Thyyar M. Ravindranath

Novel Influenza A(H1N1) in a Pediatric Health Care Facility in New York City During the First Wave of the 2009 Pandemic

OBJECTIVE To describe the burden of care experienced by our pediatric health care facility in New York, New York, from May 3, 2009, to July 31, 2009, during the novel influenza A(H1N1) pandemic that began in spring 2009. DESIGN Retrospective case series. SETTING Pediatric emergency departments and inpatient facilities of New York-Presbyterian Hospital. Patients Children presenting to the emergency departments with influenza-like illness (ILI) and children aged 18 years or younger hospitalized with positive laboratory test results for influenza A from May 3, 2009, to July 31, 2009. MAIN OUTCOME MEASURES Proportion of children with ILI who were hospitalized and proportion of hospitalized children with influenza A with respiratory failure, bacterial superinfection, and mortality. RESULTS When compared with the same period in 2008, the pediatric emergency departments experienced an excess of 3750 visits (19.9% increase). Overall, 27.7% of visits were for ILI; 2.5% of patients with ILI were hospitalized. Of the 115 hospitalized subjects with confirmed influenza A (median age, 4.3 years), 93 (80.9%) had underlying conditions. Four (3.5%) had identified bacterial superinfection, 1 (0.9%) died, and 35 (30.4%) were admitted to a pediatric intensive care unit; of these 35 patients, 11 had pneumonia and required mechanical ventilation, including high-frequency oscillatory ventilation (n = 3). CONCLUSIONS At our center, 2.5% of children with ILI presenting to the emergency departments during the first wave of the 2009 novel influenza A(H1N1) pandemic were hospitalized. Of the 115 hospitalized children with confirmed influenza A, 9.6% had respiratory failure and 0.9% died. These findings can be compared with the disease severity of subsequent waves of the 2009 novel influenza A(H1N1) pandemic.

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Objective—There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic. Methods and Results—Atherosclerosis development was quantified in 2 lines of transgenic mice expressing human AR (hAR) crossed on the apolipoprotein E knockout background. The transgenes were used to increase the normally low levels of this enzyme in wild-type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin diabetic mice. In addition, pharmacological inhibition of AR reduced lesion size. Conclusion—Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.

Novel Role for Aldose Reductase in Mediating Acute Inflammatory Responses in the Lung

Exaggerated inflammatory responses and the resultant increases in alveolar-capillary permeability underlie the pathogenesis of acute lung injury during sepsis. This study examined the functions of aldose reductase (AR) in mediating acute lung inflammation. Transgenic mice expressing human AR (ARTg) were used to study the functions of AR since mice have low intrinsic AR activity. In a mild cecal ligation and puncture model, ARTg mice demonstrated an enhanced AR activity and a greater inflammatory response as evaluated by circulating cytokine levels, neutrophil accumulation in the lungs, and activation of Rho kinase in lung endothelial cells (ECs). Compared with WT lung cells, ARTg lung cells produced more IL-6 and showed augmented JNK activation in response to LPS stimulation ex vivo. In human neutrophils, AR activity was required for fMLP-included CD11b activation and up-regulation, respiratory burst, and shape changes. In human pulmonary microvascular ECs, AR activity was required for TNF-α-induced activation of the Rho kinase/MKK4/JNK pathway and IL-6 production, but not p38 activation or ICAM-1 expression. Importantly, AR activity in both human neutrophils and ECs was required for neutrophil adhesion to TNF-α-stimulated ECs. These data demonstrate a novel role for AR in regulating the signaling pathways leading to neutrophil-EC adhesion during acute lung inflammation.

Airway CD8+ T Cells Are Associated with Lung Injury during Infant Viral Respiratory Tract Infection

Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. The objectives of the present study were to characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Daily airway secretions were sampled from infants and children 4 years of age and younger receiving mechanical ventilation owing to respiratory failure from viral infection or noninfectious causes. Samples were examined for immune cell composition and markers of T cell activation. These parameters were then correlated with clinical disease severity. Innate immune cells and total CD3(+) T cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T cell ratio was markedly increased in the airways of patients with viral infection compared with uninfected patients, and specifically in infected infants with acute lung injury. T cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. We identified a significant increase in airway cytotoxic CD8(+) T cells in infants with lung injury from viral respiratory tract infection that was distinct from the T cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage.

Plasma thrombin activatable fibrinolysis inhibitor and tissue factor pathway inhibitor changes following sepsis.

Sepsis-induced systemic inflammation results in coagulation abnormalities that may be different in gram-positive and gram-negative infections. We used ciprofloxacin to induce a predominantly gram-positive Enterococcus faecalis polymicrobial sepsis in rats. Ciprofloxacin-untreated rats exhibited a predominantly gram-negative polymicrobial sepsis. Rats were subjected to 30% body surface area burn (B), cecal ligation puncture (CLP) with a 22-gauge needle, and B + CLP. Ciprofloxacin-treated B + CLP rats showed a significant decrease in plasma thrombin activatable fibrinolysis inhibitor (TAFI) levels compared with sham rats. However, plasma tissue factor pathway inhibitor (TFPI) levels decreased significantly in B, CLP, and B + CLP groups compared with sham rats. The ciprofloxacin-untreated group showed a significant decrease in plasma TAFI levels in CLP and B + CLP and plasma TFPI levels decreased in all 3 groups compared with sham rats. Histological changes in the liver and kidney included vascular congestion and parenchyma bleed following B + CLP in ciprofloxacin-untreated rats. These results suggest that plasma TAFI and TFPI levels differ depending on the type of bacteria involved in the septic process.

Omega-3 polyunsaturated fatty acid enriched diet attenuates stress-induced lactacidemia in 10-day-old rats.

Abstract Background : Lactacidemia is often seen under stress conditions including septic shock in the newborn. Under stress conditions, plasma catecholamine concentrations are increased and play an important role in lactate metabolism. Our previous study shows that perinatal feeding of omega‐3 polyunsaturated fatty acid enriched diet (ω‐3PUFA) attenuates lactacidemia of endotoxic shock in 10‐day‐old rats. In the omega‐6 fatty acids series, decosapentanoic acid, two series prostaglandins and four series leukotrienes are synthesized through linoleic acids. As plasma lactate concentration correlates with the outcome of septic shock in the newborn, it is important to understand the effects of ω‐3PUFA on lactate metabolism. Thus, we tested the hypothesis that perinatal feeding of omega‐3 polyunsaturated fatty acid enriched diet (ω‐3PUFA) alters responses to catecholamines and attenuates the stress‐induced lactacidemia in 10‐day‐old rats.

Comparing the clinical severity of the first versus second wave of 2009 Influenza A (h1n1) in a New York City pediatric healthcare facility

Objective: We previously reported the epidemiology of 2009 Influenza A (H1N1) in our pediatric healthcare facility in New York City during the first wave of illness (May–July 2009). We hypothesized that compared with the first wave, the second wave would be characterized by increased severity of illness and mortality. Design: Case series conducted from May 2009 to April 2010. Setting: Pediatric emergency departments and inpatient facilities of New York-Presbyterian Hospital. Patients: All hospitalized patients ÷18 yrs of age with positive laboratory tests for influenza A. Measurements and Main Results: We compared severity of illness during the first and second wave assessed by the number of hospitalized children, including those in the pediatric intensive care unit, bacterial superinfections, and mortality rate. Compared to the first wave, fewer children were hospitalized during the second wave (n = 115 vs. 76), but a comparable portion were admitted to the pediatric intensive care unit (30.4% vs. 19.7%; p = .10). Pediatric Risk of Mortality III scores, length of hospitalization in the pediatric intensive care unit, incidence of respiratory failure and pneumonia, and peak oxygenation indices were similar during both waves. Bacterial superinfections were comparable in the first vs. second wave (3.5% vs. 1.3%). During the first wave, no child received extracorporeal membrane oxygenation and one died, while during the second wave, one child received extracorporeal membrane oxygenation and there were no deaths. Conclusions: At our pediatric healthcare facility in New York City, fewer children were hospitalized with 2009 Influenza A (H1N1) during the second wave, but both waves had a similar spectrum of illness severity and low mortality rate.

LPS-Induced Changes in Myocardial Markers in Neonatal Rats

Lipopolysaccharide (LPS) produces varied systemic metabolic effects. We studied the effects of LPS on the cardiac fatty acid profile and its relationship to energy metabolism and inflammatory mediators that included TNF-α and nitric oxide synthase (NOS) in 10-day-old neonatal rat pups. Rat pups received an i.p. injection of LPS after a 4-hour starvation period, followed by collection of blood and cardiac tissue 4 h following LPS administration. Compared to controls, LPS induced significant hypoglycemia and hyperlactacidemia, suggesting the development of endotoxic shock. The result was a significant depression in total fatty acid levels as well as non-esterified fatty acid in the cardiac tissue of the LPS-treated pups. In addition, LPS-treated pups also showed a significant increase in TNF-α, NOS levels with a depressed redox state and energy metabolism in cardiac tissue. These observations suggest that endotoxic shock in 10-day-old rat pups induces a systemic inflammatory response with a depression in fatty acid metabolism that may contribute to myocardial failure.

Non-invasive monitoring in the pediatric ICU, part I : Transcutaneous Oxygen monitoring (PtcO2)

ConclusionsPtcO2 monitoring is a reliable technique of predicting change in PaO2 However there are many factors that should be taken into account to minimize sources of error. Such factors include skin properties, site of application, skin perfusion, blood pressure, anesthetic agents and electrode temperature. Despite these limitations PtcO2 continues to be a useful, non-invasive monitoring device in the intensive care unit.

Developmental Regulation of Effector and Resident Memory T Cell Generation during Pediatric Viral Respiratory Tract Infection

Viral respiratory tract infections (VRTI) remain a leading cause of morbidity and mortality among infants and young children. In mice, optimal protection to VRTI is mediated by recruitment of effector T cells to the lungs and respiratory tract, and subsequent establishment of tissue resident memory T cells (Trm), which provide long-term protection. These critical processes of T cell recruitment to the respiratory tract, their role in disease pathogenesis, and establishment of local protective immunity remain undefined in pediatric VRTI. In this study, we investigated T cell responses in the upper respiratory tract (URT) and lower respiratory tract (LRT) of infants and young children with VRTI, revealing developmental regulation of T cell differentiation and Trm generation in situ. We show a direct concurrence between T cell responses in the URT and LRT, including a preponderance of effector CD8+ T cells that was associated with disease severity. During infant VRTI, there was an accumulation of terminally differentiated effector cells (effector memory RA+ T cells) in the URT and LRT with reduced Trm in the early neonatal period, and decreased effector memory RA+ T cell and increased Trm formation with age during the early years of childhood. Moreover, human infant T cells exhibit increased expression of the transcription factor T-bet compared with adult T cells, suggesting a mechanism for preferential generation of effector over Trm. The developmental regulation of respiratory T cell responses as revealed in the present study is important for diagnosing, monitoring, and treating VRTI in the critical early life stages.