HIV-infected individuals are susceptible to development of chronic lung diseases but little is known regarding prevalence and risk factors associated with different spirometric abnormalities in this population. We sought to determine the prevalence, risk factors and performance characteristics of risk factors for spirometric abnormalities among HIV-infected individuals.
Cross-sectional cohort study
We analyzed cross-sectional US data from the NHLBI-funded Lung-HIV consortium, a multi-center observational study of heterogeneous groups of HIV-infected participants in diverse geographic sites. Logistic regression analysis was performed to determine factors statistically significantly associated with spirometry patterns.
A total of 908 HIV-infected individuals were included. The median age of the cohort was 50 years, 78% were male and 68% current smokers. An abnormal spirometry pattern was present in 37% of the cohort: 27% had obstructed and 10% had restricted spirometry patterns. Overall, age, smoking status and intensity, history of Pneumocystis infection, asthma diagnosis and presence of respiratory symptoms were independently associated with an abnormal spirometry pattern. Regardless of presence of respiratory symptoms, five HIV-infected participants would need to be screened with spirometry to diagnose two individuals with any abnormal spirometry pattern.
Nearly 40% of a diverse US cohort of HIV-infected individuals had an abnormal spirometry pattern. Specific characteristics including age, smoking status, respiratory infection history and respiratory symptoms can identify those at risk for abnormal spirometry. The high prevalence of abnormal spirometry and the poor predictive capability of respiratory symptoms to identify abnormal spirometry should prompt clinicians to consider screening spirometry in HIV-infected populations.
HIV; lung disease, obstructive; respiratory tract disease; lung function; spirometry
The European Community Respiratory Health Survey is a major international study designed to assess lung health in adults. This Australian follow-up investigated changes in symptoms between sexes and the roles of asthma, smoking, age, sex, height, and change in body mass index (ΔBMI) on lung function decline (LFD), which is a major risk factor for chronic obstructive pulmonary disease (COPD).
LFD was measured as the rate of decline over time in FEV1 (mL/year) (ΔFEV1) and FVC (ΔFVC) between 1993 and 2013. Multiple linear regression was used to estimate associations between risk factors and LFD, separately for males and females. Multiple logistic regression was used to assess sex differences and changes in respiratory symptoms over time.
In Melbourne, 318 subjects (53.8% females) participated. The prevalence of most respiratory symptoms had either remained relatively stable over 20 years or decreased (significantly so for wheeze). The exception was shortness of breath after activity, which had increased. Among the 262 subjects who completed spirometry, current smoking declined from 20.2% to 7.3%. Overall mean (± standard deviation) FEV1 declined by 23.1 (±17.1) and FVC by 22.9 (±20.2) mL/year. Predictors of ΔFEV1 in males were age, maternal smoking, and baseline FEV1; and in females they were age, ΔBMI, baseline FEV1, and pack-years in current smokers. Decline in FVC was predicted by baseline FVC, age, and ΔBMI in both sexes; however, baseline FVC predicted steeper decline in females than males.
Most respiratory symptoms remained stable or decreased over time in both sexes. Age, baseline lung function, and change in BMI were associated with the rate of decline in both sexes. However, obesity and personal smoking appear to put females at higher risk of LFD than males. Health promotion campaigns should particularly target females to prevent COPD.
cohort study; lung function; body mass index; tobacco smoking; COPD; respiratory symptoms
The effect of exercise on ventilation heterogeneity has not been investigated. We hypothesized that a maximal exercise bout would increase ventilation heterogeneity. We also hypothesized that increased ventilation heterogeneity would be associated with exercise‐induced arterial hypoxemia (EIAH). Healthy trained adult males were prospectively assessed for ventilation heterogeneity using lung clearance index (LCI), Scond, and Sacin at baseline, postexercise and at recovery, using the multiple breath nitrogen washout technique. The maximal exercise bout consisted of a maximal, incremental cardiopulmonary exercise test at 25 watt increments. Eighteen subjects were recruited with mean ± SD age of 35 ± 9 years. There were no significant changes in LCI, Scond, or Sacin following exercise or at recovery. While there was an overall reduction in SpO2 with exercise (99.3 ± 1 to 93.7 ± 3%, P < 0.0001), the reduction in SpO2 was not associated with changes in LCI, Scond or Sacin. Ventilation heterogeneity is not increased following a maximal exercise bout in healthy trained adults. Furthermore, EIAH is not associated with changes in ventilation heterogeneity in healthy trained adults.
Cardiopulmonary exercise test; hypoxemia; lung clearance index; multiple breath nitrogen washout; ventilation inhomogeneity
Early diagnosis of HIV infection in infants with perinatal HIV exposure is critical for clinical management decisions. Positive HIV nucleic acid detection represents the gold standard for the diagnosis of HIV infection status in infants prior to age 18 months, but this test is not universally available, especially in resource poor regions of the world. In this study we tested the hypothesis that the CD4/CD8 T cell ratio can predict HIV infection status in HIV-exposed infants.
CD4/CD8 T cell ratios were determined from data of live born, singleton infants who had been prospectively enrolled in the Women and Infants Transmission Study (WITS). Data from 2208 infants with known HIV infection status (179 HIV infected, 2029 uninfected) were analyzed.
Receiver Operating Characteristic (ROC) curves indicated that CD4/CD8 ratio performed better than CD4% for diagnosis of HIV infection as early as age 2 months (p=0.018), and this relationship was unaffected by adjusting for maternal race/ethnicity, infant birth weight, gestational age and gender. At age 4 mos., 90% specificity for HIV diagnosis was associated with 60% sensitivity. For ease of utilization, longitudinal LMS profile-based percentile curves were developed for sensitivity/specificity of CD4/CD8 ratios in HIV-infected and -uninfected infants until age 12 months. At age 6 months, a simplified equation that incorporated sequential CD4/CD8 ratios and hematocrit values resulted in improved ROCs with 94% positive predictive value (PPV) and 98% negative predictive value (NPV). The PPV and NPV remained above 90% in simulated infant populations over a wide range of prevalence of HIV infection.
In the absence of virologic diagnosis, a presumptive diagnosis of HIV- infection status may be made on the basis of CD4/CD8 ratios in HIV-1-exposed infants after age 2 months; sensitivity and specificity can be further improved at 6 months by using a discriminant analysis equation.
HIV diagnosis; perinatal HIV transmission; HIV exposed infants; CD4/CD8 ratio
The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data.
SUBJECTS AND METHODS
After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5–18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, 99mTc sulfur colloid liver-spleen scans, and 99mTc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings.
The mean (± SD) spleen volume (108 ± 47 mL) was significantly greater than published normal control values (30 ± 14 mL; p < 0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 ± 34 mL/min/1.73 m2) was elevated compared with control GFRs (92 ± 18 mL/min/1.73 m2). Renal volumes (right kidney, 29 ± 8 mL; left kidney, 31 ± 9 mL) were significantly greater than control volumes (right kidney, 27 ± 3 mL; left kidney, 27 ± 3 mL; p < 0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results.
In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent.
abdominal ultrasound; children; kidneys; sickle cell anemia; spleen
Rationale: Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease.
Objectives: To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment.
Methods: The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George’s Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age < 65 yr, n = 393).
Measurements and Main Results: Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P < 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22–0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34–0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24–0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25–0.60). The OR for reporting that their breathing problem stops them from doing most things or everything was 0.35 (95% CI, 0.22–0.55) in older adults versus younger adults.
Conclusions: Older adults with chronic lung disease were less likely to report significant impairment in their activities compared with younger adults, suggesting they may perceive less limitation.
chronic obstructive pulmonary disease; quality of life; interstitial lung diseases; aged; respiratory function tests
In the healthy lung, ventilation is distributed heterogeneously due to factors such as anatomical asymmetry and gravity. This ventilation heterogeneity increases pathologically in conditions such as asthma, chronic obstructive lung disease, and cystic fibrosis. In chronic heart failure, lung biopsy demonstrates evidence of peripheral lung fibrosis and small airways narrowing and distortion. We hypothesized that this would lead to increased ventilation heterogeneity. Furthermore, we proposed that rostral fluid shifts when seated patients lie supine would further increase ventilation heterogeneity. We recruited 30 ambulatory chronic heart failure patients (57 ± 10 years, 83% male, left ventricular ejection fraction 31 ± 12%) as well as 10 healthy controls (51 ± 13 years, 90% male). Heart failure patients were clinically euvolemic. Subjects underwent measurement of ventilation heterogeneity using the multiple-breath nitrogen washout technique in the seated position, followed by repeat measurements after 5 and 45 min in the supine position. Ventilation heterogeneity was calculated using the lung clearance index (LCI), Sacin and Scond which represent overall, acinar, and small conducting airway function, respectively. Lung clearance index (9.6 ± 1.2 vs. 8.6 ± 1.4 lung turnovers, P = 0.034) and Scond (0.029 ± 0.014 vs. 0.006 ± 0.016/L, P = 0.007) were higher in the heart failure patients. There was no difference in Sacin (0.197 ± 0.171 vs. 0.125 ± 0.081/L, P = 0.214). Measures of ventilation heterogeneity did not change in the supine position. This study confirms the presence of peripheral airway pathology in patients with chronic heart failure. This leads to subtle but detectable functional abnormalities which do not change after 45 min in the supine position.
heart failure; multiple-breath nitrogen washout; ventilation heterogeneity
Growth impairment is a known complication of sickle cell disease. Effects of hydroxyurea (HU) on growth in very young children are not known.
Height, weight, BMI, and head circumference (HC) were compared with World Health Organization (WHO) standards in BABY HUG, a multicenter, randomized, double-blinded, placebo-controlled 2-year clinical trial of HU in 193 children 9 to 18 months of age. Anthropometric data were closely monitored and converted to z scores by using WHO standardized algorithms for descriptive analyses. The treatment and placebo groups were compared longitudinally by using a mixed model analysis.
At entry, the z scores of BABY HUG children were higher than WHO norms. After 2 years of HU or placebo treatment, there were no significant differences between the groups, except for the mean HC z scores at study exit (HU: +0.8 versus placebo: +1.0, P = .05). Baseline z scores were the best predictors of z scores at study exit. The absolute neutrophil count, absolute reticulocyte count, and total white blood cell count had significant negative correlations with growth measures.
Both groups had normal or near normal anthropometric measures during the study. The HC z scores at study entry and exit were slightly greater than WHO norms. Higher baseline white blood cell count, absolute reticulocyte count, and absolute neutrophil count were associated with poorer growth. The significance of the slightly lower HC in the treatment group at study exit is not clear. Trends toward normalization of weight and height and effects on HC will be monitored in ongoing BABY HUG follow-up studies.
sickle cell disease; growth; hydroxyurea; children; height; weight; head circumference; BMI
To investigate the concordance of blood count indices measured locally and at a central laboratory.
Design and Methods
In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated.
Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p<0.0001), and mean corpuscular volume (MCV) was higher centrally.
Overnight shipping with processing delay causes spurious reductions in absolute neutrophil count (ANC) and absolute monocyte count (AMC) that may result in incorrect monitoring decisions in multicenter clinical trials.
Neutrophil; shipping; transportation; complete blood count; clinical trial
The importance of structure coefficients and analogs of regression weights for analysis within the general linear model (GLM) has been well-documented. The purpose of this study was to investigate bias in squared structure coefficients in the context of multiple regression and to determine if a formula that had been shown to correct for bias in squared Pearson correlation coefficients and coefficients of determination could be used to correct for bias in squared regression structure coefficients. Using data from a Monte Carlo simulation, this study found that squared regression structure coefficients corrected with Pratt's formula produced less biased estimates and might be more accurate and stable estimates of population squared regression structure coefficients than estimates with no such corrections. While our findings are in line with prior literature that identified multicollinearity as a predictor of bias in squared regression structure coefficients but not coefficients of determination, the findings from this study are unique in that the level of predictive power, number of predictors, and sample size were also observed to contribute bias in squared regression structure coefficients.
structure coefficients; beta weights; multiple linear regression; general linear model
In resource-poor regions of the world, HIV virologic testing is not available.
We sought to evaluate the diagnostic usefulness of the CD4/CD8 T-cell ratio in predicting HIV infection in infants.
Data from the 3- and 9-month visits for non–breastfed infants born to HIV-infected mothers enrolled (1990–1994) in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (mother-to-child transmission of HIV, 17%) were analyzed. Data from the 3-month visit for infants enrolled (1985–1996) in the Perinatal AIDS Collaborative Transmission Study (mother-to-child transmission of HIV, 18%) were used for validation.
At 3 months of age, data were available on 79 HIV-infected and 409 uninfected non–breast-fed infants in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study. The area under the curve (AUC) of the receiver operating characteristic curve at 3 months was higher for the CD4/CD8 ratio compared with the CD4+ T-cell count (AUC, 0.83 and 0.75; P = .03). The mean CD4/CD8 ratio at the 3-month visit was 1.7 for HIV-infected infants and 3.0 for uninfected infants. A CD4/CD8 ratio of 2.4 at 3 months of age was almost 2.5 times more likely to occur in an HIV-infected infant compared with an uninfected infant (test sensitivity, 81%; posttest probability of HIV, 33%). Model performance in the Centers for Disease Control and Prevention Perinatal AIDS Collaborative Transmission Study validation test (224 HIV-infected and 1015 uninfected 3-month-old infants) was equally good (AUC, 0.78 for CD4/CD8 ratio).
The CD4/CD8 T-cell ratio is a more sensitive predictor of HIV infection in infants than the CD4+ T-cell count.
The CD4/CD8 T-cell ratio can be used with caution to predict HIV infection in children.
CD4/CD8 T-cell ratio; mother-to-child transmission of HIV; HIV infection
Prior studies comparing abnormalities in pulmonary function between HIV-infected and HIV-uninfected persons in the current era are limited.
To determine the pattern and severity of impairment in pulmonary function in HIV-infected compared to HIV-uninfected individuals.
Cross-sectional analysis of 300 HIV-infected and 289 HIV-uninfected men enrolled from 2009-2011 in two clinical centers of the Lung HIV Study. Participants completed pre- and post-bronchodilator spirometry, diffusing capacity (DLCO) measurement, and standardized questionnaires.
Most participants had normal airflow; 18% of HIV-infected and 16% of HIV-uninfected men had airflow obstruction. The mean percent predicted DLCO was 69% in HIV-infected vs. 76% in HIV-uninfected men (p<0.001). A moderately to severely reduced DLCO of ≤60% was observed in 30% of HIV-infected compared to 18% of HIV-uninfected men (p<0.001), despite the fact that 89% of those with HIV were on antiretroviral therapy. A reduced DLCO was significantly associated with HIV and CD4 cell count in linear regression adjusting for smoking and other confounders. The DLCO was lowest in HIV-infected men with CD4 cell counts <200 compared to those with CD4 cell counts ≥200 and to HIV-uninfected men. Respiratory symptoms of cough, phlegm and dyspnea were more prevalent in HIV-infected patients particularly those with abnormal pulmonary function compared to HIV-uninfected patients.
HIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.
Pulmonary function; FEV1; DLCO; gas exchange; COPD; HIV/AIDS
BACKGROUND AND OBJECTIVE:
In the BABY HUG trial, young children with sickle cell anemia randomized to receive hydroxyurea had fewer episodes of pain, hospitalization, and transfusions. With anticipated broader use of hydroxyurea in this population, we sought to estimate medical costs of care in treated versus untreated children.
The BABY HUG database was used to compare inpatient events in subjects receiving hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 MarketScan Multi-state Medicaid Database for children with sickle cell disease, aged 1 to 3 years. Inpatient costs were based on length of hospital stay, modified by the occurrence of acute chest syndrome, splenic sequestration, or transfusion. Outpatient expenses were based on the schedule required for BABY HUG and a “standard” schedule for 1- to 3-year-olds with sickle cell anemia.
There were 232 hospitalizations in the subjects receiving hydroxyurea and 324 in those on placebo; length of hospital stay was similar in the 2 groups. Estimated outpatient expenses were greater in those receiving hydroxyurea, but these were overshadowed by inpatient costs. The total estimated annual cost for those on hydroxyurea ($11 072) was 21% less than the cost of those on placebo ($13 962; P = .038).
Savings on inpatient care resulted in a significantly lower overall estimated medical care cost for young children with sickle cell anemia who were receiving hydroxyurea compared with those receiving placebo. Because cost savings are likely to increase with age, these data provide additional support for broad use of hydroxyurea treatment in this population.
hydroxyurea; medical costs; young children; sickle cell anemia
Spirometry is regarded as the primary tool for the evaluation of lung function in lung transplant (LTx) recipients. Spirometry is crucial in detecting the various phenotypes of chronic lung allograft dysfunction (CLAD), including restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS) – note that these phenotypes potentially have different etiologies and therapies. Following LTx for idiopathic pulmonary fibrosis, a 60-year-old male recipient’s lung function began to gradually improve, peaking at 5 months post-LTx. Subsequently, with increasing impairment of graft function, the diagnosis of BOS was made. A second LTx was performed and lung function subsequently began to increase again. Unfortunately, another year on, lung function deteriorated again – this time due to the development of RAS, antibody-mediated rejection was implicated as the possible underlying cause. This case report highlights the importance of spirometry in assessing the patterns of CLAD following LTx.
Lung function; lung transplant; rejection; spirometry
In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.
CMC; ICH; IVIVC; PAT; QbD
Respondents generally rated their experiences with consultants as positive. However, participants’ responses varied in terms of how much they felt that the consultants were helping their organizations to cut costs and increase revenue.
Our team surveyed a group of pharmacy directors to learn about their experiences with pharmacy consultants so that the directors might be able to use their consulting resources in a more effective manner.
In May 2012, the University HealthSystem Consortium (UHC) Pharmacy Council Financial Performance Committee developed an electronic survey that collectively measured the characteristics, goals, and methodology of historical pharmacy consultant engagements and level of satisfaction. After e-mailing the initial electronic survey, we conducted follow-up telephone interviews with respondents from July through November 2012. These interviews were designed to include questions about expected outcomes, recommendations for evaluation processes, timelines for implementing the recommendations, consultants’ expenses, and insights gained.
A total of 23 pharmacy directors responded to the initial electronic survey; their organizations had engaged at least one consultant within the previous 5 years. Data were collected for 28 consultant engagements. Subsequent telephone interviews were conducted with 20 of the 23 pharmacy directors (87%) who completed the initial electronic survey, accounting for 25 of the 28 consultant engagements (89%).
Cost reduction along with revenue enhancement was most often the focus of these engagements. These engagements were also mainly within the scope of an organization-wide effort initiated by the executive board or executive team. Consultant experiences varied greatly in terms of (1) the degree to which assistance was provided to the organization, (2) benchmarking methodologies and resources, and (3) timelines for implementing the consultants’ recommendations. In general, most respondents rated their consultant experience as positive and were able to provide “pearls of wisdom” or lessons learned.
Children with sickle cell anemia (SCA) often develop hyposthenuria and renal hyperfiltration at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. The Phase III randomized double-blinded Clinical Trial of Hydroxyurea in Infants with SCA (BABY HUG) tested the hypothesis that hydroxyurea can prevent kidney dysfunction by reducing hyperfiltration.
193 infants with SCA (mean age 13.8 months) received hydroxyurea 20 mg/kg/day or placebo for 24 months. 99mTc diethylenetriaminepentaacetic acid (DTPA) clearance, serum creatinine, serum cystatin C, urinalysis, serum and urine osmolality after parent-supervised fluid deprivation, and renal ultrasonography were obtained at baseline and at exit to measure treatment effects on renal function.
At exit children treated with hydroxyurea had significantly higher urine osmolality (mean 495 mOsm/kg H2O compared to 452 in the placebo group, p=0.007) and a larger percentage of subjects taking hydroxyurea achieved urine osmolality >500 mOsm/kg H2O. Moreover, children treated with hydroxyurea had smaller renal volumes (p=0.007). DTPA-derived glomerular filtration rate (GFR) was not significantly different between the two treatment groups, but was significantly higher than published norms. GFR estimated by the Chronic Kidney Disease in Children Schwartz formula was the best non-invasive method to estimate GFR in these children, as it was the closest to the DTPA-derived GFR.
Treatment with hydroxyurea for 24 months did not influence GFR in young children with SCA. However, hydroxyurea was associated with better urine concentrating ability and less renal enlargement, suggesting some benefit to renal function.
kidney function; glomerular filtration rate; urine osmolality; hydroxyurea
Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10–0.25 mm in diameter was assessed in COPD-explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed-effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography-based pulmonary arterial pressure (no PH, mild PH, and moderate-to-severe PH). Lobar perfusion and emphysema indices were determined from ventilation-perfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects (). Within the COPD group, %WT was greater in the upper lobes () and in the small muscular pulmonary arteries (). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling (). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD.
emphysema; pathology; pulmonary circulation; pulmonary hypertension; regional blood flow.
The laboratory and clinical benefits of hydroxyurea therapy for children with sickle cell anemia (SCA) are well recognized, but treatment in young patients is limited in part by concerns about long-term genotoxicity, and specifically possible carcinogenicity.
The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multi-center double-blinded placebo-controlled randomized clinical trial (NCT00006400) testing whether hydroxyurea could prevent chronic organ damage in very young patients with SCA. An important secondary objective was the measurement of acquired genotoxicity using 3 laboratory assays: chromosomal karyotype, illegitimate VDJ recombination events, and micronucleated reticulocyte formation.
Our data indicate that hydroxyurea treatment was not associated with any significant increases in genotoxicity compared to placebo treatment.
These data provide additional support to the safety profile of hydroxyurea for young patients with SCA, and suggest that genotoxicity in this patient population is low.
genotoxicity; hydroxyurea; mutagenicity; sickle cell anemia
Youth infected with HIV at birth often have sleep disturbances, neurocognitive deficits, and abnormal psychosocial function which are associated with and possibly resulted from elevated blood cytokine levels that may lead to a decreased quality of life. To identify molecular pathways that might be associated with these disorders, we evaluated 38 HIV-infected and 35 uninfected subjects over 18-months for intracellular cytokine levels, sleep patterns and duration of sleep, and neurodevelopmental abilities. HIV infection was significantly associated with alterations of intracellular pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12), sleep factors (total time asleep and daytime sleep patterns), and neurocognitive factors (parent and patient reported problems with socio-emotional, behavioral, and executive functions; working memory-mental fatigue; verbal memory; and sustained concentration and vigilance. By better defining the relationships between HIV infection, sleep disturbances, and poor psychosocial behavior and neurocognition, it may be possible to provide targeted pharmacologic and procedural interventions to improve these debilitating conditions.
pediatric HIV infection; intracellular cytokines; sleep behavior; neurodevelopment; neurocognition; path analysis
This study's purpose was to determine whether asthma medication use in HIV+ children is associated with HLA alleles. We reviewed HLA and medication data collected during the Women and Infants Transmission Study for 124 HIV+ children and their mothers. Analysis revealed that HLA-A68 (P=0.006) was independent and predictive for time to first asthma medication use. There was a preventive association of Cw6 (P=0.008) with AT. HAART was also associated with time to first asthma medication use (P=0.05). HLA alleles may modulate risk of developing a need for asthma medications and seem to function independently of the actions of HAART therapy.
To estimate whether HIV-infected pregnant women were at increased risk of hepatotoxicity when taking nevirapine (NVP) containing regimens compared to HIV-infected pregnant women taking antiretroviral therapy (ART) not containing NVP.
This analysis included HIV-infected pregnant women on ART from two multicenter, prospective cohorts: The Women and Infants Transmission Study (WITS) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1025. Multivariate Cox proportional hazards regression models were used to investigate the association between NVP use and hepatotoxicity. NVP use was dichotomized as use or no use and further categorized according to ART exposure history. We investigated two outcomes: any liver enzyme elevation (LEE) (grade 1-4) and severe LEE (grade 3-4).
A total of 1229 women with ART use during pregnancy were studied, 218 (17.7%) of whom received NVP. Among the women receiving NVP, 137 (62.8%) were NVP naïve. Twenty-nine women (13.3%) who received NVP developed any LEE and one (0.5%) developed severe LEE. Of the 1011 women on non-NVP regimens, 145 (14.3%) developed any LEE and 14 (1.4%) developed severe LEE. There were no maternal deaths. In univariate models, LEE was not significantly associated with CD4+ count > 250 cells/μL or NVP use. In adjusted multivariate models, no significant increased risk of LEE (any or severe) in women taking NVP was detected as compared to those taking other ART regardless of prior exposure history.
We did not observe an increased risk of hepatotoxicity among HIV-infected pregnant women on NVP versus other ART, including women who were ART naïve.
AIDS; antiretroviral therapy; hepatotoxicity; HIV; nevirapine; pregnancy; women
The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study.
HIV/AIDS; pulmonary infections; pulmonary complications; smoking
To investigate the possible effects of antiretroviral therapy (ART) in utero on cardiac development and function in HIV-negative children.
ART reduces vertical HIV transmission. Long-term cardiotoxicity after in utero exposure to ART is unknown in children but has occurred in young animals.
Using a prospective multi-site cohort study design, we compared echocardiograms taken between birth and 24 months in two groups of HIV-negative infants of HIV-positive mothers: 136 infants exposed to ART (ART+) and 216 unexposed infants (ART−).
Mean LV mass Z-scores were consistently lower in ART+ girls than in ART− girls: differences in mean Z-scores were −0.46 at birth (P=0.005), −1.02 at 6 months (P<0.001), −0.74 at 12 months (P<0.001), and −0.79 at 24 months (P<0.001). Corresponding differences in Z-scores for boys were smaller: 0.13 at 1 month (P=0.42), −0.44 at 6 months (P=0.01), −0.15 at 12 months (P=0.37), and −0.21 at 24 months (P=0.21). Septal wall thickness and LV dimension were smaller than expected in ART+ infants, but LV contractility was consistently about 1 SD higher at all ages (P<0.001). In ART+ infants, LV fractional shortening was higher than in ART− infants; girls showed a greater difference.
Fetal exposure to ART is associated with reduced LV mass, LV dimension, and septal wall thickness Z-scores and increased LV fractional shortening and contractility up to age 2 years. These effects are more pronounced in girls than in boys. Fetal ART exposure may impair myocardial growth while improving depressed LV function.
Pediatric; HIV; Antiretroviral Therapy; Cardiomyopathy
Immunoreconstitution of HIV-infected (HIV+) patients after treatment with highly antiretroviral therapy (HAART) appears to provoke inflammatory diseases.
Determine whether HIV+ children on HAART (HIV+ HAART+) have a higher incidence of asthma than HIV+ children not on HAART (HIV+ HAART−).
To investigate this possibility, 2,664 children (193 HIV+, 2,471 HIV−) born to HIV+ women were evaluated for the incidence and prevalence of asthma (i.e., asthma medication use), and change of CD4+ T cell percentage with time.
The HIV+ HAART+ children had higher CD4+ T cell percentages, lower CD8+ T cell percentages, and lower viral burdens than the HIV+ HAART− children (P≤0.05 to P≤0.01). The cumulative incidence of asthma medication use in HIV+ HAART+ children at 13.5 year rose to 33.5% vs. 11.5% in HIV+ HAART− children (hazard ratio=3.34, P=0.01) and was equal to that in the HIV− children. In children born prior to the HAART era, the prevalence of asthma medication use for HIV+ HAART+ children at 11 years of age was 10.4% vs. 3.8% for HIV+ HAART− children (odds ratio=3.38, P=0.02) and was equal to that of the HIV− children. The rate of change of CD4+ T cells (percent/year) around the time of first asthma medication for HIV+ HAART+ vs. HIV+ HAART− children was 0.81 vs. −1.43 (P=0.01).
The increased incidence of asthma in HIV+ HAART+ children may be driven by immunoreconstitution of CD4+ T cells.
This HIV model of pediatric asthma may yield clues to help explain the epidemic of asthma in the general pediatric population.
pediatric HIV infection; CD4+ T cell mediated induction of asthma; HAART-produced immunoreconstitution