Lactoferrin for prevention of neonatal sepsis

Preterm neonates are at risk to acquire infections. In addition to the high mortality associated with sepsis, these patients are at risk for long-term disabilities, particularly neurodevelopment impairment. Several interventions have been evaluated to reduce rates of infections in neonates but have not proven efficacy. Lactoferrin (LF), a milk glycoprotein with anti-inflammatory, immunomodulatory and anti-microbial properties, has the potential to prevent infections in young children. We performed a review of current and ongoing clinical trials of LF for prevention of neonatal sepsis, and found eleven registered clinical trials that include more than 6,000 subjects. Few of these trials have finished; despite their small sample size, the preliminary results show a trend towards a positive protective effect of LF on neonatal infections. Larger trials are underway to confirm the findings of these initial studies. This information will help to define LF’s role in clinical settings and, if proven effective, would profoundly affect the treatment of low birth weight neonates as a cost-effective intervention worldwide.     

Effect of lactoferrin on enteric pathogens

Much has been learned in recent years about the mechanisms by which breastfeeding improves child health and survival. However, there has been little progress in using these insights to improve pediatric care. Factors that are important for protecting the breast fed infant might be expected to decrease the adverse effects of weaning on diarrhea, growth, and development. Lactoferrin, an iron-binding protein with multiple physiological functions (anti-microbial, anti-inflammatory, and immunomodulatory), is one of the most important proteins present in mammalian milk. Protection against gastroenteritis is the most likely biologically relevant activity of lactoferrin. Multiple in vitro and animal studies have shown a protective effect of lactoferrin on infections with enteric microorganisms, including rotavirus, Giardia, Shigella, Salmonella and the diarrheagenic Escherichia coli. Lactoferrin has two major effects on enteric pathogens: it inhibits growth and it impairs function of surface expressed virulence factors thereby decreasing their ability to adhere or to invade mammalian cells. Thus, lactoferrin may protect infants from gastrointestinal infection by preventing the attachment by enteropathogens in the gut. Recently several clinical trials in children have started to address this issue. Whether lactoferrin can prevent a significant portion of diarrheal disease remains to be determined.     

The changing face of pediatric respiratory tract infections: how human metapneumovirus and human bocavirus fit into the overall etiology of respiratory tract infections in young children

Lower respiratory tract infections are one of the leading causes of morbidity and mortality in children worldwide. Recent technological advances in the field of molecular biology have allowed virologists to detect many previously undetected viral pathogens. Two of these, human metapneumovirus (hMPV) and human bocavirus (HBoV), are of particular clinical interest to pediatric health care providers. This review discusses the most common viral respiratory infections in children, explores the role of newly discovered respiratory pathogens, and describes techniques for the diagnosis of viral respiratory infections.     

Children in an ageing society

This paper explores the implications of demographic aging for children and pediatric practice in the Western society. It focuses on the social class differences in childbearing patterns, specific issues related to disability, and distribution of resources between age groups. Women in the Western world are now having children at an older age than at any time in the past 50 years. Voluntary childlessness or deliberate delay in childbearing is common among highly educated women. This changing pattern in childbearing may increase and polarize health and wealth inequalities. With advancements in neonatal and pediatric care which prolong life expectancy and survival of disabled children, it is projected that there will be an increasing number of very old parents caring for severely disabled offspring. Meanwhile, there are also many children who are carrying considerable burdens of caring for their disabled parents. The community burden of disability will continue to rise. The needs of the elderly population may drain resources from child health services. Despite this demographic pattern, care for the children is still important. Health care authorities must not become contented with the existing pediatric care services just because demographic changes require that the nation should invest more in care of the older population.     

Effective Linkages of Continuum of Care for Improving Neonatal,Perinatal, and Maternal Mortality: A Systematic Review and Meta-Analysis

Background

Continuum of care has the potential to improve maternal, newborn, and child health (MNCH) by ensuring care for mothers and children. Continuum of care in MNCH is widely accepted as comprising sequential time (from pre-pregnancy to motherhood and childhood) and space dimensions (from community-family care to clinical care). However, it is unclear which linkages of care could have a greater effect on MNCH outcomes. The objective of the present study is to assess the effectiveness of different continuum of care linkages for reducing neonatal, perinatal, and maternal mortality in low- and middle-income countries.

Methods

We searched for randomized and quasi-randomized controlled trials that addressed two or more linkages of continuum of care and attempted to increase mothers’ uptake of antenatal care, skilled birth attendance, and postnatal care. The outcome variables were neonatal, perinatal, and maternal mortality.

Results

Out of the 7,142 retrieved articles, we selected 19 as eligible for the final analysis. Of these studies, 13 used packages of intervention that linked antenatal care, skilled birth attendance, and postnatal care. One study each used packages that linked antenatal care and skilled birth attendance or skilled birth attendance and postnatal care. Four studies used an intervention package that linked antenatal care and postnatal care. Among the packages that linked antenatal care, skilled birth attendance, and postnatal care, a significant reduction was observed in combined neonatal, perinatal, and maternal mortality risks (RR 0.83; 95% CI 0.77 to 0.89, I² 79%). Furthermore, this linkage reduced combined neonatal, perinatal, and maternal mortality when integrating the continuum of care space dimension (RR 0.85; 95% CI 0.77 to 0.93, I² 81%).

Conclusions

Our review suggests that continuous uptake of antenatal care, skilled birth attendance, and postnatal care is necessary to improve MNCH outcomes in low- and middle-income countries. The review was conclusive for the reduction of neonatal and perinatal deaths. Although maternal deaths were not significantly reduced, composite measures of all mortality were. Thus, the evidence is sufficient to scale up this intervention package for the improvement of MNCH outcomes.     

The evidence base for interventions delivered to children in primary care: an overview of cochrane systematic reviews

Background

As a first step in developing a framework to evaluate and improve the quality of care of children in primary care there is a need to identify the evidence base underpinning interventions relevant to child health. Our objective was to identify all Cochrane systematic reviews relevant to the management of childhood conditions in primary care and to assess the extent to which Cochrane reviews reflect the burden of childhood illness presenting in primary care.

Methodology/Principal Findings

We used the Cochrane Child Health Field register of child-relevant systematic reviews to complete an overview of Cochrane reviews related to the management of children in primary care. We compared the proportion of systematic reviews with the proportion of consultations in Australia, US, Dutch and UK general practice in children. We identified 396 relevant systematic reviews; 358 included primary studies on children while 251 undertook a meta-analysis. Most reviews (n = 218, 55%) focused on chronic conditions and over half (n = 216, 57%) evaluated drug interventions. Since 2000, the percentage of pediatric primary care relevant reviews only increased by 2% (7% to 9%) compared to 18% (10% to 28%) in all child relevant reviews. Almost a quarter of reviews (n = 78, 23%) were published on asthma treatments which only account for 3–5% of consultations. Conversely, 15–23% of consultations are due to skin conditions yet they represent only 7% (n = 23) of reviews.

Conclusions/Significance

Although Cochrane systematic reviews focus on clinical trials and do not provide a comprehensive picture of the evidence base underpinning the management of children in primary care, the mismatch between the focus of the published research and the focus of clinical activity is striking. Clinical trials are an important component of the evidence base and the lack of trial evidence to demonstrate intervention effectiveness in substantial areas of primary care for children should be addressed.     

Reducing Neonatal Mortality in India: Critical Role of Access to Emergency Obstetric Care

Background

Neonatal mortality currently accounts for 41% of all global deaths among children below five years. Despite recording a 33% decline in neonatal deaths between 2000 and 2009, about 900,000 neonates died in India in 2009. The decline in neonatal mortality is slower than in the post-neonatal period, and neonatal mortality rates have increased as a proportion of under-five mortality rates. Neonatal mortality rates are higher among rural dwellers of India, who make up at least two-thirds of India''s population. Identifying the factors influencing neonatal mortality will significantly improve child survival outcomes in India.

Methods

Our analysis is based on household data from the nationally representative 2008 Indian District Level Household Survey (DLHS-3). We use probit regression techniques to analyse the links between neonatal mortality at the household level and households'' access to health facilities. The probability of the child dying in the first month of birth is our dependent variable.

Results

We found that 80% of neonatal deaths occurred within the first week of birth, and that the probability of neonatal mortality is significantly lower when the child''s village is closer to the district hospital (DH), suggesting the critical importance of specialist hospital care in the prevention of newborn deaths. Neonatal deaths were lower in regions where emergency obstetric care was available at the District Hospitals. We also found that parental schooling and household wealth status improved neonatal survival outcomes.

Conclusions

Addressing the main causes of neonatal deaths in India – preterm deliveries, asphyxia, and sepsis – requires adequacy of specialised workforce and facilities for delivery and neonatal intensive care and easy access by mothers and neonates. The slow decline in neonatal death rates reflects a limited attention to factors which contribute to neonatal deaths. The suboptimal quality and coverage of Emergency Obstetric Care facilities in India require urgent attention.     

Diagnostic Accuracy of NT-ProBNP for Heart Failure with Sepsis in Patients Younger than 18 Years

This clinical study investigated plasma NT-proBNP levels as a potential predictor of heart failure in pediatric patients with sepsis. Plasma NT-ProBNP levels of 211 pediatric patients with sepsis and 126 healthy children were measured. Patients were stratified as with heart failure (HF) or without heart failure (non-HF). Patients were graded as having sepsis, severe sepsis, or septic shock. The optimal cut-off values of plasma NT-ProBNP for heart failure were determined by analyzing the receiver operating characteristic (ROC). In the HF, non-HF and control groups, the median plasma NT-proBNP levels were 3640, 656, and 226 ng/L, respectively. For all patients with sepsis, the optimal diagnostic cut-off value was 1268 ng/L for differentiating heart failure. In the severe sepsis patients and septic shock patients, the optimal diagnostic cut-off values were 1368 ng/L and 1525 ng/L, respectively. This report is the first one to reveal that NT-proBNP may predict heart failure in children with sepsis. It provides an important clinical reference for the diagnosis of heart failure in pediatric patients with sepsis, and enables monitoring septic children for cardiac involvement.     

Angiopoietin-1, Angiopoietin-2 and Bicarbonate as Diagnostic Biomarkers in Children with Severe Sepsis

Severe pediatric sepsis continues to be associated with high mortality rates in children. Thus, an important area of biomedical research is to identify biomarkers that can classify sepsis severity and outcomes. The complex and heterogeneous nature of sepsis makes the prospect of the classification of sepsis severity using a single biomarker less likely. Instead, we employ machine learning techniques to validate the use of a multiple biomarkers scoring system to determine the severity of sepsis in critically ill children. The study was based on clinical data and plasma samples provided by a tertiary care center''s Pediatric Intensive Care Unit (PICU) from a group of 45 patients with varying sepsis severity at the time of admission. Canonical Correlation Analysis with the Forward Selection and Random Forests methods identified a particular set of biomarkers that included Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), and Bicarbonate (HCO) as having the strongest correlations with sepsis severity. The robustness and effectiveness of these biomarkers for classifying sepsis severity were validated by constructing a linear Support Vector Machine diagnostic classifier. We also show that the concentrations of Ang-1, Ang-2, and HCO enable predictions of the time dependence of sepsis severity in children.     

Bloodstream Infection among Children Presenting to a General Hospital Outpatient Clinic in Urban Nepal

Background

There are limited data on the etiology and characteristics of bloodstream infections in children presenting in hospital outpatient settings in South Asia. Previous studies in Nepal have highlighted the importance of murine typhus as a cause of febrile illness in adults and enteric fever as a leading bacterial cause of fever among children admitted to hospital.

Methods

We prospectively studied a total of 1084 febrile children aged between 2 months and 14 years presenting to a general hospital outpatient department in Kathmandu Valley, Nepal, over two study periods (summer and winter). Blood from all patients was tested by conventional culture and by real-time PCR for Rickettsia typhi.

Results

Putative etiological agents for fever were identified in 164 (15%) patients. Salmonella enterica serovar Typhi (S. Typhi) was identified in 107 (10%), S. enterica serovar Paratyphi A (S. Paratyphi) in 30 (3%), Streptococcus pneumoniae in 6 (0.6%), S. enterica serovar Typhimurium in 2 (0.2%), Haemophilus influenzae type b in 1 (0.1%), and Escherichia coli in 1 (0.1%) patient. S. Typhi was the most common organism isolated from blood during both summer and winter. Twenty-two (2%) patients were PCR positive for R. typhi. No significant demographic, clinical and laboratory features distinguished culture positive enteric fever and murine typhus.

Conclusions

Salmonella infections are the leading cause of bloodstream infection among pediatric outpatients with fever in Kathmandu Valley. Extension of immunization programs against invasive bacterial disease to include the agents of enteric fever and pneumococcus could improve the health of children in Nepal.     

Rare Fungal Infections in Children: An Updated Review of the Literature

An increasing trend of reports of rare fungal diseases has been observed to be mainly associated with the substantial increase of high-risk immunocompromised children, as well as with the selective pressure of antifungal drugs. On the other hand, recent reports have shown that several species of these rare fungi may also cause infections in immunocompetent children without obvious underlying conditions. The clinical spectrum of these infections, and most importantly their outcome, varies greatly, implying for a rather heterogenic group of pediatric infections. Various types of superficial and subcutaneous fungal infections, as well as systemic and disseminated life-threatening infections, have been reported. Prompt diagnosis and appropriate treatment of rare fungal diseases in children remains a great challenge. Several treatment options have been used, ranging from localized to combination treatment with extensive surgical excision and long-term antifungal therapy. We review contemporary data of rare fungal infections in pediatric patients focusing on epidemiology, mycology, management and outcome, published during the last three years.     

Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis

BackgroundNeonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR.Methods and findingsAll studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria.ConclusionsGram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are associated with significant rates of resistance to WHO-recommended first- and second-line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required.

Sophie Wen and co-workers report a meta-analysis on bacterial isolates and antimicrobial resistance in neonatal sepsis in low- and lower-middle-income countries.     

Chlamydia trachomatis infections in infants.

In recent years considerable progress has been made in understanding chlamydial infections. The spectrum of pediatric Chlamydia trachomatis infection includes neonatal inclusion conjunctivitis, infantile pneumonia, occasional respiratory or genital tract infections in older children and sexually transmitted diseases in adolescents. The role of maternal chlamydial infection in prematurity and in perinatal death is currently an area of active study. We outline the current knowledge of the biologic characteristics of C. trachomatis, the epidemiologic features of chlamydial infection, and the clinical aspects, diagnosis and treatment of neonatal chlamydial infections.     

Primary and Secondary Antifungal Prophylaxis in the Immunocompromised Child: Where do we Stand?

Invasive opportunistic fungal infections are important causes of morbidity and mortality in immunocompromised children undergoing chemotherapy or haematopoietic stem cell transplantation (HSCT). Primary and secondary chemoprophylaxis of invasive fungal infections targets high risk disease-related patients with acute myeloid leukaemia, high risk acute lymphoblastic leukaemias, recurrent leukaemias and those following allogeneic HSCT. The rationale for antifungal prophylaxis in high risk patients comes from two different aspects. On the one hand, is the difficulty of instant diagnosis and, on the other hand, the consequences of morbidity and mortality by invasive infectious diseases. Although we have limited pediatric data concerning antifungal prophylaxis, it has become part of infectious disease supportive care schemes in most of paediatric leukaemia and HSCT centres. This review has insights on the evidence concerning primary and secondary antifungal prophylaxis in immunocompromised children. Although our knowledge comes from large adult studies concerning antifungal agents, there is a great need for evidence of primary or secondary antifungal prophylaxis in large pediatric clinical trials in order to have a consensus in primary and secondary antifungal prophylaxis in immunocompromised children.     

Prevalence of Escherichia coli among samples collected from the genital tract in pregnant and nonpregnant women: relationship with virulence

Escherichia coli are enteric Gram-negative bacilli that can colonize the female genital tract and become implicated in different infections in pregnant women, including intra-amniotic infection, puerperal infections and neonatal infections. The virulence profiles of E. coli isolates from vaginal swabs from pregnant and nonpregnant women were compared. The hly-, cnf-, pap- and iroN-genes were found significantly more frequently in E. coli isolated from pregnant women in comparison with those isolated from nonpregnant women. Escherichia coli from pregnant women seem to be more virulent than from nonpregnant women developing severe infections, thereby increasing possible neonatal sepsis.     

COVID-19 and children: medical impact and collateral damage

Children mostly experience mild SARS-CoV-2 infections, but the extent of paediatric COVID-19 disease differs between geographical regions and the distinct pandemic waves. Not all infections in children are mild, some children even show a strong inflammatory reaction resulting in a multisystem inflammatory syndrome. The assessments of paediatric vaccination depend on the efficacy of protection conferred by vaccination, the risk of adverse reactions and whether children contribute to herd immunity against COVID-19. Children were also the target of consequential public health actions such as school closure which caused substantial harm to children (educational deficits, sociopsychological problems) and working parents. It is, therefore, important to understand the transmission dynamics of SARS-CoV-2 infections by children to assess the efficacy of school closures and paediatric vaccination. The societal restrictions to contain the COVID-19 pandemic had additional negative effects on children’s health, such as missed routine vaccinations, nutritional deprivation and lesser mother–child medical care in developing countries causing increased child mortality as a collateral damage. In this complex epidemiological context, it is important to have an evidence-based approach to public health approaches. The present review summaries pertinent published data on the role of children in the pandemic, whether they are drivers or followers of the infection chains and whether they are (after elderlies) major sufferers or mere bystanders of the COVID-19 pandemic.     

The epidemiology of acute intestinal infections of undetermined etiology in children

Materials obtained in the study of conditions for contacting acute enteric infections of uncertain etiology, based on the analysis of the age structure of patients, the structure of clinical diagnoses and the monthly dynamics of cases registered in one of the districts of Moscow for 3 years (1984-1986), are presented. An important role of the alimentary factor in the spread acute enteric infections of uncertain etiology among the population of different age groups and everyday contacts in the spread of such infections among young children has been shown. The authors put forward a suggestion concerning the formation of natural immunity to infective agents, serving as etiological factors in the development of enteric infections of uncertain etiology, in children of preschool age.     

The etiological structure of acute intestinal infections in children in the Republic of Tajikistan]

The Republic of Tajikistan belongs to the territories, traditionally hyperendemic with respect to acute enteric diseases (AED). The problem of AED still remains topical in recent years, especially among child population. The study of the etiological structure of AED in children has made it possible to establish that more than 70% of these diseases are of infectious nature. The leading role in the etiological structure of these diseases belongs to Shigella infections (32.4%), enterovirus diarrhea (12.1%) and Escherichia infections (8.9%). No significant differences in the character of the etiological structure of AED in children of urban and rural areas have been detected with the exception of enterovirus diarrhea, found to occur 2.7 times more frequently on children of urban areas (15.9%) than in those of rural areas (5.8%). The ascertaining of the etiological structure of AED in Tajikistan will make it possible to essentially increase epidemiological surveillance on AED and render it more concrete.     

The Recognition of and Care Seeking Behaviour for Childhood Illness in Developing Countries: A Systematic Review

Background

Pneumonia, diarrhoea, and malaria are among the leading causes of death in children. These deaths are largely preventable if appropriate care is sought early. This review aimed to determine the percentage of caregivers in low- and middle-income countries (LMICs) with a child less than 5 years who were able to recognise illness in their child and subsequently sought care from different types of healthcare providers.

Methods and Findings

We conducted a systematic literature review of studies that reported recognition of, and/or care seeking for episodes of diarrhoea, pneumonia or malaria in LMICs. The review is registered with PROSPERO (registration number: CRD42011001654). Ninety-one studies met the inclusion criteria. Eighteen studies reported data on caregiver recognition of disease and seventy-seven studies on care seeking. The median sensitivity of recognition of diarrhoea, malaria and pneumonia was low (36.0%, 37.4%, and 45.8%, respectively). A median of 73.0% of caregivers sought care outside the home. Care seeking from community health workers (median: 5.4% for diarrhoea, 4.2% for pneumonia, and 1.3% for malaria) and the use of oral rehydration therapy (median: 34%) was low.

Conclusions

Given the importance of this topic to child survival programmes there are few published studies. Recognition of diarrhoea, malaria and pneumonia by caregivers is generally poor and represents a key factor to address in attempts to improve health care utilisation. In addition, considering that oral rehydration therapy has been widely recommended for over forty years, its use remains disappointingly low. Similarly, the reported levels of care seeking from community health workers in the included studies are low even though global action plans to address these illnesses promote community case management. Giving greater priority to research on care seeking could provide crucial evidence to inform child mortality programmes.     

Prevalence of Cryptosporidium-Associated Diarrhea in a High Altitude-Community of Saudi Arabia Detected by Conventional and Molecular Methods

Cryptosporidium diarrhea represents a relevant clinical problem in developing countries. In Al-Taif, a city of Saudi Arabia that lies at an altitude of an around 2 km above the sea level, Cryptosporidium infection seems to be undiagnosed in nearly all clinical laboratories. Furthermore, nothing was published regarding Cryptosporidium-associated diarrhea in this area. The objectives of this research were to (1) determine the Cryptosporidium prevalence among patients with diarrhea and (2) to estimate the performances of 3 different diagnostic methods. Total 180 diarrheal fecal samples, 1 sample per patient, were collected between January and August 2013. Samples were screened for Cryptosporidium with modified Zeihl Neelsen (ZN) microscopy, RIDA® Quick lateral flow (LF) immunotest, and a previously published PCR. The Cryptosporidium prevalence rate was 9.4% (17/180), 10% (18/180), and 11.6% (21/180) by microscopy, LF, and PCR test, respectively. Infection was significantly (P=0.004) predominant among children <5 years (22%) followed by children 5-9 years (11.1%). Although infection was higher in males than in females (16.2% males and 8.5% females), the difference was not statistically significant (P=0.11). Compared to PCR, the sensitivity of microscopy and the LF test were 80.9%, 85.7%, respectively. To conclude, high Cryptosporidium-associated diarrhea was found in this area especially in children ≤9 years. The PCR test showed the best performance followed by the LF test and ZN staining microscopy. The primary health care providers in Al-Taif need to be aware of and do testing for this protozoon, particularly for children seen with diarrhea.