Patricia L. Hibberd

A randomized, double-blind trial of lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease

&NA; Probiotics are widely used by patients with Crohns disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo‐controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6‐mercaptopurine, azathioprine, and low‐dose alternate day corticosteroids. Seventy‐five children (age range, 5‐21 yr) with CD in remission were randomized to either LGG (n = 39) or placebo (n = 36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P = 0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P = 0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

Respiratory risks from household air pollution in low and middle income countries

A third of the worlds population uses solid fuel derived from plant material (biomass) or coal for cooking, heating, or lighting. These fuels are smoky, often used in an open fire or simple stove with incomplete combustion, and result in a large amount of household air pollution when smoke is poorly vented. Air pollution is the biggest environmental cause of death worldwide, with household air pollution accounting for about 3·5-4 million deaths every year. Women and children living in severe poverty have the greatest exposures to household air pollution. In this Commission, we review evidence for the association between household air pollution and respiratory infections, respiratory tract cancers, and chronic lung diseases. Respiratory infections (comprising both upper and lower respiratory tract infections with viruses, bacteria, and mycobacteria) have all been associated with exposure to household air pollution. Respiratory tract cancers, including both nasopharyngeal cancer and lung cancer, are strongly associated with pollution from coal burning and further data are needed about other solid fuels. Chronic lung diseases, including chronic obstructive pulmonary disease and bronchiectasis in women, are associated with solid fuel use for cooking, and the damaging effects of exposure to household air pollution in early life on lung development are yet to be fully described. We also review appropriate ways to measure exposure to household air pollution, as well as study design issues and potential effective interventions to prevent these disease burdens. Measurement of household air pollution needs individual, rather than fixed in place, monitoring because exposure varies by age, gender, location, and household role. Women and children are particularly susceptible to the toxic effects of pollution and are exposed to the highest concentrations. Interventions should target these high-risk groups and be of sufficient quality to make the air clean. To make clean energy available to all people is the long-term goal, with an intermediate solution being to make available energy that is clean enough to have a health impact.

Preemptive Ganciclovir Therapy To Prevent Cytomegalovirus Disease in Cytomegalovirus Antibody-Positive Renal Transplant Recipients: A Randomized Controlled Trial

Cytomegalovirus is the most important infectious cause of complications and death in organ transplant recipients. The three major consequences of infection with this virus are cytomegalovirus disease; superinfection with opportunistic pathogens resulting from host defects caused by the virus; and allograft injury [1, 2]. The interaction of the following three factors determines whether cytomegalovirus disease develops in a transplant recipient infected with cytomegalovirus: 1) whether the donor and donor organ or the recipient, or both, harbor latent virus that can be reactivated after transplant [1]; 2) whether the transplant recipient can mount an immune response to the virus [both cellular and humoral]; and 3) the type of immunosuppressive therapy administered after transplant [4]. Transplant recipients in whom primary infection develops at the time of transplant (donor: cytomegalovirus antibody positive; recipient: cytomegalovirus antibody negative) or who test positive for cytomegalovirus antibody before transplantation and require antilymphocyte antibody therapy after transplantation have a greater than 50% attack rate of cytomegalovirus disease [4]. Each risk group accounts for 10% to 20% of all transplant recipients. Preventing cytomegalovirus disease in these two patient populations is a priority for transplant physicians. Cytomegalovirus disease has been prevented by prolonged administration (3 to 4 months) of antiviral therapies such as acyclovir [5], anticytomegalovirus hyperimmune globulin [6], or the combination of these two therapies [7]. These prophylactic strategies reduce the attack rate of cytomegalovirus disease, but this benefit is attenuated in patients who receive antilymphocyte antibody therapy [1]. Because the risk for developing cytomegalovirus disease depends on the type of immunosuppression administered after transplantation, we have proposed an alternative approach to preventing cytomegalovirus disease. This approach targets patients at greatest risk for cytomegalovirus disease for treatment with the most potent anticytomegalovirus therapy available. The antiviral therapy is administered when the risk is greatest (for example, during treatment with antilymphocyte antibodies). To distinguish this approach from preventive strategies used in all patients (nontargeted prophylaxis), we introduced the term preemptive therapy [8]. Preliminary studies suggested that ganciclovir administered as preemptive therapy to patients receiving antilymphocyte antibodies might reduce the attack rate of cytomegalovirus disease in transplant recipients who are positive for cytomegalovirus antibody. This multiinstitutional, randomized clinical trial was designed to assess the efficacy and safety of preemptive ganciclovir therapy in preventing cytomegalovirus disease in transplant recipients who are positive for cytomegalovirus antibody and who are receiving antilymphocyte antibodies. Methods Patients Consecutive renal transplant recipients who tested positive for cytomegalovirus antibody and who received a kidney from cytomegalovirus antibody-positive or antibody-negative donors at Albany Medical Center, Emory University Hospital, Massachusetts General Hospital, New England Medical Center, University of Chicago Medical Center, and Yale-New Haven Hospital were eligible for enrollment in the study. Patients were randomly assigned to receive either preemptive ganciclovir or no ganciclovir every day that antilymphocyte antibody therapy (muromonab-CD3 [OKT3], antithymocyte globulin, or antilymphocyte globulin) was administered. Separate randomization lists were used in each transplantation center; within each center, separate randomization lists were used for cadaveric and living, related donors. The investigators at each site knew which patients received the study drug and which patients received no anticytomegalovirus therapy. The cytomegalovirus antibody status of donors and recipients was determined using enzyme immunoassay on recipient serum obtained before transplantation and on donor serum obtained before transfusion. Patients were excluded from the study if they were younger than 20 years of age, were pregnant, had received another organ in addition to a kidney, had received any anticytomegalovirus therapy (defined as more than 1.2 g of acyclovir per day, unselected immune globulin, or cytomegalovirus hyperimmune globulin), or refused to give consent. The committees on human experimentation at each institution approved the study. All study participants were observed for the following outcomes during the 6 months after they received antilymphocyte antibodies: 1) cytomegalovirus disease; 2) other infectious diseases; 3) and noninfectious diagnoses. Allograft function 6 months after administration of antilymphocyte antibody was recorded as either present (for those not requiring dialysis) or absent (for those receiving dialysis). Serum creatinine levels were recorded for all patients with functioning allografts 6 months after antilymphocyte antibody therapy. Patients were evaluated for cytomegalovirus viremia and disease in three ways. First, the virology laboratory at each program tried to isolate cytomegalovirus from buffy-coat specimens at least every month using either centrifugation culture [9], conventional culture techniques [10], or both. Second, buffy-coat specimens were cultured for cytomegalovirus when any of the following signs, symptoms, or laboratory abnormalities were present: temperature greater than 38 C, leukocyte count less than 3.0 109 cells/L, dyspnea, abdominal pain, or gastrointestinal bleeding. Third, a biopsy specimen was obtained from any abnormal site, and all biopsy specimens were examined histologically for the presence of characteristic cytomegalovirus inclusion bodies and uptake of immunofluorescent-labeled anticytomegalovirus antibodies. Patients with other signs or symptoms suggesting infection (such as cough, headache, diarrhea, allograft discomfort, or dysuria) were evaluated using standard diagnostic protocols. At all study sites, the diagnostic protocol included at least a chest radiograph, leukocyte count, renal and liver function tests, two sets of blood cultures, urinalysis, urine culture, and cultures from other potential sites of infection. For patients who did not survive the 6-month observation period, data on the cause and date of death were collected. Definition of Cytomegalovirus Disease Cytomegalovirus disease was defined as either the cytomegalovirus syndrome or tissue-invasive disease developing within 6 months of antilymphocyte antibody therapy or within 1 month of discontinuing immunosuppression after allograft loss. The cytomegalovirus syndrome was diagnosed when both virologic and clinical criteria were met within a 7-day period. Virologic criteria were fulfilled when cytomegalovirus was isolated from a buffy-coat specimen or bronchoalveolar fluid. Clinical criteria were fulfilled when patients had a temperature higher than 38 C [without antipyretic agents] for 3 or more consecutive days and within 7 days of two or more of the following: 1) leukopenia [leukocyte count <3.0 109 cells/L on two consecutive measurements after stopping azathioprine therapy]; 2) hepatitis [serum alanine aminotransferase >1.5 times the upper limit of normal, without serologic evidence of active hepatitis B or hepatitis C virus]; 3) atypical lymphocytosis [more than 20% of leukocytes]; and 4) pneumonitis (an abnormal result on chest radiograph and no alternative explanation [including absence of Pneumocystis carinii in respiratory secretions]). These criteria were modified slightly from those used by other researchers [6] because isolation of cytomegalovirus from buffy-coat specimens or bronchoalveolar fluid predicts presence of cytomegalovirus disease, whereas isolation of cytomegalovirus from urine and saliva may not [11]. Tissue-invasive cytomegalovirus disease was diagnosed histopathologically by showing the presence of inclusion bodies characteristic of cytomegalovirus or by an immunochemical stain positive for cytomegalovirus antigens in a biopsy specimen from a lesion or an abnormal site (gastrointestinal tract, lung, or liver). The investigator at each study site made decisions about treating cytomegalovirus disease. Study Drug Administration The study drug was given daily (or according to the schedule in Table 1 only when the patient already had intravenous access for administration of antilymphocyte antibodies. The study medication was started within 24 hours of the first dose of each course of antilymphocyte antibodies. Patients receiving the study drug were given ganciclovir infusions based on daily serum creatinine concentrations (Table 1). Table 1. Ganciclovir Dosage Schedule according to Daily Serum Creatinine Concentration Leukocyte count, platelet count, and serum creatinine concentration were monitored daily during antilymphocyte antibody therapy in patients who received preemptive ganciclovir therapy and in controls. Sample Size and Statistical Analysis In the primary analysis, the proportion of patients with cytomegalovirus disease in the two study groups were compared. On the basis of our previous study [4], we assumed that cytomegalovirus disease would develop in 60% of controls. We wanted to enroll 48 patients who could be evaluated in each group (for a total of 96) to detect a decrease in the proportion of patients with cytomegalovirus disease from 60% (in controls) to 30% or less (in patients receiving preemptive ganciclovir therapy); that is, we predicted that preemptive ganciclovir treatment would yield a 50% lower attack rate (using a two-sided test, = 0.05 and power = 0.8). Initial analyses were done on an intention-to-treat basis and included all eligible patients. We defined the primary outcome and potential predictors of cytomegalovirus disease before beginning the study. At the end of therapy and follow-up, the study nurse purged all study si

Tai Chi is Effective in Treating Knee Osteoarthritis: A Randomized Controlled Trial

OBJECTIVE To evaluate the effectiveness of Tai Chi in the treatment of knee osteoarthritis (OA) symptoms. METHODS We conducted a prospective, single-blind, randomized controlled trial of 40 individuals with symptomatic tibiofemoral OA. Patients were randomly assigned to 60 minutes of Tai Chi (10 modified forms from classic Yang style) or attention control (wellness education and stretching) twice weekly for 12 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 12 weeks. Secondary outcomes included WOMAC function, patient and physician global assessments, timed chair stand, depression index, self-efficacy scale, and quality of life. We repeated these assessments at 24 and 48 weeks. Analyses were compared by intent-to-treat principles. RESULTS The 40 patients had a mean age of 65 years and a mean body mass index of 30.0 kg/m(2). Compared with the controls, patients assigned to Tai Chi exhibited significantly greater improvement in WOMAC pain (mean difference at 12 weeks -118.80 mm [95% confidence interval (95% CI) -183.66, -53.94; P = 0.0005]), WOMAC physical function (-324.60 mm [95% CI -513.98, -135.22; P = 0.001]), patient global visual analog scale (VAS; -2.15 cm [95% CI -3.82, -0.49; P = 0.01]), physician global VAS (-1.71 cm [95% CI -2.75, -0.66; P = 0.002]), chair stand time (-10.88 seconds [95% CI -15.91, -5.84; P = 0.00005]), Center for Epidemiologic Studies Depression Scale (-6.70 [95% CI -11.63, -1.77; P = 0.009]), self-efficacy score (0.71 [95% CI 0.03, 1.39; P = 0.04]), and Short Form 36 physical component summary (7.43 [95% CI 2.50, 12.36; P = 0.004]). No severe adverse events were observed. CONCLUSION Tai Chi reduces pain and improves physical function, self-efficacy, depression, and health-related quality of life for knee OA.

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for >3 days with viremia or unexplained fever for >3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4–17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P<0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.

The Spectrum and Burden of Ocular Injury

The authors conducted a hospital-based study to ascertain basic, descriptive epidemiologic information about ocular trauma in an urban setting. Over a 6-month period, 3184 patients presenting to our emergency ward with ocular trauma were studied. Severe injuries totaled 5.1% (ruptured globe, intraocular foreign body, hyphema, orbital/facial fracture) and 94.9% were superficial injuries and contusions. A disproportionate burden of severe ocular injury was borne by those less than 15 years of age. The work place accounted for 48% of all injuries and 50% of ruptured globes. Automobile repair-related tasks were specifically associated with injury. Sports injuries, although accounting for 3.4% of all injuries, were responsible for 60% of hyphemas and 10% of ruptured globes. Annual direct and indirect costs for these ocular injuries are estimated conservatively at

Predicting Bacteremia in Patients with Sepsis Syndrome

5 million and a loss of 60 work years. A large burden of preventable eye trauma is borne by both patients and society.

Disseminated Varicella Infection Due to the Vaccine Strain of Varicella-Zoster Virus, in a Patient with a Novel Deficiency in Natural Killer T Cells

The goal of this study was to develop and validate clinical prediction rules for bacteremia and subtypes of bacteremia in patients with sepsis syndrome. Thus, a prospective cohort study, including a stratified random sample of 1342 episodes of sepsis syndrome, was done in eight academic tertiary care hospitals. The derivation set included 881 episodes, and the validation set included 461. Main outcome measures were bacteremia caused by any organism, gram-negative rods, gram-positive cocci, and fungal bloodstream infection. The spread in probability between low- and high-risk groups in the derivation sets was from 14.5% to 60.6% for bacteremia of any type, from 9.8% to 32.8% for gram-positive bacteremia, from 5.3% to 41.9% for gram-negative bacteremia, and from 0.6% to 26.1% for fungemia. Because the model for gram-positive bacteremia performed poorly, a model predicting Staphylococcus aureus bacteremia was developed; it performed better, with a low- to high-risk spread of from 2.6% to 21.0%. The prediction models allow stratification of patients according to risk of bloodstream infections; their clinical utility remains to be demonstrated.

Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures

An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patients illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.

Gut microbial colonisation in premature neonates predicts neonatal sepsis

ABSTRACT Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. IMPORTANCE While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes. While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.