Samer S. El-Kamary

Adjuvanted Intranasal Norwalk Virus-Like Particle Vaccine Elicits Antibodies and Antibody-Secreting Cells That Express Homing Receptors for Mucosal and Peripheral Lymphoid Tissues

BACKGROUNDnNoroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide.nnnMETHODSnWe conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18-49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50- and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors.nnnRESULTSnThe most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8- and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50- or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues.nnnCONCLUSIONSnThe intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study.

Statistical Analysis and Application of Quasi Experiments to Antimicrobial Resistance Intervention Studies

Quasi-experimental study designs are frequently used to assess interventions that aim to limit the emergence of antimicrobial-resistant pathogens. However, previous studies using these designs have often used suboptimal statistical methods, which may result in researchers making spurious conclusions. Methods used to analyze quasi-experimental data include 2-group tests, regression analysis, and time-series analysis, and they all have specific assumptions, data requirements, strengths, and limitations. An example of a hospital-based intervention to reduce methicillin-resistant Staphylococcus aureus infection rates and reduce overall length of stay is used to explore these methods.

All-Cause, Liver-Related, and Non–Liver-Related Mortality Among HCV-Infected Individuals in the General US Population

BACKGROUNDnLiver-related mortality among those infected with hepatitis C virus (HCV) has been described, but little is known about non-liver-related mortality. Our objective was to determine HCV-associated all-cause, liver-, and non-liver-related mortality in the general US population.nnnMETHODSnA prospective cohort study of 9378 nationally representative adults aged 17-59 years was performed utilizing the Third National Health and Nutrition Examination Survey (NHANES III) Linked Mortality File that was made publicly available in 2010. HCV status was assessed from 1988 to 1994, with mortality follow-up of the same individuals through 2006.nnnRESULTSnThere were 614 deaths over a median follow-up of 14.8 years. After adjusting for all covariate risk factors, HCV chronic infection had a 2.37 times higher all-cause mortality rate ratio [MRR] (95% CI: 1.28-4.38; P = .008), a 26.46 times higher liver-related MRR (95% CI: 8.00-87.48; P < .001), and 1.79 times higher non-liver-related MRR (95% CI: .77-4.19; P = .18), compared with being HCV-negative. This represents an estimated 2.46 million US adults aged 17-59 years with chronic HCV infection who had an estimated 31,163 deaths from all causes per year, of which 57.8% (95% CI: 21.9%-77.2%) were attributable to HCV. Among those, there was an estimated 9569 liver-related deaths per year, of which 96.2% (95% CI: 87.5-98.9%) were attributable to HCV. Non-liver-related deaths were not significantly associated with HCV status.nnnCONCLUSIONSnChronic HCV all-cause mortality is more than twice that of HCV-negative individuals. This suggests that those with chronic HCV infection are at a higher risk of death even after accounting for liver-related morbidity and should be closely monitored.

Hepatitis C vaccine: supply and demand

Despite difficulties associated with extreme variability and mutability of hepatitis C virus (HCV), several vaccines that prevent initial infection or viral persistence, or that clear viraemia in individuals with chronic HCV infections, are currently in development. At least one vaccine that may prevent chronic persistent infections will soon be available for testing. We review the widespread importance of HCV infection and disease, the immune response to HCV and correlates of protection, prevention strategies and vaccine candidates, and groups that will need the vaccine and provide suitable populations for assessing vaccine safety and efficacy. The evaluation of prophylactic vaccines is particularly problematic since distribution must focus upon individuals at high risk of exposure-for example, intravenous drug users and health-care providers in areas with high HCV prevalence. Although there is a huge need for therapeutic vaccines, further immunological hurdles must be cleared before one becomes available.

Hepatitis C virus infection during pregnancy and the newborn period--are they opportunities for treatment?

Summary.u2002 The worldwide prevalence of hepatitis C virus (HCV) infection in pregnant women is estimated to be between 1 and 8% and in children between 0.05% and 5%. While parenteral transmission is still common in children living in developing countries, perinatal transmission is now the leading cause of HCV transmission in developed countries. The absence of an HCV vaccine or approved therapy during pregnancy means that prevention of vertical transmission is still not possible. However, a low vertical transmission rate of 3–5%, a high rate of spontaneous clearance (25–50%) and delayed morbidity have resulted in HCV being overlooked in pregnant women and their infants. Yet a study of the natural history in mothers and children demonstrates that the prognosis of HCV can vary greatly and should be taken seriously. Factors known to increase the risk of perinatal transmission include HIV coinfection and higher maternal viral loads, while elective C‐section and withholding breastfeeding have not been demonstrated to reduce vertical transmission. Current guidelines for the diagnosis of persistent perinatal infection require a positive anti‐HCV test in infants born to infected mothers after 12u2003months or two positive HCV RNA tests at least 6u2003months apart. Current HCV treatment options using pegylated interferon and ribavirin are both unsuitable for use in pregnancy and infancy. However, new agents currently in preclinical phases of development, along with the recently identified association between single‐nucleotide polymorphisms within the IL28 gene and treatment response, may serve to create a therapeutic window for these patients.

A Randomized Controlled Trial to Assess the Safety and Efficacy of Silymarin on Symptoms, Signs and Biomarkers of Acute Hepatitis

PURPOSEnMilk thistle or its purified extract, silymarin (Silybum marianum), is widely used in treating acute or chronic hepatitis. Although silymarin is hepatoprotective in animal experiments and some human hepatotoxic exposures, its efficacy in ameliorating the symptoms of acute clinical hepatitis remains inconclusive. In this study, our purpose was to determine whether silymarin improves symptoms, signs and laboratory test results in patients with acute clinical hepatitis, regardless of etiology.nnnMETHODSnThis is a randomized, placebo-controlled trial in which participants, treating physicians and data management staff were blinded to treatment group. The study was conducted at two fever hospitals in Tanta and Banha, Egypt where patients with symptoms compatible with acute clinical hepatitis and serum alanine aminotransferase (ALT) levels >2.5 times the upper limit of normal were enrolled. The intervention consisted of three times daily ingestion of either a standard recommended dose of 140 mg of silymarin (Legalon, MADAUS GmbH, Cologne, Germany), or a vitamin placebo for four weeks with an additional four-week follow-up. The primary outcomes were symptoms and signs of acute hepatitis and results of liver function tests on days 2, 4 and 7 and weeks 2, 4, and 8. Side-effects and adverse events were ascertained by self-report.nnnRESULTSnFrom July 2003 through October 2005, 105 eligible patients were enrolled after providing informed consent. No adverse events were noted and both silymarin and placebo were well tolerated. Patients randomized to the silymarin group had quicker resolution of symptoms related to biliary retention: dark urine (p=0.013), jaundice (p=0.02) and scleral icterus (p=0.043). There was a reduction in indirect bilirubin among those assigned to silymarin (p=0.012), but other variables including direct bilirubin, ALT and aspartate aminotransferase (AST) were not significantly reduced.nnnCONCLUSIONSnPatients receiving silymarin had earlier improvement in subjective and clinical markers of biliary excretion. Despite a modest sample size and multiple etiologies for acute clinical hepatitis, our results suggest that standard recommended doses of silymarin are safe and may be potentially effective in improving symptoms of acute clinical hepatitis despite lack of a detectable effect on biomarkers of the underlying hepatocellular inflammatory process.

Prospective cohort study of mother‐to‐infant infection and clearance of hepatitis C in rural Egyptian villages

Although persistent transmission of hepatitis C virus (HCV) from infected mothers to their infants is reported in 4–8%, transient HCV perinatal infection also occurs. This prospective cohort study determined perinatal HCV infection‐ and early and late clearance‐rates in 1,863 mother‐infant pairs in rural Egyptian villages. This study found 15.7% and 10.9% of pregnant women had HCV antibodies (anti‐HCV) and HCV‐RNA, respectively. Among 329 infants born of these mothers, 33 (10.0%) tested positive for both anti‐HCV and HCV‐RNA 2 months following birth—29 (12.5%) having HCV‐RNA positive mothers and 4 (with transient infections) having mothers with only anti‐HCV. Fifteen remained HCV‐RNA positive at one and/or 2 years (persistent infections), while 18 cleared both virus and antibody by 1 year (transient infections). Among the 15 persistent cases, 7 cleared their infections by 2 or 3 years. At 2‐ to 6‐ and at 10‐ to 12‐month maternally acquired anti‐HCV was observed in 80% and 5% of infants, respectively. Four perinatally infected and one transiently infected infant were confirmed to be infected by their mothers by the sequence similarity of their viruses. Viremia was 155‐fold greater in mothers of infants with persistent than mothers of infants with transient infections. Maternal‐infant transmission of HCV is more frequent than generally reported. However, both early and late clearance of infection frequently occurs and only 15 (4.6%) and 8 (2.4%) infants born of HCV‐RNA positive mothers had detectable HCV‐RNA at one and 2–3 years of age. Investigating how infants clear infection may provide important information about protective immunity to HCV. J. Med. Virol. 81:1024–1031, 2009.

Low-serum carotenoid concentrations and carotenoid interactions predict mortality in US adults: the Third National Health and Nutrition Examination Survey

Evidence regarding the health benefits of carotenoids is controversial. Effects of serum carotenoids and their interactions on mortality have not been examined in a representative sample of US adults. The objective was to examine whether serum carotenoid concentrations predict mortality among US adults. The study consisted of adults aged ≥20 years enrolled in the Third National Health and Nutrition Examination Survey, 1988 to 1994, with measured serum carotenoids and mortality follow-up through 2006 (N = 13,293). Outcomes were all-cause, cardiovascular disease, and cancer mortality. In adjusted Cox proportional hazards models, participants in the lowest total carotenoid quartile (<1.01 μmol/L) had significantly higher all-cause mortality (mortality rate ratio, 1.38; 95% confidence interval, 1.15-1.65; P = .005) than those in the highest total carotenoid quartile (>1.75 μmol/L). For α-carotene, the highest quartile (>0.11 μmol/L) had the lowest all-cause mortality rates (P < .001). For lycopene, the middle 2 quartiles (0.29-0.58 μmol/L) had the lowest all-cause mortality rates (P = .047). Analyses with continuous carotenoids confirmed associations of serum total carotenoids, α-carotene, and lycopene with all-cause mortality (P < .001). In a random survival forest analysis, very low lycopene was the carotenoid most strongly predictive of all-cause mortality, followed by very low total carotenoids. α-Carotene/β-cryptoxanthin, α-carotene/lutein+zeaxanthin and lycopene/lutein+zeaxanthin interactions were significantly related to all-cause mortality (P < .05). Low α-carotene was the only carotenoid associated with cardiovascular disease mortality (P = .002). No carotenoids were significantly associated with cancer mortality. Very low serum total carotenoid, α-carotene, and lycopene concentrations may be risk factors for mortality, but carotenoids show interaction effects on mortality. Interventions of balanced carotenoid combinations are needed for confirmation.

Incidence and risk factors for hepatitis C infection in a cohort of women in rural Egypt

A prospective cohort study of the incidence and risk factors for hepatitis C virus (HCV) infection was performed in 2171 pregnant women in three rural Egyptian villages who were HCV antibody (anti-HCV) and RNA (HCV-RNA) negative at baseline. During an average of 2.2 years follow up, 25 incident cases were observed, giving an estimated HCV incidence of 5.2/1000 person-years (PY). The infection rate correlated with community anti-HCV prevalence in pregnant women, while the perinatal incidence rate of 11.2/1000 PY was almost five times that of the non-perinatal rate (2.3/1000 PY). The data suggested iatrogenic perinatal risk factors were associated with infection in one village, while health education reduced infections in another. Among the 25 incident cases, eight were HCV-RNA negative when they were first found to be anti-HCV positive and one-third of the 15 viraemic cases with follow-up data available cleared their HCV-RNA after an average of 1.3 years. None of the 25 incident cases were jaundiced or had symptoms of hepatitis but elevated serum alanine aminotransferase levels confirmed hepatitis in nine. Our data suggest that asymptomatic HCV infections frequently occurred during the perinatal period but often cleared and that educating medical personnel on safe practices possibly reduced HCV transmission.

Prevalence of non-tuberculous mycobacterial infections among tuberculosis suspects in Nigeria.

Background Nigeria is ranked in the top five countries for tuberculosis deaths worldwide. This study investigated the mycobacterial agents associated with presumptive clinical pulmonary tuberculosis (TB) in Nigeria and evaluated the pattern and frequency of mycobacterial infections over twelve calendar months period. Methods Sputum samples from 1,603 consecutive new cases with presumptive diagnosis of TB were collected from August 2010 to July 2011. All sputum samples were incubated for detection of mycobacterial growth and those with positive acid fast bacilli (AFB) growth were tested to detect mycobacterium tuberculosis (MTB) complex and characterized to differentiate between MTB complex species. Cultures suggestive of Non-tuberculous mycobacterial infections (NTM) were sub-cultured and characterized. Results Of the 1,603 patients screened, 444 (28%) culture-positive cases of pulmonary tuberculosis were identified. Of these, 375 (85%) were due to strains of MTB complex (354 cases of M. tuberculosis, 20 M. africanum and one case of M. bovis) and 69 (15%) were due to infection with NTM. In contrast to the MTB complex cases, the NTM cases were more likely to have been diagnosed during the calendar months of the Harmattan dust season (ORu200a=u200a2.34, 1.28–4.29; pu200a=u200a0.01), and aged older than 35 years (ORu200a=u200a2.77, 1.52–5.02, pu200a=u200a0.0007), but less likely to have AFB identified on their sputum smear (ORu200a=u200a0.06, 0.02–0.14, p<0.0001). Among those with NTM infection, cases 35 years or younger were more likely to have co-infection with HIV (3.76, 1.72–8.22; pu200a=u200a0.0009) compared to those older than 35 years. Interpretation The high proportion of younger patients with clinical pulmonary TB due to NTM and co-infection with HIV and the likely role of the seasonal dust exposure in the occurrence of the disease, present novel public health challenges for prevention and treatment.