Daniela Manno

Human Cytomegalovirus Infant Infection Adversely Affects Growth and Development in Maternally HIV-Exposed and Unexposed Infants in Zambia

Maternally human immunodeficiency virus (HIV)-exposed but seronegative Zambian infants had reduced length and psychomotor development associated with human cytomegalovirus infection. Slower growth was also associated with human cytomegalovirus in HIV-unexposed infants. We conclude that human cytomegalovirus impacts negatively on child health in HIV-endemic regions of sub-Saharan Africa.

The knowledge system underpinning healthcare is not fit for purpose and must change

The medical literature is biased and inundated with poor quality trials. Ian Roberts and colleagues explain how these problems affect systematic reviews and how they might be overcome

Prediction models to identify hospitalized patients at risk of being colonized or infected with multidrug-resistant Acinetobacter baumannii calcoaceticus complex

BACKGROUND The multidrug-resistant (MDR) Acinetobacter baumannii calcoaceticus complex (Abc) has emerged as an important cause of nosocomial infections. The aims of the study were to evaluate risk factors for MDR-Abc in intensive care units (ICUs) as well as in medical and surgical wards, to define the likelihood ratios (LRs) of risk factors and to determine if risk factors differ depending on whether colonization or infections are considered. METHODS Two prospective matched case-control studies were performed. MDR-Abc was defined as a strain resistant to four or more classes of antibiotics. The two case groups included patients with MDR-Abc infections or colonization. Controls were selected among patients not harbouring Abc. Matching criteria were the number of days from admission to MDR-Abc isolation among cases and the duration of hospitalization among controls. RESULTS Overall, 514 patients were included in the study. One hundred and thirty-seven patients were infected and 120 colonized. A Charlson score >3 and previous methicillin-resistant Staphylococcus aureus isolation and beta-lactam use were independent risk factors for colonization and infection. Bedridden status and previous ICU admission were associated with colonization, while the presence of a central venous catheter and surgery were related to infection. The analysis of LRs showed an association between the presence of more than two risk factors and colonization or infection. The highest predicting value was observed for the presence of more than two risk factors and colonization in patients with no history of ICU admission. CONCLUSIONS This study provides novel information that can be used to identify interventions for different stages of the spread of MDR-Abc.

Reduced Poliovirus vaccine neutralising-antibody titres in infants with maternal HIV-exposure.

BACKGROUND Maternally HIV-exposed (mHIV-EU) infants have poor health even without HIV-1 infection. The responses to vaccination are less well defined. Immunity to oral Poliovirus vaccine (OPV) was studied in Zambian infants participating in a randomised controlled trial of micronutrient fortification to improve child health. METHOD Maternally HIV-unexposed and mHIV-EU infants were recruited at 6 months age and randomised to basal or enriched micronutrient-fortified diets for 12 months. HIV-exposed mother-infant pairs had received perinatal nevirapine to prevent mother-to-child-transmission. In the cohort of 597 infants, neutralising-antibody titres to OPV were analysed at 18 months with respect to micronutrient fortification, maternal or infant HIV-1 infection, and human cytomegalovirus (HCMV) infection detected by antibodies and viraemia (serum DNA). Vaccine protection was defined as log2 titre>3. RESULTS Compared to uninfected children, HIV-1-infected children had reduced neutralising antibody titres to OPV, irrespective of diet: log2 titre difference (95% confidence interval) -3.44 (-2.41; -4.46), P<0.01. OPV antibody titres were lower in HIV-infected children with HCMV viraemia compared to those without viraemia at 18 months, but did not reach significance: difference -2.55 (-6.10; 1.01), P=0.14. Breast-feeding duration was independently associated with increasing OPV titre (P-value<0.01). In mHIV-EU children there were reduced neutralising antibody titres to Poliovirus compared with maternally HIV-unexposed, irrespective of diet, maternal education and socioeconomic status: log2 titre difference (95% confidence interval) -0.56 (-0.98; -0.15), P<0.01. This difference was noticeably decreased after adjusting for breast-feeding duration, suggesting that in our study population less breast-feeding by HIV-positive mothers could explain the reduced OPV titres in mHIV-EU infants. CONCLUSION The mHIV-EU infants had reduced polio vaccine antibody titres which were associated with reduced breast-feeding duration. This has important implications for polio eradication and control of vaccine-preventable diseases, in countries where childhood HIV-1 infection and maternal exposure are public health threats.

How effective is tranexamic acid for acute gastrointestinal bleeding

Acute gastrointestinal bleeding is a common emergency. It encompasses upper gastrointestinal bleeding (such as from peptic ulcers and oesophageal varices)1 and lower gastrointestinal bleeding (commonly from diverticular disease, colitis, and cancer).2 The risk is greater in older adults, and many cases are associated with the use of non-steroidal anti-inflammatory drugs.3 In the UK acute gastrointestinal bleeding accounts for about 75 000 hospital admissions each year and has a case fatality of about 10%.3 4 Case fatality may be higher in patients already hospitalised for another condition.1 More effective treatments for acute gastrointestinal bleeding are needed. Tranexamic acid (TXA) reduces clot breakdown by inhibiting the action of plasmin, which is involved in fibrinolysis. A systematic review of randomised controlled trials in surgical patients shows that TXA, given before or during surgery, reduces the probability of receiving a blood transfusion by about a third (relative risk 0.62, 95% confidence interval 0.58 to 0.65).5 The effect of tranexamic acid on thromboembolic events such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism, however, was uncertain.5 The CRASH-2 trial showed that administration of TXA to bleeding trauma patients reduced death due to bleeding (relative risk 0.85, 0.76 to 0.96) and all cause mortality (relative risk 0.91, 0.85 to 0.97) with no apparent increase in thromboembolic events.6 Among patients treated soon after injury, the reduction in mortality with TXA was even greater.7 The knowledge that TXA reduces bleeding in surgery and reduces mortality in trauma …

The effects of micronutrient-fortified complementary/replacement food on intestinal permeability and systemic markers of inflammation among maternally HIV-exposed and unexposed Zambian infants

The present randomised trial investigated the effects of feeding Zambian infants from 6 to 18 months old either a richly or basal micronutrient-fortified complementary/replacement food on gut integrity and systemic inflammation. Blood samples were obtained from all infants (n 743) at 6 and 18 months for the assessment of serum C-reactive protein (CRP) and α1-acid glycoprotein (AGP). A subsample of 502 infants, selected from the main cohort to include a larger proportion of infants with HIV-positive mothers, was assigned to lactulose/mannitol gut permeability tests. Lactulose:mannitol (L:M) ratio analyses were adjusted for baseline urinary L:M ratio, socio-economic status, mothers education, season of birth and baseline stunting, and stratified by maternal antenatal HIV status, childs sex, concurrent breast-feeding status and anaemia at baseline. There was no significant difference in geometric mean L:M ratio between the richly fortified and basal-fortified porridge arms at 12 months (0·47 (95 % CI 0·41, 0·55) v. 0·41 (95 % CI 0·34, 0·49); P = 0·16 adjusted). At 18 months, the richly fortified porridge group had a significantly higher geometric mean L:M ratio than the basal-fortified group (0·23 (95 % CI 0·19, 0·28) v. 0·15 (95 % CI 0·12, 0·19); P = 0·02 adjusted). This effect was evident for all stratifications, significantly among boys (P = 0·04), among the infants of HIV-negative mothers (P = 0·01), among the infants of HIV-negative mothers not concurrently breast-fed (P = 0·01) and among those who were not anaemic at baseline (P = 0·03). CRP, but not AGP, was positively associated with L:M ratio, but there were no significant effects of the diet on either CRP or AGP. In conclusion, a richly fortified complementary/replacement food did not benefit and may have worsened intestinal permeability.

Effect of multiple micronutrient-fortified food on mild morbidity and clinical symptoms in Zambian infants: results from a randomised controlled trial

Background/Objectives:We aimed to assess the effects on mild morbidity of a richly micronutrient-fortified complementary/replacement food given to Zambian infants aged 6-18 months. Previous results (The Chilenje Infant Growth, Nutrition and Infection Study Team, 2010) showed an increase in the rate of hospital referral for pneumonia in the same cohort.Subject/Methods:A total of 743 six-month-old healthy Zambian infants were randomised to receive either a richly or a basal micronutrient-fortified porridge for 12 months. Mild morbidity was defined as an illness that did not cause death or require hospitalisation and was diagnosed on clinical examination at scheduled visits.Results:There was no evidence of an effect of trial arm on overall mild morbidity during the study (odds ratio (OR)=1.04, 95% confidence interval (CI)=0.90, 1.20, P=0.62). Infants in the richly fortified arm had significantly more visits in which they were diagnosed with lower respiratory tract infections/pneumonia (OR=1.65, 95% CI=1.06, 2.59, P=0.03) and fewer visits in which a diagnosis of urinary tract infection was made (OR=0.43, 95% CI=0.21, 0.87, P=0.02). Maternally reported symptoms were similar between trial arms.Conclusion:Compared with the basal diet, the richly micronutrient-fortified food was associated with more episodes of lower respiratory infections/pneumonia diagnosed at scheduled visits, which reinforces our previously reported findings of a higher incidence in hospital referral for pneumonia.

EBOVAC-Salone: Lessons learned from implementing an Ebola vaccine trial in an Ebola-affected country:

Background/aims During the 2014–2016 West African Ebola epidemic, clinical trials were fast-tracked in order to identify prophylactic vaccines and experimental treatments that might be useful in preventing or treating Ebola. These trials included the ongoing EBOVAC-Salone study, which was established and implemented in Sierra Leone to assess the safety and immunogenicity of the Ad26.ZEBOV/MVA-BN-Filo prime-boost Ebola vaccine regimen. Methods This article describes the experiences of the EBOVAC-Salone research team in setting up and implementing the trial, and provides recommendations for research teams aiming to conduct clinical trials in future outbreak situations. Results Establishing a clinical trial during an outbreak brought some unique challenges, including those related to trial design and the regulatory environment, operational issues, and community engagement. The situation was further complicated by the weak infrastructure and limited experience of clinical trials in Sierra Leone. However, operating in an outbreak context also brought some benefits to the research team, including strong stakeholder support. The EBOVAC-Salone study recruited participants both during and after the outbreak, leading to additional challenges to trial implementation during the post-outbreak transition. Conclusion Many lessons have been learned about setting up and implementing a clinical trial during a devastating Ebola epidemic, and some of the experiences of the EBOVAC-Salone team were mirrored by those of other researchers operating in the region. Common to several of these research groups is a recommendation that research should be more closely incorporated into outbreak response planning, which could expedite the establishment of timely and appropriate research projects. We recommend that the lessons learned by researchers during the West African Ebola epidemic are built into programmes and strategies to improve the responses to future epidemics, wherever they occur.

PTU-185 Update On The Halt-it Trial Progress: Tranexamic Acid For The Treatment Of Gastrointestinal Haemorrhage – An International, Randomised, Double Blind Placebo Controlled Trial

Introduction Gastrointestinal (GI) bleeding is a common medical emergency and an important cause of morbidity and mortality in high, middle and low income countries. Despite advances in resuscitative, pharmacological and endoscopic therapy, re-bleeding occurs in 10% of patients with non-variceal bleeding and up to 25% of those with variceal bleeding and is an important predictor of death. Excessive fibrinolysis may play an important role both in the failure to control initial bleeding and in the precipitation of re-bleeding through premature breakdown of blood clots at sites of vascular injury. This raises the possibility that an antifibrinolytic drug administered following GI bleeding could limit severity of bleeding and transfusion requirements. Methods HALT-IT has been designed as a large, pragmatic randomised controlled trial which aims to quantify the efficacy and safety of tranexamic acid (TXA) in adults with significant acute upper or lower gastrointestinal bleeding. The trial will determine the effect of early administration of TXA on mortality, morbidity, blood transfusion, surgical intervention and health status in patients with GI bleeding. The primary outcome is death in hospital within 28 days of randomisation. Secondary outcomes include re-bleeding, need for surgery or radiological intervention, blood product transfusion and thromboembolic events. Results UK recruitment began in August 2013. By January 2014, a total of 507 patients were randomised across 26 actively recruiting sites, averaging a recruitment rate of 20 patients per week. Centralised and statistical data monitoring ensures trial participants meet inclusion criteria and allows real time monitoring of event rates for the primary and secondary outcomes. The results will be presented by intention to treat and a pre-specified subgroup analysis will also determine the treatment effect in patients with liver cirrhosis and variceal bleeding. Conclusion HALT-IT aims to recruit 8000 participants in hospitals worldwide and recruitment is ahead of schedule based upon a strong performance in the UK. The success of the trial to date has been dependent upon multi-disciplinary and societal engagement as well as infrastructural support provided by NIHR research networks. The results will add to our expanding knowledge about the role of tranexamic acid as an agent for patients with significant bleeding. It is anticipated that the full trial results will be available in 2017. Disclosure of Interest None Declared.

Extending evidence for the use of tranexamic acid from traumatic haemorrhage to other patients with major bleeding: do we need more than one haemorrhage protocol? The case of gastrointestinal bleeding

Dear Sir, Haematologists, and specifically those with responsibility for transfusion including through the Hospital Transfusion Committee, have an important role to provide direction and guidance for the appropriate resuscitation of patients with major bleeding. Major bleeding is an emergency, and all hospitals should have local policies for managing patients with significant haemorrhage, which are referred to as massive haemorrhage protocols. We wish to highlight one important issue regarding the broader use of tranexamic acid (TXA) as part of a massive haemorrhage protocol: Should all types of bleeding patients be managed using the same policies typically developed initially for use in trauma? It is now well recognised that many different causes of bleeding other than due to trauma often present in the emergency department including gastrointestinal (GI). Acute upper GI bleeding remains a common reason for emergency hospital admission with an annual incidence of 50–150/100 000 adults (Rockall et al., 1995; Blatchford et al., 1997). TXA, given its good safety profile, ease of administration and low cost, is considered one of the components of most major haemorrhage protocols. Whilst there has been a marked increase in use of TXA for a variety of indications, we have reservations about a broader extrapolation to all groups of bleeding patients beyond use in trauma. This issue has been a significant topic of discussion during the running of the ‘HALT-IT’ (Haemorrhage ALleviation with Tranexamic acid – InTestinal system) trial, as described below. Following on from the results of CRASH2, all trauma patients with severe bleeding should be treated with TXA (The CRASH-2 Collaborators, 2010). Timing is critical, given the recognition that death directly from bleeding occurs within a few hours and that CRASH2 indicated that TXA is beneficial only when given within 3 h after injury (The CRASH-2 Collaborators, 2011); after 3 h, use of TXA was associated with a greater risk of death due to bleeding (The CRASH-2 Collaborators, 2011). Additionally, TXA was shown to be equally effective for every category of trauma severity (Perel et al., 2013). The CRASH2 population