Pierre M. Barker

Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism.

Genetic evidence supports a critical role for the epithelial sodium channel (ENaC) in both clearance of fetal lung liquid at birth and total body electrolyte homeostasis. Evidence from heterologous expression systems suggests that expression of the alphaENaC subunit is essential for channel function, whereas residual channel function can be measured in the absence of beta or gamma subunits. We generated mice without gammaENaC (gammaENaC -/-) to test the role of this subunit in neonatal lung liquid clearance and total body electrolyte balance. Relative to controls, gammaENaC (-/-) pups showed low urinary [K+] and high urinary [Na+] and died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l). Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3). This study suggests that gammaENaC facilitates neonatal lung liquid clearance and is critical for renal Na+ and K+ transport, and that low level Na+ transport may be sufficient for perinatal lung liquid absorption but insufficient to maintain electrolyte balance by the distal nephron. The gammaENaC (-/-) newborn exhibits a phenotype that resembles the clinical manifestations of human neonatal PHA1.

Decreased sodium ion absorption across nasal epithelium of very premature infants with respiratory distress syndrome

OBJECTIVE AND STUDY DESIGN Successful adaptation to air breathing at birth depends on rapid absorption of fetal lung liquid that is mediated by activation of amiloride-sensitive sodium ion channels. To test the relationship between respiratory epithelial Na+ transport and development of respiratory distress syndrome (RDS), we measured nasal transepithelial potential difference (PD) in 31 very premature (< or = 30 weeks of gestation) newborn infants. Infants were retrospectively assigned to RDS (22 infants) and non-RDS (9 infants) groups on the basis of clinical and chest x-ray criteria. RESULTS Maximal nasal epithelial PD increased with birth weight (-1.2 mV/100 gm) and was lower in infants with RDS (-16.5 +/- 0.6 mV) than in those without RDS (-22.0 +/- 1.3 mV). Infants without RDS had PD values similar to normal fullterm infants. Amiloride inhibition of PD, an index of Na+ absorption, was significantly lower, within the first 24 hours of life, in infants in whom RDS developed (3.8 +/- 0.2 mV; 29.5% +/- 0.8% inhibition) than in those without RDS (6.1 +/- 0.6 mV; 38.6% +/- 0.5% inhibition). Maximal and amiloride-sensitive PD returned to normal during the recovery phase of RDS. CONCLUSIONS We conclude that Na+ absorption across nasal epithelium increases with increasing birth weight and that impairment of Na+ absorption across the respiratory epithelia of very premature infants may contribute to the pathogenesis of RDS.

Challenges for Routine Health System Data Management in a Large Public Programme to Prevent Mother-to-Child HIV Transmission in South Africa

Background Recent changes to South Africas prevention of mother-to-child transmission of HIV (PMTCT) guidelines have raised hope that the national goal of reducing perinatal HIV transmission rates to less than 5% can be attained. While programmatic efforts to reach this target are underway, obtaining complete and accurate data from clinical sites to track progress presents a major challenge. We assessed the completeness and accuracy of routine PMTCT data submitted to the district health information system (DHIS) in three districts of Kwazulu-Natal province, South Africa. Methodology/Principal Findings We surveyed the completeness and accuracy of data reported for six key PMTCT data elements between January and December 2007 from all 316 clinics and hospitals in three districts. Through visits to randomly selected sites, we reconstructed reports for the same six PMTCT data elements from clinic registers and assessed accuracy of the monthly reports previously submitted to the DHIS. Data elements were reported only 50.3% of the time and were “accurate” (i.e. within 10% of reconstructed values) 12.8% of the time. The data element “Antenatal Clients Tested for HIV” was the most accurate data element (i.e. consistent with the reconstructed value) 19.8% of the time, while “HIV PCR testing of baby born to HIV positive mother” was the least accurate with only 5.3% of clinics meeting the definition of accuracy. Conclusions/Significance Data collected and reported in the public health system across three large, high HIV-prevalence Districts was neither complete nor accurate enough to track process performance or outcomes for PMTCT care. Systematic data evaluation can determine the magnitude of the data reporting failure and guide site-specific improvements in data management. Solutions are currently being developed and tested to improve data quality.

Antiretroviral drugs in the cupboard are not enough: the impact of health systems' performance on mother-to-child transmission of HIV.

Objective:To model the effect of health systems performance on rates of mother-to-child HIV transmission. Methods:We modeled the effect of variation in performance of the multiple steps of different prevention of mother-to-child transmission (PMTCT) protocols using hypothetical and reported data. Setting:Data from a PMTCT program in a large province in South Africa was used to compare model predictions with reported outcomes for mother-to-child HIV transmission. Main Outcome Measure:Perinatal HIV transmission was predicted for infants of 6 weeks of age. Results:HIV-infected pregnant women who fulfill eligibility criteria are initiated on lifelong antiretroviral treatment, whereas noneligible HIV-infected women and their infants receive single-dose nevirapine in a health system functioning at reported performance levels, and the overall vertical transmission rate would be 19.5%. Adding azidothymidine for women not eligible for lifelong treatment would further decrease the overall transmission rates only marginally to 17%. If the same steps were accomplished at 95% reliability, then the overall transmission rates would be 9.4% and 4.1%, respectively. Conclusions:Introduction of more effective combination antiretroviral interventions will yield only marginal reductions in childhood HIV infections and mortality unless health systems achieve high levels of performance at each step of the PMTCT pathway. Investment in and support for the mechanisms of delivering and sustaining PMTCT interventions at scale are required if gains in maternal and child survival are to be realized in countries highly affected by HIV.

Improving a mother to child HIV transmission programme through health system redesign: quality improvement, protocol adjustment and resource addition.

Background Health systems that deliver prevention of mother to child transmission (PMTCT) services in low and middle income countries continue to underperform, resulting in thousands of unnecessary HIV infections of newborns each year. We used a combination of approaches to health systems strengthening to reduce transmission of HIV from mother to infant in a multi-facility public health system in South Africa. Methodology/Principal Findings All primary care sites and specialized birthing centers in a resource constrained sub-district of Cape Metro District, South Africa, were enrolled in a quality improvement (QI) programme. All pregnant women receiving antenatal, intrapartum and postnatal infant care in the sub-district between January 2006 and March 2009 were included in the intervention that had a prototype-innovation phase and a rapid spread phase. System changes were introduced to help frontline healthcare workers to identify and improve performance gaps at each step of the PMTCT pathway. Improvement was facilitated and spread through the use of a Breakthrough Series Collaborative that accelerated learning and the spread of successful changes. Protocol changes and additional resources were introduced by provincial and municipal government. The proportion of HIV-exposed infants testing positive declined from 7.6% to 5%. Key intermediate PMTCT processes improved (antenatal AZT increased from 74% to 86%, PMTCT clients on HAART at the time of labour increased from 10% to 25%, intrapartum AZT increased from 43% to 84%, and postnatal HIV testing from 79% to 95%) compared to baseline. Conclusions/Significance System improvement methods, protocol changes and addition/reallocation of resources contributed to improved PMTCT processes and outcomes in a resource constrained setting. The intervention requires a clear design, leadership buy-in, building local capacity to use systems improvement methods, and a reliable data system. A systems improvement approach offers a much needed approach to rapidly improve under-performing PMTCT implementation programmes at scale in sub-Saharan Africa.

Improving public health information: a data quality intervention in KwaZulu-Natal, South Africa

OBJECTIVE To evaluate the effect of an intervention to improve the quality of data used to monitor the prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus in South Africa. METHODS The study involved 58 antenatal clinics and 20 delivery wards (37 urban, 21 rural and 20 semi-urban) in KwaZulu-Natal province that provided PMTCT services and reported data to the District Health Information System. The data improvement intervention, which was implemented between May 2008 and March 2009, involved training on data collection and feedback for health information personnel and programme managers, monthly data reviews and data audits at health-care facilities. Data on six data elements used to monitor PMTCT services and recorded in the information system were compared with source data from health facility registers before, during and after the intervention. Data completeness (i.e. their presence in the system) and accuracy (i.e. being within 10% of their true value) were evaluated. FINDINGS The level of data completeness increased from 26% before to 64% after the intervention. Similarly, the proportion of data in the information system considered accurate increased from 37% to 65% (P < 0.0001). Moreover, the correlation between data in the information system and those from facility registers rose from 0.54 to 0.92. CONCLUSION A simple, practical data improvement intervention significantly increased the completeness and accuracy of the data used to monitor PMTCT services in South Africa.

Azithromycin for cystic fibrosis

During what is a relatively barren time for new therapies for cystic fibrosis (CF), azithromycin has received a lot of attention as a potential treatment for CF lung disease. Laboratory studies suggest that azithromycin may have indirect actions, including anti-inflammatory, in addition to the standard antibacterial properties. The unique pharmacokinetics of azithromycin sets it aside from other macrolide antibiotics, but may result in increased resistance patterns. Three well-designed randomised controlled trials have demonstrated a small but significant improvement in respiratory function (forced expiratory volume in one second) with azithromycin compared with placebo. These trial results are confirmed by a recent meta-analysis. Mild adverse events (wheeze, diarrhoea and nausea) were significantly increased in one trial. There is no clear consensus regarding the correct dose and length of treatment with azithromycin. The present review discusses the role of azithromycin in the management of cystic fibrosis and the need for close monitoring of patients started on this drug. In addition, clinics should liaise closely with their microbiology departments and monitor resistance patterns.

Primary pulmonary lymphangiectasia in infancy and childhood

Primary pulmonary lymphangiectasia (PPL) is a rare disorder of unknown aetiology characterised by dilatation of the pulmonary lymphatics. PPL is widely reported to have a poor prognosis in the neonatal period and little is known about the clinical features of patients who survive the newborn period. The current authors report the outcome in nine patients diagnosed in infancy with PPL over a 15-yr period at a single university-based hospital clinic and followed for a median of 6 yrs. Although all of the patients initially experienced respiratory distress, respiratory symptoms improved in most patients after infancy and were notably better by the age of 6 yrs. Many patients had poor weight gain in the first years of life, which eventually improved. Radiological scans showed progressive resolution of neonatal infiltrates, but were characterised by hyperinflation and increased interstitial markings in older children. Most patients had evidence of bronchitis and grew pathogenic organisms from quantitative bronchoalveolar lavage culture. Pulmonary function tests showed predominantly obstructive disease that did not deteriorate over time. In conclusion, these results suggest that primary pulmonary lymphangiectasia does not have as dismal a prognosis as previously described and symptoms and clinical findings improve after the first year of life.

Strategies for the Scale-Up of Antiretroviral Therapy in South Africa through Health System Optimization

In the face of the massive burden created by human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases, developing nations must find ways to rapidly begin treatment for infected persons. Although infusions of personnel, supplies, and diagnostics would make a major contribution to expanding the capacity to treat these diseases, the lack of these resources creates a long-term challenge, and there is a need for additional approaches to spread effective interventions that can leverage existing resources and the much-needed infusions of new resources. This article describes one such approach-applied in several forms in South Africa-that aims to significantly increase the number of patients receiving antiretroviral therapy.

Pulmonary oedema fluid induces non‐α‐ENaC‐dependent Na+ transport and fluid absorption in the distal lung

To determine if pulmonary oedema fluid (EF) alters ion and fluid transport of distal lung epithelium (DLE), EF was collected from rats in acute heart failure. EF, but not plasma, increased amiloride‐insensitive short circuit current (Isc) and Na+‐K+ ATPase protein content and pump activity of DLE grown in primary culture. Inhibitors of Cl− transport or cGMP‐gated cation channels had a significant (P < 0.05), but limited ability to block the increased Isc. EF increased amiloride‐insensitive, but not amiloride‐sensitive, DLE apical membrane Na+ conductance. The level of mRNA encoding epithelial sodium channel (ENaC) subunits was unchanged (α, β), or decreased (γ, P < 0.05) in EF‐exposed DLE. EF also induced an amiloride‐insensitive increase in the potential difference across murine tracheal cysts. Distal lung explants from late gestation wild‐type and α‐ENaC‐deficient fetal mice, which normally expand due to liquid secretion, decreased in size due to liquid absorption when exposed to EF. Trypsin digestion or heat treatment of EF abrogated the ability of EF to increase amiloride‐insensitive Isc in DLE and liquid absorption by distal lung explants. Thus proteins or protein‐dependent factors within cardiogenic EF induce an α‐ENaC‐independent and amiloride‐insensitive apical membrane Na+ conductance and liquid absorption in the distal lung.