Burden and risk factors for relapse following successful treatment of uncomplicated severe acute malnutrition in young children: Secondary analysis from a randomised trial in Niger.

This study aimed to quantify the burden of relapse following successful treatment for uncomplicated severe acute malnutrition (SAM) and to identify associated risk factors in rural Niger. We used data from 1490 children aged 6-59 months discharged as recovered from an outpatient nutritional programme for SAM and followed for up to 12 weeks after admission. Postdischarge SAM relapse was defined as weight-for-height Z-score <-3, mid-upper arm circumference (MUAC) <115 mm or bipedal oedema after having been discharged as recovered. Postdischarge hospitalisation was defined as admission to inpatient SAM treatment or hospitalisation for any cause after having been discharged as recovered. We used multivariate log-binomial models to identify independent risk factors. After programmatic discharge, 114 (8%) children relapsed to SAM and 89 (6%) were hospitalised. Factors associated with SAM relapse were discharge during the lean season (relative risk [RR] = 1.80 [95% confidence interval [CI] = 1.22-2.67]) and larger household size (RR = 1.56 [95% CI = 1.01-2.41]), whereas older child age (RR = 0.94 [95% CI = 0.88-1.00]), higher child MUAC at discharge (RR = 0.93 [95% CI = 0.87-1.00]) and maternal literacy (RR = 0.54 [95% CI = 0.29-0.98]) were protective factors. Discharge during the lean season (RR = 2.27 [95% CI = 1.46-3.51]) was independently associated with postdischarge hospitalisation. Future nutritional programmes in the context of Niger may consider modification of anthropometric discharge criteria or the provision of additional home support or follow-up during the lean season as potential interventions to prevent relapse. More research including postdischarge follow-up is needed to better understand the sustainability of treatment outcomes after discharge and the type of intervention that may best sustain recovery over time. Clinical Trial Registration: ClinicalTrials.gov number, NCT01613547.

Risk of community- and hospital-acquired bacteremia and profile of antibiotic resistance in children hospitalized with severe acute malnutrition in Niger.

OBJECTIVE: To estimate the prevalence and antibiotic resistance profile of community- and hospital-acquired bacteremia among hospitalized children with severe acute malnutrition in Niger. METHODS: A descriptive, longitudinal study was conducted in an intensive nutritional rehabilitation center in Madarounfa, Niger. Children aged 6 to 59 months admitted for inpatient treatment of complicated severe acute malnutrition (n=2187) had blood specimens drawn at admission to assess prevalence of community-acquired bacteremia. Subsequent specimens were drawn per physician discretion to assess incidence of hospital-acquired bacteremia. Antibiotic susceptibility testing was performed on positive blood cultures. RESULTS: The prevalence of community-acquired bacteremia at admission was at least 9.1% (95% confidence interval [CI]: 8.1, 10.4%), with non-typhoid Salmonella identified in over half (57.8%) of cases. The cumulative incidence of hospital-acquired bacteremia was estimated at 1.2% (95% CI: 0.8, 1.7%), among which the most common organisms were Klebsiella pneumoniae (19.4%), Acinetobacter baumannii (16.1%), Enterococcus faecalis (12.9%), and Escherichia coli (12.9%). In community-acquired bacteremia, 58% cases were resistant to amoxicillin-clavulanate; 100% of hospital-acquired bacteremia cases were resistant to amoxicillin and amoxicillin-clavulanate. Mortality risk was elevated among children with hospital-acquired bacteremia (risk ratio [RR] = 9.32) and community-acquired bacteremia (RR = 2.67). CONCLUSION: Bacteremia was a significant contributor to mortality. Antibiotic resistance poses a challenge to effective clinical management of severe acute malnutrition.

Energy needs in the treatment of uncomplicated severe acute malnutrition: Secondary analysis to optimize delivery of ready-to-use therapeutic foods.

Outpatient therapeutic feeding protocols for the treatment of uncomplicated severe acute malnutrition in children were initially based on weight gain data from inpatient settings and expert knowledge of the physiological requirements during recovery. However, weight gain and energy requirements from historic inpatient settings may differ from modern outpatient settings and therefore may not be appropriate to guide current therapeutic feeding protocols. We calculated the weight gain and average estimated total daily energy requirement of children successfully treated for uncomplicated severe acute malnutrition as outpatients in Niger (n = 790). Mean energy provided by six therapeutic feeding protocols was calculated and compared with average estimated energy requirements in the study population. Overall weight gain was 5.5 g·kg-1 ·day-1 among recovered children. Average energy requirements ranged from 92 to 110 kcal·kg-1 ·day-1 depending on the estimation approach. Two current therapeutic feeding protocols were found to provide an excess of energy after the first week of treatment in our study population, whereas four research protocols tended to provide less energy than the estimated requirement after the first week of treatment. Alternative feeding protocols have the potential to simplify and lead to important savings for programmes but should be evaluated to show adequacy to meet the energy needs of children under treatment, as well as feasibility and cost efficiency. Our findings rely on theoretical calculations based on several assumptions and should be confirmed in field studies.

Feasibility of engaging caregivers in at-home surveillance of children with uncomplicated severe acute malnutrition.

Many factors can contribute to low coverage of treatment for severe acute malnutrition (SAM), and a limited number of health facilities and trained personnel can constrain the number of children that receive treatment. Alternative models of care that shift the responsibility for routine clinical and anthropometric surveillance from the health facility to the household could reduce the burden of care associated with frequent facility-based visits for both healthcare providers and caregivers. To assess the feasibility of shifting clinical surveillance to caregivers in the outpatient management of SAM, we conducted a pilot study to assess caregivers' understanding and retention of key concepts related to the surveillance of clinical danger signs and anthropometric measurement over a 28-day period. At the time of a child's admission to nutritional treatment, a study nurse provided a short training to groups of caregivers on two topics: (a) clinical danger signs in children with SAM that warrant facility-based care and (b) methods to measure and monitor their child's mid-upper arm circumference. Caregiver understanding was assessed using standardized questionnaires before training, immediately after training, and 28 days after training. Knowledge of most clinical danger signs (e.g., convulsions, edema, poor appetite, respiratory distress, and lethargy) was low (0-45%) before training but increased immediately after and was retained 28 days after training. Agreement between nurse-caregiver mid-upper arm circumference colour classifications was 77% (98/128) immediately after training and 80% after 28 days. These findings lend preliminary support to pursue further study of alternative models of care that allow for greater engagement of caregivers in the clinical and anthropometric surveillance of children with SAM.

MUAC as the sole discharge criterion from community-based management of severe acute malnutrition in Burkina Faso.

The use of mid upper arm circumference (MUAC) measurement to screen and determine eligibility for admission to therapeutic feeding programs has been established, but evidence and programmatic experience to inform guidance on the use of MUAC as a discharge criterion is limited. We present results from a large-scale nutritional program using MUAC for admission and discharge and compare program outcomes and response to treatment when determining eligibility for discharge by proportional weight gain versus discharge by MUAC. The study population included all children admitted to the Ministry of Health therapeutic feeding program supported by Médecins Sans Frontières in northern Burkina Faso from September 2007 to December 2011 (n = 50,841). Recovery was high overall using both discharge criteria, with low risks of death, nonresponse, and transfer to inpatient care and high daily gains in weight, MUAC, weight-for-height Z score, and height. When discharge was made by MUAC only, recovery increased, while all adverse program outcomes and length of stay decreased, with increasing MUAC on admission. MUAC-based programming, where MUAC is integrated into program screening, admission, and discharge, is one of several new approaches that can be used to target resources to the most at-risk malnourished children and improve program efficiency and coherency. This analysis provides additional programmatic experience on the use of MUAC-based discharge criterion, but more work may be needed to inform optimal discharge thresholds across settings.

Outpatient treatment of severe acute malnutrition: response to treatment with a reduced schedule of therapeutic food distribution.

Background: Community-based management of severe acute malnutrition (SAM) has been shown to be safe and cost-effective, but program coverage remains low. Treatment models that maintain high levels of clinical effectiveness but allow for increased coverage are still needed. A reduced schedule of follow-up, in which children receive clinical follow-up and therapeutic foods on a monthly rather than weekly basis, may be one alternative.Objective: We aimed to describe the safety and feasibility of a monthly distribution of ready-to-use therapeutic food (RUTF) in the treatment of uncomplicated SAM, in terms of clinical response to treatment and household RUTF use.Design: We conducted a nonrandomized pilot intervention study in which 115 children eligible for outpatient treatment of SAM were provided a monthly ration of RUTF. Anthropometric measurements were taken weekly for 4 wk to monitor treatment response. Unannounced household spot checks were conducted over 4 wk to assess household use of RUTF and storage practices.Results: Adequate weight and midupper arm circumference (MUAC) gain were found throughout the 4-wk follow-up period. Observed mean ± SD weight gain from admission was 9.8 ± 6.8 g · kg-1 · d-1 in week 1 and 4.2 ± 2.1 g · kg-1 · d-1 by week 4. Unplanned household spot checks found an average surplus of RUTF sachets compared with the number expected based on the date of distribution and recommended dosing throughout the 4 wk of follow-up. The frequency at which more than the recommended dose was used (i.e., deviance of >2 sachets between available and expected stocks) was 4% and 22% of households visited in week 1 and week 4, respectively.Conclusion: Adequate treatment response and RUTF use in the outpatient treatment of SAM was maintained over 4 wk of follow-up with a monthly schedule of RUTF distribution. This study was registered at clinicaltrials.gov as NCT02994212.

Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice.

The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.

Plasminogen activator inhibitor-1 impairs alveolar epithelial repair by binding to vitronectin.

The pathogenesis of pulmonary fibrosis is thought to involve alveolar epithelial injury that, when successfully repaired, can limit subsequent scarring. The plasminogen system participates in this process with the balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) being a critical determinant of the extent of collagen accumulation that follows lung injury. Because the plasminogen system is known to influence the rate of migration of epithelial cells, including keratinocytes and bronchial epithelial cells, we hypothesized that the balance of uPA and PAI-1 would affect the efficiency of alveolar epithelial cell (AEC) wound repair. Using an in vitro model of AEC wounding, we show that the efficiency of repair is adversely affected by a deficiency in uPA or by the exogenous administration of PAI-1. By using PAI-1 variants and AEC from mice transgenically deficient in vitronectin (Vn), we demonstrate that the PAI-1 effect requires its Vn-binding activity. Furthermore, we have found that cell motility is enhanced by the availability of Vn in the matrix and that the AEC-Vn interaction is mediated, in part, by the alpha(v)beta(1) integrin. The significant effect of uPA and PAI-1 on epithelial repair suggests a mechanism by which the plasminogen system may modulate pulmonary fibrosis.

Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1.

Mice with homozygous deletion of the plasminogen activator inhibitor-1 gene (PAI-1(-/-)) are relatively protected from bleomycin-induced pulmonary fibrosis. At least part of the protective effect appears to occur during the latter stages of the pathological process when fibrotic tissue is being deposited. To investigate the effect of PAI-1 deficiency on fibrosis, we studied the accumulation of fibrotic tissue within subcutaneously implanted polyvinyl alcohol sponges. Similar to the effect of PAI-1 deficiency on bleomycin-induced pulmonary fibrosis, the accumulation of fibrotic tissue within implanted sponges occurred more slowly in PAI-1(-/-) compared to wild-type mice. Another striking difference observed in the PAI-1(-/-) mice was the rapid removal of a fibrin-rich matrix that formed within the sponges by 1 day after implantation in both wild-type and PAI-1(-/-) mice. The pattern of connective tissue invasion also differed: cells in wild-type mice infiltrated as individually penetrating cells whereas in PAI-1(-/-) mice they did so as a well-demarcated advancing front. Providing an alternative provisional matrix by impregnating sponges with a low concentration of collagen before implantation corrected the changes induced by PAI-1 deficiency. In conclusion, PAI-1 deficiency appears to affect fibrotic tissue formation in part by altering the provisional matrix that forms soon after tissue injury.

Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.

Plasminogen activator inhibitor-1 (PAI-1)-deficient transgenic mice have improved survival and less fibrosis after intratracheal bleomycin instillation. We hypothesize that PAI-1 deficiency limits scarring through unopposed plasminogen activation. If this is indeed true, then we would expect increased urokinase-type plasminogen activator (uPA) expression to result in a similar reduction in scarring and improvement in mortality. To test our hypothesis, using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung-specific uPA production. After doxycycline administration, these transgenic animals expressed increased levels of uPA in their bronchoalveolar lavage (BAL) fluid that accelerated intrapulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality after bleomycin-induced injury. These results suggest that PAI-1 deficiency does protect against the effects of bleomycin-induced lung injury through unopposed plasmin generation. By allowing the manipulation of plasminogen activation at different phases of the fibrotic process, this model will serve as a powerful tool in further investigations into the pathogenesis of pulmonary fibrosis.