism. Methods: Retrospective analysis of patients in a tertiary paediatric facility in northern Taiwan. Results: Ten children were identified with septic pulmonary emboli in a four year retrospective chart review between 1998 and 2001. Seven were immunocompetent, two were premature infants, one had β thalassemia major. Seven had community acquired staphylococcal infections and bacteraemia, of which six were methicillin resistant Staphylococus aureus (MRSA) isolates. Five had soft tissue infections, two bone infections, one suppurative otitis media, one catheter related infection, and one unknown foci of infection. Multiple and bilateral nodular pulmonary parenchymal lesions were common on plain chest radiographs, but chest computed tomography scans showed the additional findings of a “vessel sign” and central cavitations, confirming the existence of septic pulmonary embolism. Conclusions: Community acquired MRSA infections occurred in seven patients with septic pulmonary embolism but without predisposing high risk factors. Critically ill children with skin, soft tissue, or bone infections, when associated with septic pulmonary embolism in an area with a high rate of MRSA, should be empirically treated with glycopeptides (such as vancomycin or teicoplanin) before susceptibility results are known, in order to minimise morbidity and avoid mortality.

An investigation of epidemic enterovirus 71 infection in Taiwan, 2008: Clinical, virologic, and serologic features

Background: Enterovirus 71 (EV71) is causing life-threatening hand-foot-mouth disease in Asia. In Taiwan, EV71 epidemics with different predominant genotypes occurred in 1998 (C2), 2000–2001 (B4), and 2004–2005 (C4). This genotype replacement may have important implications for vaccine development and prediction of epidemics. A nationwide EV71 outbreak occurred again in 2008, which provided a unique opportunity to characterize clinical, virologic, and serologic features of this epidemic. Methods: We analyzed clinical and virologic data of 111 EV71 patients hospitalized in 2008 and prospectively conducted follow-ups of healthy children from June 2006 to December 2008. Results: Among the 111 EV71 inpatients, 21 (19%) developed complications. Among the 21 complicated cases, 15 had central nervous system complication only, 2 had acute heart failure, and 4 had central nervous system and pulmonary complications. In the prospective study, 11 symptomatic infections and 4 asymptomatic infections were detected. Twenty-two EV71 isolates were genotyped, and 21 of them belong to genotype B5, which is phylogenetically close to B5 viruses circulating in Southeast Asia. Serologic tests show that children infected with B5 viruses have lower geometric mean titers of neutralizing antibody against genotype C4 than those against genotype B5 (P = 0.004, t test). Conclusions: The 2008 nationwide EV71 epidemic was caused by genotype B5 that was likely introduced to Taiwan from Southeast Asia. Clinical features of the 2008 epidemic were not different from those observed before in Taiwan. Potential antigenic variations between genotype C4 and B5 viruses could be detected and its long-term epidemiologic significance needs further investigation to clarify.

Adenovirus Serotype 3 and 7 Infection with Acute Respiratory Failure in Children in Taiwan, 2010–2011

Objective Increased incidence of adenovirus infection in children was noticed since September 2010 in Taiwan and severe cases requiring intensive care were noted later. We did this study to find the clinical characteristics and risk factors associated with severe adenovirus infection. Patients and Methods We collected cases of severe adenovirus infection between November 2010 and June 2011 to analyze their clinical characteristics in two medical centers in northern Taiwan. Severe adenovirus infection was defined as laboratory-confirmed adenovirus cases with required intensive care. Hexon gene sequencing was performed for molecular genotyping. Results 45 patients were included, 22 cases (49%) were infected with serotype 7, 19 (42%) with serotype 3, and 4 with serotype 2. The median age (range) was 2.75 years (0.08–15.43 years); 87% were below 5 years. Male to female ratio was 1.65 (28 to 17). Of these patients, 56% had underlying neurological diseases, 50% experienced fever higher than 40°C and 69% suffered fever longer than one week. The clinical diagnosis included pneumonia in 40 (89%) patients, bronchopneumonia in 5 (11%), and encephalitis in 7 (16%). At least 22 patients had pleural effusion. They had complications of respiratory failure (53%), acute respiratory distress syndrome (24%), hypotension (40%), and 6 (13%) patients needed extracorporeal membranous oxygenation. Ten (22%) patients died, all with underlying major systemic diseases and 7 (70%) infected with serotype 7. Conclusions Adenovirus serotype 7 and 3 can cause severe disease–even death–in children, especially those with underlying neurological diseases. Patients infected with adenovirus serotype 7 tended to have a higher case-fatality rate.

Predictors of unfavorable outcomes in enterovirus 71-related cardiopulmonary failure in children.

Background: Enterovirus 71 (EV71) can sometimes cause fatal or disabling diseases in children; therefore EV71-infected children with cardiopulmonary failure were investigated at Chang Gung Childrens Hospital to discover the prognostic predictors. Methods: We investigated 27 EV71-infected children with cardiopulmonary failure from May 2000 to September 2001 and analyzed their clinical data to find predictors associated with unfavorable outcomes of deaths or ventilator dependence. Results: Of the 27 patients, 8 (30%) died and 10 (37%) were ventilator-dependent. Troponin I levels correlated most strongly with fatality, with 5 of the 6 children with troponin I levels >40 ng/ml dying (P = 0.001). Other factors correlated with fatality were cerebrospinal fluid white blood cell count ≥100/μL (P = 0.002) and initial systolic pressure ≤100 mm Hg (P = 0.05). Of the 19 survivors, 10 (53%) were left with central hypoventilation, dysphagia and/or limb weakness plus atrophy. The factors associated with ventilator dependence included higher inotrope equivalent (P < 0.001), duration of hypotension ≥40 hours, initial blood systolic pressure ≤100 mm Hg, positive EV71 isolation and age ≥12 months. Conclusions: Poor prognostic factors were related to cardiovascular and neurologic damage; therefore physicians may consider advanced cardiovascular support for EV71-infected children with cardiopulmonary failure.

Adnexal torsion in children

Objectives: Adnexal torsion is an acute abdominal condition often confused with other diseases in children. The objective of this study is to evaluate the diagnosis and characteristics of adnexal torsion in children. Methods: We reviewed the medical records of all cases of children whose adnexal torsion diagnosis was proven by surgery from 1992 to 2005. Neonatal cases were excluded. Results: A total of 49 cases were included in this study, with a mean age of 12.5 years. Sixteen (32.6%) cases were premenarchal girls, who were more likely to have adnexal torsion missed at first clinical diagnosis when compared with postmenarchal girls (P = 0.032). Presenting symptoms included severe abdominal pain (32%) and a history of recurrent pain of more than 2 weeks (14.2%). Abdominal gray-scale ultrasound (US) in 43 patients revealed 41 cases that were suggestive of ovarian pathology and identified 3 torsions. Seventeen patients had both US and abdominal computed tomography, but no definitive adnexal torsion was diagnosed with the combined studies. When multiple radiographic studies were used, there was a significantly longer time from studies to operation as compared with US alone. Conclusions: Ultrasound usually plays an important, but not definitive, role in diagnosis. Multiple radiographic studies with combined computed tomography and US did not provide a diagnostic advantage over US alone. Most pediatric adnexal torsion occurs in postmenarchal patients, but the potential exists for this diagnosis in premenarchal girls. Adnexal torsion should be considered in any girl with an abdominal mass and any degree of abdominal pain.

Clinical Variants of Guillain-Barré Syndrome in Children

Guillain-Barré syndrome is characterized by acute progressive weakness, areflexia, and maximal motor disability that occur within 4 weeks of onset. Various clinical subtypes have been described since the original description of the syndrome. This study aimed to identify characteristics of clinical variants of Guillain-Barré syndrome through retrospective review of cases in Chang Gung Childrens Hospital from 2000-2010. Forty-three Guillain-Barré syndrome patients were evaluated based on clinical presentations and an electrodiagnostic study. The most frequent variant of Guillain-Barré syndrome was demyelinating polyneuropathy (67.4%), followed by acute axonal neuropathy (7.0%), Miller Fisher syndrome (7.0%), Bickerstaff brainstem encephalitis (7.0%), pharyngo-cervical-brachial variant (4.7%), and polyneuritis cranialis (4.7%). Follow-up revealed that 35 recovered satisfactorily, eight were persistently disabled, and none died during hospitalization. At the earliest stage, differentiating clinical variants from typical Guillain-Barré syndrome was difficult. Children with clinical variants of Guillain-Barré syndrome are more likely to manifest rapid onset from disease onset to nadir, increasing the severity of disability, cranial nerve involvement, urine incontinence, respiratory impairment, and need for ventilator support than in typical Guillain-Barré syndrome.

Therapeutic Hypothermia for Febrile Infection-Related Epilepsy Syndrome in Two Patients

Despite advances in critical care, febrile infection-related epilepsy syndrome remains the most important cause of mortality and neurologic deficits during childhood. Only a few therapeutic agents were reported to shorten the acute phase and improve outcomes. Therapeutic hypothermia was reported effective in stabilizing immune activation, brain edema, and seizure activity, to protect the brain from ongoing functional, apoptotic neural, and glial damage and the systemic expansion of the cytokine storm. We present two pediatric cases of febrile infection-related epilepsy syndrome, refractory to conventional medical therapy. Moderate therapeutic hypothermia at 33°C resulted in fast, sustained control of refractory status epilepticus. After 3 months, both patients recovered with a Glasgow Outcome Scale score of 4. Therapeutic hypothermia may play an important role in children with febrile infection-related epilepsy syndrome.