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.

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.

Severe hemorrhagic coagulopathy with hemophagocytic lymphohistiocytosis secondary to Epstein-Barr virus-associated T-cell lymphoproliferative disorder.

OBJECTIVE: We describe the coagulopathy and hemorrhagic complications associated with fulminant, secondary hemophagocytic lymphohistiocytosis in a cohort of patients with Epstein-Barr virus-associated T-cell lymphoproliferative disorder. PATIENTS AND METHODS: Institutional Review Board-approved retrospective review of all patients at our children's hospital over 3 years (2008-2010) with hemophagocytic lymphohistiocytosis secondary to acute Epstein-Barr virus-associated T-cell lymphoproliferative disorder. RESULTS: Four males (2, 3, 17, and 20 yr old) presented with fever, hepatosplenomegaly, and pancytopenia with elevated serum ferritin, and all met clinical and laboratory criteria for secondary hemophagocytic lymphohistiocytosis. d-dimer on admission was elevated in all patients and remained extremely elevated during hospitalization, while the median prothrombin and activated partial thromboplastin times as well as fibrinogen were all in the normal range. Within a few weeks to months following admission, all patients developed multiorgan system failure with episodes of severe, life-threatening hemorrhage; in all four patients, hemorrhage was not associated with a nadir in platelet count. There were no survivors beyond 4 months from diagnosis. CONCLUSIONS: A coagulopathy characterized by persistent, extreme elevations in plasma d-dimer and severe, life-threatening hemorrhage was noted in association with hemophagocytic lymphohistiocytosis secondary to Epstein-Barr virus-associated T-cell lymphoproliferative disorder. We speculate that this coagulopathy is a marker of severe hemophagocytic lymphohistiocytosis in this setting.

Nitric oxide-associated pulmonary edema in children with pulmonary venous hypertension.

Nitric oxide (NO)-associated pulmonary edema is rarely reported in children; in adults, it is often associated with left-sided heart failure. We report a case series of children with NO-associated pulmonary edema, which was defined as new multilobar alveolar infiltrates and worsening hypoxemia within 24 h of initiation or escalation of NO and radiologic or clinical improvement after NO discontinuation. We identified six patients (0.4-4 years old) with ten episodes of NO-associated pulmonary edema. Diagnoses included atrioventricular canal defect with mitral valve disease (n = 2), pulmonary atresia and major aorta-pulmonary collateral arteries (n = 2), total anomalous pulmonary venous return (n = 1), and pulmonary veno-occlusive disease (n = 1). All patients had evidence of pulmonary venous hypertension, and two had mitral valve disease resulting in clinical evidence of left-sided heart failure. Pulmonary edema improved or resolved within 24 h of discontinuing NO. At cardiac catheterization, mean left atrial pressure was <15 mmHg in three of three patients (none with mitral valve disease), whereas pulmonary artery occlusion pressure was >15 mmHg in two of five patients. In conclusion, we describe six young children with NO-associated pulmonary edema and pulmonary venous hypertension. Only two of these children had left-sided heart failure: Left atrial pressure as well as pulmonary artery occlusion pressure may not be helpful in identifying children at risk for NO-associated pulmonary edema.

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. CONCLUSIONS: 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.

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.

Standalone Ayurvedic treatment of high-risk COVID-19 patients with multiple co-morbidities: A case series.

We report a case-series of Ayurvedic treatment in seven COVID-19 positive patients with multiple co-morbidities, categorized as high-risk for poor outcome from SARS-CoV-2 infection. All of them recovered completely from their illness with resolution of symptoms following Ayurvedic treatment. The data was collected from patients treated during the early months of the COVID-19 pandemic (June 2020 to September 2020) at an out-patient Ayurvedic Clinic, Chennai, India. This is a retrospective case series from among the initial 247 COVID-19 patients out of whom 39% were found to be suffering from co-morbidities. We have chosen seven of these patients who fulfilled the criteria for high-risk category, represented by multiple co-morbidities that included cancer, chronic kidney disease (CKD), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), hypertension, and an elderly person over the age of 90 years. Classical Ayurvedic formulations for COVID -19 were chosen so as to avoid complicating co-morbid conditions and patients were maintained on a modified diet. All these high-risk patients were treated at an out-patient setting. The patients were under home quarantine and self-monitored their progress with daily follow-up over the phone by the treating Ayurvedic physician. The main outcome measure included resolution of symptoms and complete recovery from COVID-19 disease in all patients. This case series demonstrates the scope of Ayurvedic interventions in the management of high-risk COVID-19 patients with severe co-morbidities with successful outcome in an out-patient setting.

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-alpha-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-alpha-stimulated ECs. These data demonstrate a novel role for AR in regulating the signaling pathways leading to neutrophil-EC adhesion during acute lung inflammation.

Pediatric acute respiratory distress syndrome associated with human metapneumovirus and respiratory syncytial virus.

OBJECTIVES: To study the incidence, risk factors, clinical course, and outcome of ARDS in children with HMP and RSV. WORKING HYPOTHESIS: We hypothesized that ARDS in children with HMP was similar in incidence, risk factors, clinical course, and outcomes to ARDS in children with RSV. STUDY DESIGN: Retrospective, observational study over 2 years. PATIENT-SUBJECT SELECTION: Patients included were <18 years old with HMP or RSV detected from nasopharyngeal specimens by commercial reverse transcriptase polymerase chain reaction assay admitted to a study site. METHODOLOGY: We described the incidence of ARDS within 1 week following the detection of HMP or RSV using recently developed Pediatric ARDS (PARDS) criteria. We also assessed risk factors, clinical course, and outcomes of children in the PICU with HMP or RSV and PARDS or non-PARDS. RESULTS: We identified 57 patients with HMP and 161 patients with RSV: the proportions of patients with either virus who developed PARDS (HMP: 23%, RSV: 20%) and severe PARDS (HMP: 9%, RSV: 7%) were similar, as were the proportions of patients with acute (or acute-on-chronic) respiratory failure who developed PARDS (HMP: 41%, RSV: 31%). In a logistic regression model, risk factors associated with PARDS included neurologic comorbidity and PIM 3 probability of mortality, but not virus type. The risk factors, clinical course, and outcomes were similar for patients with PARDS associated with HMP and RSV. CONCLUSIONS: About 1/3 of children with HMP or RSV and acute (or acute-on-chronic) respiratory failure developed PARDS. Children with either virus and a neurologic comorbidity or an increased PIM 3 probability of mortality were at increased risk for PARDS.

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.

Internal jugular phlebectasia in Menkes disease.

Pediatric neck masses should trigger a high index of suspicion for certain genetic disorders of connective tissue. To highlight this, we report on three infants with Menkes disease, an inherited disorder of copper transport, who developed large, unilateral neck masses at between 7 and 17 months of age. All were identified in imaging studies as internal jugular phlebectasia. The masses, which enlarged on crying or exertion, have remained clinically benign in these patients for 20, 17, and 2 months, respectively. While arterial tortuosity and aneurysms have been reported often in Menkes disease, venous phlebectasia has rarely been described. We speculate that low activity of the copper-dependent enzyme, lysyl oxidase, leading to reduced tensile strength in the deep cervical fascia comprising the carotid sheath may predispose to internal jugular phlebectasia in these individuals. Improved survival and neurological outcomes in infants with Menkes disease due to advances in early diagnosis and treatment may be associated with recognition of novel clinical stigmata of this condition such as internal jugular phlebectasia.

Albuterol-induced myocardial ischemia in sickle cell anemia after hemolysis from ceftriaxone administration.

Hemolysis induced by ceftriaxone is a complication that has been described in sickle cell anemia. Albuterol is known to induce myocardial ischemia. We describe a case of albuterol-induced cardiac dysfunction in a patient with sickle cell anemia who developed severe anemia after administration of ceftriaxone.

Vitamin B deficiencies in a critically ill autistic child with a restricted diet.

An 11-year-old male with autism became less responsive and was hospitalized with hepatomegaly and liver dysfunction, as well as severe lactic acidosis. His diet for several years was self-limited exclusively to a single "fast food"-a particular type of fried chicken-and was deficient in multiple micronutrients, including the B vitamins thiamine and pyridoxine. Lactic acidosis improved rapidly with thiamine; 2 weeks later, status epilepticus-with low serum pyridoxine-resolved rapidly with pyridoxine. Dietary B vitamin deficiencies complicated the care of this critically ill autistic child and should be considered in this setting.

Effects of pentoxyfylline on mesenteric lymph node T-cells in a rat model of thermal injury.

Cutaneous burn injury-induced T lymphocyte suppression is a well-known phenomenon. In this study, we evaluated the effect of treatment of burn rats with pentoxifylline (PTX) on the burn-induced suppression of T lymphocytes. Anesthetized rats were subjected to 30% total body surface area burn by exposing skin to 95 degrees C water for 10 s. T lymphocytes were isolated from sham and burn rats with or without PTX treatment (120 mg/kg, ip). T cell proliferation and interleukin (IL)-2 production in response to T cell mitogen concanavalin A was measured using 3 H-thymidine uptake and enzyme-linked immunosorbent assay, respectively. P59 fyn autophosphorylation and its kinase activity was determined using in vitro kinase assay. In addition, T lymphocyte Ca2+ signaling was assessed using Ca2+ imaging technique. Two days after injury, there was a significant decrease in mesenteric lymph node T cell proliferation and IL-2 production in burn injured rats compared with those obtained from sham-injured rats. This decrease in T cell proliferation and IL-2 production in burn-injured rats was accompanied by a significant suppression in both P59 autophophorylation and kinase activity as well as Ca2+ signaling. Treatment of burn-injured rats with PTX produced a near complete recovery of T cell proliferation and IL-2 production. Furthermore, PTX treatment also prevented the burn-mediated suppression in P59fyn and kinase activity as well as restored Ca2+ signaling similar to those observed in sham injured rats. These findings altogether suggested that PTX treatment attenuate T cell suppression in burn-injured rats and that the effects of PTX are mediated via modulating P59 fyn and Ca2+ signaling.

Enterococcus faecalis exacerbates burn injury-induced host responses in rats.

Pathophysiology of burn injury with complications of gram-positive infections is not well characterized. We have developed an in vivo rat model to study the effects of burn injury along with intra-abdominal inoculation of Enterococcus faecalis. We hypothesized that although burn injury or E. faecalis inoculation by itself may not induce significant pathophysiological responses, the combination of the two can lead to adverse pathophysiological consequences. Sprague-Dawley rats were divided into 4 groups: group 1(C), controls; group 2(B), burn injury on 30% total body surface area; group 3(EF), intra-abdominal implantation of bacterial pellet impregnated with E. faecalis; group 4(B+EF), burn injury plus bacterial pellet implantation. The mortality was 25% and 60% on day 1 and 2 in Group 4(B+EF), respectively; no significant mortality was observed in other groups. In group 4(B+EF), metabolic acidosis, respiratory alkalosis, and a hyperdynamic state developed on day 1, and metabolic and respiratory acidosis and a hypodynamic state on day 2. There were no significant alterations in metabolic or hemodynamic measurements in other groups. Intestinal microvascular permeability to albumin on day 1 and 2 was increased in group 4(B+EF). In group 2(B), microvascular permeability was not increased significantly. Although the permeability was increased on day 1 in group 3(EF), it declined on day 2. The metabolic and hemodynamic alterations were correlated with increased intestinal microvascular permeability to albumin. E. faecalis appeared to be involved in initiating a vicious cycle of burn injury-mediated disruption of intestinal integrity along with metabolic and hemodynamic derangements.

Tissue factor pathway inhibitor and thrombin activatable fibrinolytic inhibitor plasma levels following burn and septic injuries in rats.

Burn and septic injuries induce profound changes in coagulation status. This study examined the changes in plasma tissue factor pathway inhibitor (TFPI) and thrombin activatable fibrinolytic inhibitor (TAFI) levels in a rat model of burn and septic injuries. Rats underwent 30% TBSA cutaneous scald burn injury and septic insult was induced by caecal ligation and puncture (CLP). CLP was superimposed on burn injury to mimic the clinical model of sepsis complicating burn injury. Rats were pretreated with Cprofloxacin orally to colonize their gut with Enterococcus faecalis. TFPI and TAFI plasma levels were measured using functional activity assay kit with a chromogenic method at 24 and 72 hours following the injuries. TFPI levels decreased significantly at 24 hours in burn, CLP, and burn+CLP groups, followed by incomplete rebound recovery at 72 hours in all three groups. On the other hand, TAFI levels increased significantly at 24- and 72-hour time points in all three groups. These results suggest that burn, septic, and their combined injuries perturb coagulation cascade and thrombotic process toward the procoagulant pathway by impairing fibrinolysis.

Out-of-hospital noninvasive ventilation: epidemiology, technology and equipment.

Noninvasive ventilation has been utilized successfully in the pre- and out-of-hospital settings for a variety of disorders, including respiratory distress syndrome in neonates, neurologic and pulmonary diseases in infants and children, and heart failure as well as chronic obstructive pulmonary disease in adults. A variety of interfaces as well as mechanical positive pressure devices have been used: simple continuous positive airway pressure devices are available which do not require sophisticated equipment, while a broad spectrum of ventilators have been used to provide bilevel positive airway pressure. Extensive training of transport teams may be important, particularly when utilizing bilevel positive airway pressure in infants and children.

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.