Search

Background: Pulmonary hypertension due to interstitial lung disease (PH-ILD) is associated with high rates of respiratory failure and death. Healthcare resource utilization (HCRU) and cost data are needed to characterize PH-ILD disease burden., Methods: A retrospective cohort analysis of the Truven Health MarketScan ® Commercial Claims and Encounters Database and Medicare Supplemental Database between June 2015 to June 2019 was conducted. Patients with ILD were identified and indexed based on their first claim with a PH diagnosis. Patients were required to be 18 years of age on the index date and continuously enrolled for 12-months pre- and post-index. Patients were excluded for having a PH diagnosis prior to ILD diagnosis or the presence of other non-ILD, PH-associated conditions. Treatment patterns, HCRU, and healthcare costs were compared between the 12 months pre- versus 12 months post-index date., Results: In total, 122 patients with PH-ILD were included (mean [SD] age, 63.7 [16.6] years; female, 64.8%). The same medication classes were most frequently used both pre- and post-index (corticosteroids: pre-index 43.4%, post-index 53.5%; calcium channel blockers: 25.4%, 36.9%; oxygen: 12.3%, 25.4%). All-cause hospitalizations increased 2-fold, with 29.5% of patients hospitalized pre-index vs. 59.0% post-index (P < 0.0001). Intensive care unit (ICU) utilization increased from 6.6 to 17.2% (P = 0.0433). Mean inpatient visits increased from 0.5 (SD, 0.9) to 1.1 (1.3) (P < 0.0001); length of stay (days) increased from 5.4 (5.9) to 7.5 (11.6) (P < 0.0001); bed days from 2.5 (6.6) to 8.0 (16.3) (P < 0.0001); ICU days from 3.8 (2.3) to 7.0 (13.2) (P = 0.0362); and outpatient visits from 24.5 (16.8) to 32.9 (21.8) (P < 0.0001). Mean (SD) total all-cause healthcare costs increased from $43,201 ($98,604) pre-index to $108,387 ($190,673) post-index (P < 0.0001); this was largely driven by hospitalizations (which increased from a mean [SD] of $13,133 [$28,752] to $63,218 [$75,639] [P < 0.0001]) and outpatient costs ($16,150 [$75,639] to $25,604 [$93,964] [P < 0.0001])., Conclusion: PH-ILD contributes to a high HCRU and cost burden. Timely identification, management, and treatment are needed to mitigate the clinical and economic consequences of PH-ILD development and progression., (© 2024. The Author(s).)

Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) remains significantly underdiagnosed in patients with a history of pulmonary embolism. These patients complain of persistent shortness of breath and present with hypoxemia despite proper anticoagulation. Further investigation reveals evidence of right ventricular dysfunction on echocardiogram, which progresses to right heart failure. CTEPH is associated with a significant increase in patient morbidity and mortality if left untreated. This article offers an approach for the timely recognition of this condition, in addition to suggesting a management protocol with an emphasis on the role of interventional radiology and balloon pulmonary angioplasty., (Copyright © 2022 American Academy of Physician Assistants.)

Background: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population., Methods: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion., Results: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively., Conclusions: Each of the antibiotic regimens are safe in premature infants with cIAI., Clinical Trial Registration: NCT0199499., Competing Interests: The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown., Methods: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections open-label multicenter trial infants ≥34 weeks gestation at birth and <121 days postnatal age with cIAIs were administered metronidazole as part of multimodal therapy. Metronidazole safety was evaluated by reporting of adverse events (AEs) and safety events of special interest. Cure from disease was determined by blood cultures and a clinical cure score >4. A blinded adjudication committee reviewed all safety events of special interest., Results: Fifty-five infants were included, median gestational age was 36 weeks (range: 34-41) and postnatal age was 7 days (0-63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin and vancomycin. Only one AE, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was 1 (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4., Conclusions: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

There is limited guidance on how to treat extremely premature infants with HIV infection. This can lead to delay of antiretroviral therapy initiation adversely affecting magnitude of HIV reservoir and disease progression. We report perinatal HIV-1 infection in an extremely low birth weight infant born at 24 5/7 weeks of gestation. Treatment challenges, viral dynamics and clinical outcomes are described.

Forkhead box protein 3 (FoxP3)(+) regulatory T cells (Tregs ) are important not only in regulating the development of autoimmune conditions, but also in chronic infectious diseases. Given their cardinal function in suppressing immune activation, research has focused upon whether they play a detrimental role in chronic infections, particularly HIV. While the role of Tregs in HIV has been investigated intensively, it remains an unresolved topic. However, it is generally accepted that Tregs are susceptible to HIV infection and are preferentially preserved over conventional CD4(+) T cells. It is unknown whether the peripheral-induced or the thymic-derived Tregs are more susceptible to HIV cytotoxicity. It has been recognized that Tregs can be segregated into two subsets based on Helios expression, with the vast majority being Helios(+) . This study examines the impact of HIV infection on total Tregs and their Helios subsets in a perinatal-acquired HIV-infected paediatric population. The finding indicates a selective expansion or survival of Tregs in association with CD4 depletion and increased viraemia. The Helios(+) and Helios(-) subsets within Tregs appear to be equally affected. However, the Helios(+) Tregs seem to be more preserved in patients with low CD4(+)  ≤ 25% and detectable plasma HIV RNA >20 copies/ml. In this group, the frequencies of Tregs are increased, but their numbers appear insufficient to restrain immune activation. In conclusion, our findings suggest that both Helios subsets of Tregs are susceptible to HIV infection and are preferentially preserved compared to conventional CD4(+) T cells., (© 2014 British Society for Immunology.)

Pulmonary hypertension (PH) is a frequently under recognized complication of myelofibrosis (MF). The pathophysiology of PH in MF is unknown and no definitive therapies have been established. We studied 15 patients with MF-associated PH and compared their echocardiographic and PH relevant biomarkers (nitric oxide (NO), N-terminal pro-hormone of brain natriuretic peptide (NT-pro BNP), von Willebrand antigen (vWB), ristocetin-cofactor activity (RCA) and uric acid (UA)) pre- and post-ruxolitinib treatment. Ruxolitinib decreased the plasma levels of NT-pro BNP (73%; P=0.043), UA (60%), vWB (86%) and RCA (73%; P=0.036). Improvements in echocardiographic findings were also seen in 66% of patients (P=0.022). Furthermore, marked increase in NO compared with baseline (69.75 vs 40.1 picomolar (pM); P=0.001) was observed post-ruxolitinib therapy, whereas no changes were noted with conventional therapies. Treatment with ruxolitinib also resulted in the reduction of key cytokines (tumor necrosis factor alpha, interleukin-4 (IL-4), IL-6 and IL-8) and induction of interferon-gamma. Animal studies further supported the role of ruxolitinib in the induction of NO levels. In conclusion, aberrant Janus kinase (JAK)-signal transducer and activator of transcription signaling in MF may mediate PH through dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors suggesting that inhibition of this pathway is a novel target for the management of patients with PH.

Objective: In adults, nucleoside reverse transcriptase inhibitor-only antiretroviral regimens (NOARs) with ≥3 nucleoside reverse transcriptase inhibitors are less potent than highly active antiretroviral therapy (HAART). Published pediatric experience with NOARs is limited; thus, we wished to better define the virological, immunological and toxicological effects of NOARs in children and adolescents., Methods: We analyzed data from NOAR-treated participants in LEGACY, a multicenter observational cohort study of HIV-infected children and adolescents. NOAR-treated case-participants were matched to participants without prior NOAR who initiated HAART during the same year for comparison., Results: Of 575 participants with data from time of HIV diagnosis through 2006, 67 (12%) received NOARs for at least 24 weeks; most (46%) received the fixed dose combination of zidovudine/lamivudine/abacavir. NOAR use peaked in 2001 to 2002. NOAR-treated participants were significantly older and more treatment experienced than HAART-treated participants. Virologic outcomes, including the percentage of participants with a plasma HIV RNA viral load <400 copies/mL at week 24 (47% versus 34%) and the mean 24-week change in log10 plasma HIV RNA viral load from baseline (-0.63 versus -1.02), were similar between NOAR- and HAART-treated participants, but virologic rebound was more likely in NOAR-treated participants (77% versus 54%, P = 0.02). Increase in CD4 percentage points from baseline to 24 weeks was negligible in NOAR-treated participants compared with HAART-treated participants (0.95% versus 10.1%, P < 0.001). Anemia and leukopenia were more commonly reported with NOARs than HAART., Discussion: Week 24 virologic outcomes were similar between NOAR- and HAART-treated participants, but NOAR durability was poorer and their use was associated with less immunologic reconstitution. NOARs should play a limited role in pediatric and adolescent antiretroviral therapy.

Circulating cardiac troponins are markers of myocardial injury. We sought to determine whether cardiac troponin I (cTnI), measured by a sensitive assay, is associated with disease severity and prognosis in pulmonary arterial hypertension (PAH). cTnI was measured in 68 patients with PAH diagnostic category 1 in a research-based sensitive immunoanalyser with a lower limit of detection of 0.008 ng · mL(-1). The associations between cTnI and PAH severity and clinical outcomes were assessed using Chi-squared and Wilcoxon rank sum tests, Kaplan-Meier analysis and Cox regression models. cTnI was detected in 25% of patients. Patients with detectable cTnI had more advanced functional class symptoms, a shorter 6-min walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels. 36-month transplant-free survival was 44% in patients with detectable cTnI versus 85% in those with undetectable cTnI. cTnI was associated with a 4.7-fold increased risk of death related to right ventricular failure or transplant (hazard ratio 4.74, 95% CI 1.89-11.89; p<0.001), even when adjusted individually for known parameters of PAH severity. Elevated plasma cTnI, even at subclinically detectable levels, is associated with more severe disease and worse outcomes in patients with PAH.

Biomarkers are objectively measured characteristics used as indicators of disease in clinical practice and as surrogate endpoints in clinical trials. The six-minute walk test has been widely used as a trial endpoint in pulmonary arterial hypertension (PAH) to gain approval for targeted therapies. Other biomarkers have been studied to overcome certain limitations of the walk test. Potential clinical applications for biomarkers in PAH include screening, determination of prognosis, and monitoring response to therapy. Measurement of the B-type natriuretic peptides is currently recommended by guidelines, despite a lack of appropriate validation in the PAH population. Novel biomarkers based on recently discovered pathobiologic pathways have been identified, like CXC chemokine ligand 10, C-reactive protein, high-density lipoprotein cholesterol and growth-differentiation factor-15. Rigorous statistical, biologic and clinical validation should be necessary before any biomarker can be endorsed for widespread clinical use., (© 2010 Blackwell Publishing Ltd.)

Background: Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME., Methods: We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation., Results: Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg., Conclusions: These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

We report the development of Campylobacter jejuni enteritis in a patient with preexisting humoral and cellular immune recognition of C. jejuni antigens. This is one of few studies in which the immunologic status of a person with regard to C. jejuni before and after C. jejuni infection is directly compared, and it is the only study of which we are aware that includes measurements of cellular immunity. The findings may be important to Campylobacter vaccine development efforts.

A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus septicemia. After the second episode rifampin was given to the infant, but further Ia/c exposure to maternal breast milk ensued. We propose rifampin treatment for both the mother and infant in cases of recurrent group B streptococcus disease.

Shigella sonnei infection resulting from oral administration of 500 colony-forming units was followed in 11 volunteers with the objective of studying the immune response and pathogenesis. Characterization of infection included recording of signs and symptoms, excretion of S. sonnei in stool, measurement of humoral tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN-gamma), C-reactive protein, IL-2 receptor, soluble CD8, antibody-antigen complexes, and endotoxin. Measurements were also made of the immune response including lymphocytes secreting antibody to S. sonnei O antigen and serum antibody to this antigen. Six of the volunteers developed typical shigellosis with excretion of bacteria in stool and systemic signs and symptoms, three excreted bacteria but did not show illness, and two showed no evidence of infection or illness. Shigellosis was characterized by excretion in stool of S. sonnei beginning on average 1.3 days after ingestion. Excretion of S. sonnei (mean of time of the first positive cultures) was followed in sequence by the onset of increases in TNF-alpha (10 hr), liquid stools (14 hr), fever and dysentery (18 hr), IFN-gamma (22 hr), and C-reactive protein (34 hr). A S. sonnei-specific immune response was demonstrated somewhat later, between days 4 and 7 postinfection by antibody-secreting cells, and between days 7 and 14 postinfection by humoral antibody. Shigellosis was not associated with increased humoral IL-1 beta, endotoxin, or antigen-antibody complexes.

To address the hypothesis that increased infectious morbidity is associated with iron supplementation, 783 randomly selected infants were provided with a powdered full fat cow's milk (non-fortified group) and 872 with a powdered acidified full fat cow's milk fortified with 15 mg of iron as ferrous sulfate (fortified group). All infants were followed from birth to 15 months of age with a monthly home visit by a nurse who recorded morbidity occurring during the previous 30 days. At 9 months of age, 15% of infants in each cohort were receiving breast milk only; data for these infants were segregated to make the third group. Episodes (mean +/- SD) of diarrhea/infant/year were 1.06 +/- 1.29, 1.14 +/- 1.37, and 0.82 +/- 1.04 for the fortified, non-fortified and breast-fed groups, respectively; the fortified and non-fortified bottle-fed groups had a very similar incidence of respiratory illness; 2.66 +/- 2.07 and 2.74 +/- 2.24 episodes/infant/year, respectively. The incidence of respiratory illness for both bottle-fed groups was significantly higher than that for the breast-fed group (2.22 +/- 1.84 respiratory episodes/infant/year). We conclude that for the infants the tested form of iron fortified milk, which is sufficient to lower iron deficiency anemia, does not result in an increased incidence of diarrhea or respiratory illness.

Three siblings with alloimmune neonatal neutropenia are presented. An immunoglobulin G (IgG) antineutrophil antibody specific for NA-2 antigen was demonstrated in maternal serum and in both of the three affected infants who were studied as neonates. The mother's neutrophils were negative for NA-2 antigen. The father and all four children, including the three known to be affected, had neutrophils that expressed NA-2 antigen. One patient studied sequentially demonstrated an inverse relationship between the antineutrophil antibody titer and the absolute neutrophil count. Exchange transfusions did not appear to benefit two of the infants.

We evaluated the effect of iron-supplemented milk on 86 healthy infants who were followed from 3 to 12 months of age. Whole milk was supplemented with 15 mg elementary iron as ferrous sulphate and 100 mg ascorbic acid per 100 g powder. 104 infants received the same milk with no supplement and served as control. All iron nutritional parameters were higher in the supplemented group at 9 and 12 months of treatment (p < 0.01). Iron-deficiency anemia was shown in 34% of the control as compared to 0% of the treatment group. The product exhibited excellent tolerance and could therefore be used to eradicate iron-deficiency anemia of the infant.

We tested in the field an extruded rice flour, fortified with a bovine haemoglobin concentrate (Fe:14 mg/100 g of powder). This cereal has a high iron bioavailability, good protein quality and amino acid score. Healthy, term breast-fed infants were prospectively studied. One group (n = 92) received the fortified cereal (from 4 to 12 months of age). As control, 96 infants received regular solid foods (cooked vegetables and meat) from age 4 months. At the end of the field trial, a subsample of infants in both groups was supplemented with 45 mg Fe during 90 d. Iron nutrition status was determined at 9, 12 and 15 months. At 12 months, iron deficiency anaemia was present in 17 per cent of controls, in 10 per cent of fortified infants as a whole, but only in 6 per cent of the babies who consumed over 30 g of cereal/d. In addition, this latter group did not show any significant changes in iron nutrition status after the supplementation trial. Results demonstrate that the consumption of a haemoglobin fortified cereal is effective in markedly reducing the incidence of iron deficiency in breast-fed infants.

1. Serum thymic hormone was assayed in genetically-obese (C57B1/6J ob/ob) mice and lean controls (+/+, +/-) of the same strain. 2. The thymic hormone activity was higher in the majority of the obese animals compared with non-obese mice. 3. The number of antibody-forming cells in the spleen expressed as a proportion of the total mononuclear cells was increased in the obese mice. 4. It is suggested that obesity is associated with significant changes in the thymic hormone levels which may alter the relative proportion of lymphocyte subsets and cell-mediated immunity.

In a double-blind, controlled, crossover study involving 47 subjects documented with seasonal allergic rhinitis, repeated intranasal administration of 4% sodium cromoglycate solution was associated with significant reduction in symptoms and decrease in consumption of antihistaminic drugs. Side effects were mild and transitory. It is concluded that intranasal sodium cromoglycate administration is an efficacious preventive and therapeutic approach in the management of patients with seasonal allergic rhinitis.

To evaluate the effect of zinc on growth and immune function, 32 marasmic infants were selected on admission to the nutrition recovery center; 16 received 2 mg/kg daily of elemental zinc supplement as acetate and the remaining received a placebo. Immunity was assessed by skin-test response, T-cell blastic proliferation immunoglobulins, and infectious morbidity. Weight-for-length gain for initial 60 days in Zn-supplemented group was 9% of standard vs 3% for placebo (p less than 0.05). Energy intake was similar in both groups. Incidence of infections, especially pyoderma, was significantly higher in placebo group: 10 of 16 vs 3 of 16 in the supplemented group (p less than 0.025). Plasma Zn was correlated with number of febrile days in the prospective month (r = -0.66, p less than 0.05). The percent anergic infants decreased and serum IgA increased significantly only in Zn-supplemented group. Zinc supplementation has significant effects on weight gain and host defense mechanisms despite normal plasma levels. Zinc supplementation is recommended for optimal recovery from marasmus.

The thymic factor (TF) activity and lymphocyte stimulation response to phytohemagglutinin (PHA) was studied in calorie-restricted rats. Sprague-Dawley rats (28 days old) were fed a calorie-restricted diet (30% of the average food intake of control) for 4 weeks. The control group was allowed food ad libitum. After this period the body weight was 232.9 +/- 41.8 g for control rats and 66.1 +/- 4.5 g for the calorie-restricted group. The mean thymus weight was 0.699 +/- 0.153 g and 0.099 +/- 0.030 g for the control and experimental groups respectively. The TF activity was makedly reduced in the calorie-restricted group compared with the control. There was an overlap between lymphocyte stimulation responses of the two groups; however, the mean number of counts per minute (cpm) of stimulated cultures with PHA was lower and the mean cpm of unstimulated cultures without PHA was higher in the starved animals. Thus, the stimulation index was significantly lower in the deprived rats. It is suggested that deficiency of thymic inductive factors may be important in the pathogenesis of impaired cell-mediated immunity in nutritional deficiency states.

Cell-mediated immunity is invariably impaired in protein-energy malnutrition. The effect of selected nutrient deficiencies on serum thymic factor activity was assessed in deprived rats and pair-fed controls. Deficits of calories, zinc or pyridoxine resulted in significant lowering of serum thymic factor activity whereas vitamin A deficiency did not have any effect. It is suggested that variants nutrients modulate different steps of cell-mediated immunity and that reduced thymic hormone activity may be the underlying mechanism of imparied immunity in some but not all nutritional deficiencies.

Production of leukocyte migration inhibition factor was measured in vitro with purified protein derivative and phytohemagglutinin in 14 marasmic infants 6 to 18 months of age. Twenty-seven well-nourished infants served as controls. All the children had received BCG vaccine in the neonatal period. Tuberculin reaction was positive in four of 14 of the marasmic infants and 13 of 27 of the controls. When leukocyte migration inhibition factor was induced with purified protein derivative, the four tuberculin positive malnourished subjects had a mean migration inhibition index of 55.7% which was significantly higher than the mean migration inhibition index of 38.2% in the tuberculin positive controls. In the tuberculin negative subjects the mean migration inhibition index was 24.7 and 16.6% in the marasmic and control groups, respectively. The difference was not statistically significant. Phytohemagglutinin-induced migration inhibition was comparable in malnourished and control infants. There was no correlation between leukocyte migration inhibition factor production and biochemical indices of iron nutrition, erythrocyte or serum folate, vitamin A, carotene, or serum zinc levels in either group. It is suggested the capacity of lymphocytes to produce leukocyte migration inhibition factor is unchanged in marasmus.