HIV, TB, inflammation and other correlates of serum phosphate: A cross-sectional study.

BACKGROUND: There is little information about serum phosphate levels among patients with pulmonary tuberculosis (TB) and HIV infection. OBJECTIVE: We aimed to assess the role of TB, HIV, inflammation and other correlates on serum phosphate levels. METHODS: A cross-sectional study was conducted among TB patients and age- and sex-matched non-TB controls. Pulmonary TB patients were categorized as sputum -negative and -positive, based on culture. Age- and sex-matched non-TB controls were randomly selected among neighbours to sputum-positive TB patients. Data on age, sex, alcohol and smoking habits were obtained. HIV status, serum phosphate, and the acute phase reactants C-reactive protein (serum CRP) and α1-acid glycoprotein (serum AGP) were determined. Linear regression analysis was used to identify correlates of serum phosphate. RESULTS: Of 1605 participants, 355 (22.1%) were controls and 1250 (77.9%) TB patients, of which 9.9% and 50.4% were HIV-infected. Serum phosphate was determined before start of TB treatment in 44%, and 1-14 days after start of treatment in 56%. Serum phosphate was up to 0.10 mmol/L higher 1-3 days after start of TB treatment, and lowest 4 days after treatment, after which it increased. In multivariable analysis, TB patients had 0.09 (95% CI: 0.05; 0.13) mmol/L higher serum phosphate than controls, and those with HIV had 0.05 (95% CI: 0.01; 0.08) mmol/L higher levels than those without. Smoking was also a positive correlate of serum phosphate, whereas male sex and age were negative correlates. CONCLUSION: While HIV and TB are associated with higher serum phosphate, our data suggest that TB treatment is followed by transient reductions in serum phosphate, which may reflect hypophosphataemia in some patients.

Trends and differences in tuberculosis incidences and clustering among natives in Denmark, Sweden and Finland: comparison of native incidences and molecular epidemiology among three low-incidence countries.

OBJECTIVES: To compare the epidemiology of tuberculosis (TB) in Denmark, Sweden and Finland, by focusing on the native population in order to identify epidemiologic differences and thus indirectly possible differences in TB control. METHODS: TB incidence trends from 1990 through 2015 were compared among the countries. In addition, for the periods 2012-2013 and 2014-2015, genotyping data were compared. Genotyping was performed using the 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) method in Denmark and Sweden. For Finland, spoligotyping in conjunction with the 15-locus MIRU-VNTR method was used for 2012-2013 and translated into the 24-locus MIRU-VNTR when feasible, and for 2014-2015 only MIRU-VNTR was used. Both incidence trends and molecular epidemiology were assessed for native cases. RESULTS: The average annual rate of change in TB incidence for native Danes was -2.4% vs. -6.1% and -6.9% for native Swedes and Finns respectively. In 2012-2013 Denmark had 52 native cases in the largest transmission chain vs. three cases in Sweden and ten in Finland, and during the same period the clustering rate for native Danes was 48.8% vs. 6.5% and 18.2% for native Swedes and Finns respectively. For 2014-2015, a similar pattern was seen. CONCLUSIONS: The decline of TB among natives in Denmark is slower than for Sweden and Finland, and it seems Denmark has more active transmission among natives. The focused assessment on basic native TB epidemiology reveals striking differences in TB transmission among otherwise similar low-TB-incidence countries.

Plasma volume reduction and hematological fluctuations in high-level athletes after an increased training load.

The time course of plasma volume (PV) reduction following an increased training load period is unknown and was investigated. The accompanying fluctuations in [Hb] and OFF-hr score were analyzed in the Athlete Biological Passport. Further, whether fluctuations in plasma albumin, soluble transferrin receptors (sTfR), and pro-atrial natriuretic peptide (proANP) concentrations correlate with PV fluctuations was investigated. Eleven high-level competitive cyclists were investigated for 3 weeks. After initial measurements in week 1, training load was increased ~250% in week 2 followed by a reversion to baseline training load in week 3. PV and hematological variables were determined frequently during all weeks. The higher training load in week 2 increased (P<.001) PV 10%, while [Hb] and OFF-hr score decreased ~6% (P<.01) and ~16% (P<.001), respectively. PV and [Hb] returned to baseline within 2 and 4 days after week 2, respectively, while OFF-hr score remained reduced for 6 days. Further, one and three atypical blood profiles of the ABP occurred during weeks 2 and 3, respectively. Individual changes in albumin, sTfR, and proANP only correlated weakly (R2 <.20) with PV fluctuations. In conclusion, PV and [Hb] fluctuations caused by an elevated training load period were reverted within 2 and 4 days after returning to baseline training load, respectively, while OFF-hr remained altered for 6 days. Furthermore, some atypical blood profiles were induced during and subsequent to the increased training load, demonstrating the importance of knowledge on naturally occurring hematological fluctuations. Finally, concentrations of albumin, sTfR, and proANP could not explain PV fluctuations.

Tracing Mycobacterium tuberculosis transmission by whole genome sequencing in a high incidence setting: a retrospective population-based study in East Greenland.

In East Greenland, a dramatic increase of tuberculosis (TB) incidence has been observed in recent years. Classical genotyping suggests a genetically similar Mycobacterium tuberculosis (Mtb) strain population as cause, however, precise transmission patterns are unclear. We performed whole genome sequencing (WGS) of Mtb isolates from 98% of culture-positive TB cases through 21 years (n = 182) which revealed four genomic clusters of the Euro-American lineage (mainly sub-lineage 4.8 (n = 134)). The time to the most recent common ancestor of lineage 4.8 strains was found to be 100 years. This sub-lineage further diversified in the 1970s, and massively expanded in the 1990s, a period of lowered TB awareness in Greenland. Despite the low genetic strain diversity, WGS data revealed several recent short-term transmission events in line with the increasing incidence in the region. Thus, the isolated setting and the uniformity of circulating Mtb strains indicated that the majority of East Greenlandic TB cases originated from one or few strains introduced within the last century. Thereby, the study shows the consequences of even short interruptions in TB control efforts in previously TB high incidence areas and demonstrates the potential role of WGS in detecting ongoing micro epidemics, thus guiding public health efforts in the future.

Effect of alterations in blood volume with bed rest on glucose tolerance.

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose are also reduced with bed rest, but the potential influence on glucose tolerance has not been investigated. Accordingly, the aim was to investigate whether bed rest-induced impairments in glucose tolerance are related to a concomitant reduction in plasma volume. This hypothesis was tested mechanistically by restoring plasma volume with albumin infusion after bed rest and parallel determination of glucose tolerance. Fifteen healthy volunteers (age 24 ± 3 yr, body mass index 23 ± 2 kg/m2, maximal oxygen uptake 44 ± 8 ml·min-1·kg-1; means ± SD) completed 4 days of strict bed rest. Glucose tolerance [oral glucose tolerance test (OGTT)] and plasma and blood volumes (carbon monoxide rebreathing) were assessed before and after 3 days of bed rest. On the fourth day of bed rest, plasma volume was restored by means of an albumin infusion prior to an OGTT. Plasma volume was reduced by 9.9 ± 3.0% on bed rest day 3 and area under the curve for OGTT was augmented by 55 ± 67%. However, no association (R2 = 0.09, P = 0.33) between these simultaneously occurring responses was found. While normalization of plasma volume by matched albumin administration (408 ± 104 ml) transiently decreased (P < 0.05) resting plasma glucose concentration (5.0 ± 0.4 to 4.8 ± 0.3 mmol/l), this did not restore glucose tolerance. Bed rest-induced alterations in dilution space may influence resting glucose values but do not affect area under the curve for OGTT.

Direct DNA Extraction from Mycobacterium tuberculosis Frozen Stocks as a Reculture-Independent Approach to Whole-Genome Sequencing.

Culturing before DNA extraction represents a major time-consuming step in whole-genome sequencing of slow-growing bacteria, such as Mycobacterium tuberculosis. We report a workflow to extract DNA from frozen isolates without reculturing. Prepared libraries and sequence data were comparable with results from recultured aliquots of the same stocks.

Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients.

OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS containing whey (LNS/w), an LNS containing soy (LNS/s) or no LNS. Trough plasma concentrations of efavirenz and nevirapine were measured at 1 and 2 months. Genotyping for 516 G>T and 983 T>C polymorphisms of the cytochrome P450 (CYP) 2B6 locus was performed. Multilevel linear mixed-effects models were used to assess the associations between LNS and plasma efavirenz and nevirapine concentrations. RESULTS: In patients with BMI > 17 kg/m(2), nevirapine concentrations were lower in the LNS/w and LNS/s groups by a median of -2.3 µg/mL [interquartile range (IQR) -3.9; -0.9 µg/mL; P = 0.002] and -2.1 µg/mL (IQR -3.9; -0.9 µg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 µg/mL higher plasma efavirenz concentration compared with the wild type (P < 0.0001), while it was not associated with plasma nevirapine concentrations. CONCLUSIONS: Intake of an LNS was associated with lower plasma nevirapine trough concentrations, indicating possible drug-LNS interactions. The clinical relevance of such reductions in nevirapine exposure is not clear. Plasma efavirenz concentration was not affected by the LNS.

Predictors of body composition changes during tuberculosis treatment in Mwanza, Tanzania.

BACKGROUND/OBJECTIVES: Gains in fat mass and lean mass during tuberculosis (TB) treatment may determine functional recovery and survival; yet, data are scarce. We aimed to assess predictors of fat and fat-free mass during 2 months of intensive TB treatment in a cohort in Mwanza, Tanzania. SUBJECTS/METHODS: Fat and fat-free mass were determined at the start of TB treatment and repeated after 2 months using the deuterium dilution technique. Gains in fat and fat-free mass were determined and predictors assessed using regression analysis. RESULTS: Data for 116 patients were available at baseline and during follow-up. Of these, 38.8% were females, mean age was 37.3 (s.d. 13.5) years, 69% (81) had sputum-positive TB, 45.7% (53) were HIV infected and 25% (29) were current smokers. The mean weight gain was 3.3 kg (95% confidence interval: 2.7; 3.8), and it did not differ by sex. However, compared with females, males had 1.0 (0.4; 1.6) kg/m(2) lower fat mass but 0.7 (0.2; 1.3) kg/m(2) higher fat-free mass gain. Current smoking was associated with higher fat mass (0.7 kg/m(2), 0.04; 1.4) but lower fat-free mass (-0.5 kg/m(2), -1.2; 0.07) gain. Among HIV-infected patients, antiretroviral therapy (ART) led to a lower fat gain (-1.2 kg/m(2), -2.2; -0.2) but to a higher fat-free mass among sputum-negative (2.9 kg/m(2), 0.8; 5.1) but not sputum-positive patients. CONCLUSIONS: During intensive phase of TB treatment, sex, smoking and ART were predictors of body composition. Larger studies are needed to further understand predictors of body composition during recovery, to help design interventions to improve treatment outcomes.

Physical activity and capacity at initiation of antiretroviral treatment in HIV patients in Ethiopia.

SUMMARY We described levels of habitual physical activity and physical capacity in HIV patients initiating antiretroviral treatment in Ethiopia and assessed the role of HIV and nutritional indicators on these outcomes. Physical activity energy expenditure (PAEE) and activity levels were measured with combined heart rate and movement sensors. Physical capacity was assessed by grip strength, sleeping heart rate and heart rate economy. Grip strength data was also available from a sex- and age-matched HIV-negative reference group. Median PAEE was 27.9 (interquartile range 17.4-39.8) kJ/kg per day and mean ± s.d. grip strength was 23.6 ± 6.7 kg. Advanced HIV disease predicted reduced levels of both physical activity and capacity; e.g. each unit viral load [log(1+copies/ml)] was associated with -15% PAEE (P < 0.001) and -1.0 kg grip strength (P < 0.001). Grip strength was 4.2 kg lower in patients compared to HIV-negative individuals (P < 0.001). Low body mass index (BMI) predicted poor physical activity and capacity independently of HIV status, e.g. BMI <16 was associated with -42% PAEE (P < 0.001) and -6.8 kg grip strength (P < 0.001) compared to BMI ≥18.5. The study shows that advanced HIV and malnutrition are associated with considerably lower levels of physical activity and capacity in patients at initiation of antiretroviral treatment.

The use of combined heart rate response and accelerometry to assess the level and predictors of physical activity in tuberculosis patients in Tanzania.

SUMMARY: We assessed the role of tuberculosis (TB) disease and HIV infection on the level of physical activity. A combined heart rate and movement sensor was used to assess habitual physical activity in TB patients and non-TB controls. The association between sputum-negative TB, sputum-positive TB, HIV and physical activity estimates were assessed in multivariable linear regression models adjusted for age, sex, haemoglobin and alpha-1-acid glycoprotein (AGP). Sputum-positive [eB 0·43, 95% confidence interval (CI) 0·29-0·64] and sputum-negative (eB 0·67, 95% CI 0·47-0·94) TB as well as HIV infection (eB 0·59, 95% CI 0·46-0·75) were associated with reduced activity compared to controls. Anaemia accounted for a substantial part of the effects of HIV, while elevated AGP primarily mediated the TB effect. The level of physical activity is highly influenced by TB and HIV, and mainly mediated through anaemia of infection and associated with elevated acute phase response.

Mycobacterium tuberculosis outbreak strain of Danish origin spreading at worrying rates among greenland-born persons in Denmark and Greenland.

Transmission of Mycobacterium tuberculosis continues at high rates among Greenland-born persons in Greenland and Denmark, with 203 and 450 notified cases per 10(5) population, respectively, in the year 2010. Here, we document that the predominant M. tuberculosis outbreak strain C2/1112-15 of Danish origin has been transmitted to Greenland-born persons in Denmark and subsequently to Greenland, where it is spreading at worrying rates and adding to the already heavy tuberculosis burden in this population group. It is now clear that the C2/1112-15 strain is able to gain new territories using a new population group as the "vehicle." Thus, it might have the ability to spread even further, considering the potential clinical consequences of strain diversity such as that seen in the widely spread Beijing genotype. The introduction of the predominant M. tuberculosis outbreak strain C2/1112-15 into the Arctic circumpolar region is a worrying tendency which deserves attention. We need to monitor whether this strain already has, or will, spread to other countries.

First report of lung transplantation in a patient with active pulmonary Mycobacterium simiae infection.

Mycobacterium simiae is a slow-growing mycobacteria that in rare cases can cause chronic pulmonary infection. We report the first case of lung transplantation in a patient with active M simiae infection at the time of transplantation. A 56-year-old immunocompetent nonsmoking woman underwent bilateral lung transplantation for end-stage idiopathic bronchiectasis and chronic M simiae infection. The disease proved manageable on a regimen of clarithromycin, moxifloxacin, and cotrimoxazole with a successful outcome 1-year posttransplantation. There is increasing evidence that nontuberculous mycobacterium infection should no longer be an absolute contraindication for lung transplantation.

The role of anthropometric and other predictors for diabetes among urban Tanzanians with tuberculosis.

BACKGROUND: As diabetes impairs tuberculosis (TB) treatment outcomes, it is essential to identify diabetes among TB patients. While little is known about predictors of diabetes among healthy individuals in Africa, predictors among TB patients are almost non-existent. OBJECTIVE: To assess potential predictors for diabetes among newly diagnosed pulmonary TB patients in Tanzania. METHODS: TB patients were tested for diabetes using an oral glucose tolerance test, demographic information was collected and anthropometric measurements taken. The association between diabetes and possible predictors were examined using logistic regression analyses. RESULTS: Of 1205 TB patients, 16.4% (n = 197) had diabetes, 9.0% (n = 108) were aged ≥55 years, 3.3% (n = 40) were overweight (body mass index [BMI] ≥ 25 kg/m(2)) and 12.7% (n = 152) severely underweight (BMI < 16 kg/m(2)). Diabetes was most prevalent in the 45-55 year age group, and increasing weight, BMI and waist circumference were associated with diabetes. Severe underweight (BMI < 16 kg/m(2)) among male TB patients (sex-BMI interaction, P = 0.02) was associated with diabetes (OR 2.52, P = 0.004). CONCLUSION: Diabetes is a common comorbidity among TB patients. Although diabetes was associated with obesity and was more prevalent among the middle-aged, the majority of TB patients with diabetes comorbidity were young and lean. With diabetes as a major risk factor for TB, and with the lack of strong predictors for diabetes, universal diabetes screening should be implemented in the TB programme.

Clustered tuberculosis in a low-burden country: nationwide genotyping through 15 years.

Molecular genotyping of Mycobacterium tuberculosis has proved to be a powerful tool in tuberculosis surveillance, epidemiology, and control. Based on results obtained through 15 years of nationwide IS6110 restriction fragment length polymorphism (RFLP) genotyping of M. tuberculosis cases in Denmark, a country on the way toward tuberculosis elimination, we discuss M. tuberculosis transmission dynamics and point to areas for control interventions. Cases with 100% identical genotypes (RFLP patterns) were defined as clustered, and a cluster was defined as cases with an identical genotype. Of 4,601 included cases, corresponding to 76% of reported and 97% of culture-verified tuberculosis cases in the country, 56% were clustered, of which 69% were Danes. Generally, Danes were more often in large clusters (≥ 50 persons), older (mean age, 45 years), and male (male/female ratio, 2.5). Also, Danes had a higher cluster frequency within a 2-year observation window (60.8%), and higher clustering rate of new patterns over time, compared to immigrants. A dominant genotype, cluster 2, constituted 44% of all clustered and 35% of all genotyped cases. This cluster was primarily found among Danish males, 30 to 59 years of age, often socially marginalized, and with records of alcohol abuse. In Danes, cluster 2 alone was responsible for the high cluster frequency level. Immigrants had a higher incidence of clustered tuberculosis at a younger age (0 to 39 years). To achieve tuberculosis elimination in Denmark, high-risk transmission environments, like the cluster 2 environment in Danes, and specific transmission chains in immigrants in the capital area, e.g., homeless/socially marginalized Somalis/Greenlanders, often with alcohol abuse, must be targeted, including groups with a high risk of reactivation.

Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.

BACKGROUND: Proton pump inhibitors (PPIs) may activate the immune system and cause asthma. AIM: To investigate the association of prenatal exposure to PPIs and histamine 2-receptor antagonists (H2RAs) with risk of asthma. METHODS: In this cohort study, 197,060 singletons born between 1996 and 2008 in northern Denmark were followed until the end of 2009. Data were obtained through Danish medical registries. Asthma in offspring was defined as at least two prescriptions of both a ß-agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during the follow-up. Cox proportional-hazard regression was used to compute incidence rate ratios, adjusting for covariates. RESULTS: A total of 2238 (1.1%) children were prenatally exposed to PPIs and 24,506 (12.4%) children developed asthma during follow-up (median follow-up = 6.8 years). The adjusted IRR (aIRR) of asthma associated with prenatal exposure to PPIs was 1.41 (95% confidence interval (CI): 1.27-1.56), compared with those unexposed. The association did not vary by trimester of exposure, and prenatal exposure to H2RAs was associated with similar increase in risk. The aIRR for maternal PPI and H2RA use in the year after, but not during pregnancy was 1.32 (95% CI: 1.20-1.46) and 1.13 (0.93-1.36), respectively, compared with non-use during and in the year after pregnancy. CONCLUSIONS: Prenatal exposure to both PPIs and H2RAs was associated with an increased risk of asthma in our study. Because the observed association is not drug specific and also observed for maternal postnatal use it may be explained by a 'class effect' or maternal underlying condition.

Combined IL-12 receptor and IgA deficiency in an adult man intestinally infested by an unknown, non-cultivable mycobacterium.

Interleukin-12 receptor deficiency is a well-described cause of human susceptibility to infection with low-virulent mycobacteria and Salmonella species. We identified a male patient presenting in his late forties with severe gastroenteropathy because of outbred infestation by a previously unknown mycobacterium. In addition to selective IgA deficiency, the patient was found to carry a not previously described R283X homozygous mutation in his IL12RΒ1 gene. Two of his sisters, a brother, and his four children were healthy, heterozygous carriers of the mutation. In this patient, the combination of two deficiencies could promote illness. Even though the IgA deficiency in itself does not predispose to mycobacterial disease, the lack of secreted IgA may have disturbed the intestinal homoeostasis and increased the susceptibility to the low-virulent mycobacterium that the patient was not able to clear because of his IL12R deficiency. Antimycobacterial chemotherapy and interferon-γ treatment for 2 years significantly improved his condition. This is the first description of IL12RΒ1 deficiency combined with another immunodeficiency, and we suggest that combinatory defects may circumvent the otherwise low penetrance of IL12RB1 deficiency.

Ongoing tuberculosis transmission to children in Greenland.

Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5-17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67-0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.

Recurrent tuberculosis in Denmark: relapse vs. re-infection.

SETTING: Denmark, a country with a low-incidence of tuberculosis (TB). OBJECTIVE: To analyse the proportion of relapse vs. re-infection and to compare selected characteristics between the two subgroups. DESIGN: A population-based cohort study. All 4154 Mycobacterium tuberculosis isolates from patients in Denmark genotyped by insertion sequence 6110 restriction fragment length polymorphism were followed for recurrent TB over 13.5 years. Recurrent cases were classified as relapse or re-infection by genotype patterns in initial and serial disease episodes. RESULTS: Recurrent TB was found in 73 (1.8%) cases. Identical M. tuberculosis genotypes in initial and serial episodes were found in 54 (1.3%), indicating relapse, whereas different genotypes, representing re-infection, were found in 19 (0.5%) cases. Cavitary TB in the initial episode was significantly associated with relapse (OR 4.6, 95%CI 1.1-26.9) compared to re-infection. CONCLUSION: The rate of recurrent TB is low in Denmark. Comparing selected characteristics between the relapse and re-infection subgroups revealed that only the presence of cavitary disease was associated with relapse. Although recurrent TB was rarely due to re-infection, the risk of re-infection increased with time.