Mycobacterial antigens accumulation in foamy macrophages in murine pulmonary tuberculosis lesions: Association with necrosis and making of cavities.

Understanding mechanisms of cavitation in tuberculosis (TB) is the missing link that could advance the field towards better control of the infection. Descriptions of human TB suggest that postprimary TB begins as lipid pneumonia of foamy macrophages that undergoes caseating necrosis and fragmentation to produce cavities. This study aimed to investigate the various mycobacterial antigens accumulating in foamy macrophages and their relation to tissue destruction and necrosis. Pulmonary tissues from mice with slowly progressive TB were studied for histopathology, acid-fast bacilli (AFB) and presence of mycobacterial antigens. Digital quantification using Aperio ImageScope was done. Until week 12 postinfection, mice were healthy, and lesions were small with scarce AFB and mycobacterial antigens. Colony-forming units (CFUs) increased exponentially. At week 16-33, mice were sick, macrophages attained foamy appearance with an increase in antigens (P < .05), 1.5 log increase in CFUs and an approximately onefold increase in AFB. At week 37-41, mice started dying with a shift in morphology towards necrosis. A >20-fold increase in mycobacterial antigens was observed with only less than one log increase in CFUs and sevenfold increase in AFB. Secreted antigens were significantly (P < .05) higher compared to cell-wall antigens throughout infection. Focal areas of necrosis were associated with an approximately 40-fold increase in antigen MPT46, functionally active thioredoxin, and a significant increase in all secreted antigens. In conclusion, mycobacterial antigens accumulate in the foamy macrophages in TB lesions during slowly progressive murine pulmonary TB. Secreted antigens and MPT46 correlated with necrosis, thereby implying that they might trigger the formation of cavities.

Exploring the consequences of decentralization: has privatization of health services been the perceived effect of decentralization in Khartoum locality, Sudan?

BACKGROUND: The health system of Sudan has experienced several forms of decentralization, as well as, a radical reform. Authority and governance of secondary and tertiary health facilities have been shifted from federal to state levels. Moreover, the provision of health care services have been moved from large federal tertiary level hospitals such as Khartoum Teaching Hospital (KTH) and Jafaar Ibnoaf Hospital (JIH), located in the center of Khartoum, to smaller district secondary hospitals like Ibrahim Malik (IBMH), which is located in the southern part of Khartoum. Exploring stakeholders' perceptions on this decentralisation implementation and its relevant consequences is vital in building an empirical benchmark for the improvement of health systems. METHODS: This study utilised a qualitative design which is comprised of in-depth interviews and qualitative content analysis with an inductive approach. The study was conducted between July and December 2015, and aimed at understanding the personal experiences and perceptions of stakeholders towards decentralisation enforcement and the implications on public health services, with a particular focus on the Khartoum locality. It involved community members residing in the Khartoum Locality, specifically in catchments area where hospital decentralisation was implemented, as well as, affiliated health workers and policymakers. RESULTS: The major finding suggested that privatisation of health services occurred after decentralisation. The study participants also highlighted that scrutiny and reduction of budgets allocated to health services led to an instantaneous enforcement of cost recovery user fee. Devolving KTH Khartoum Teaching and Jafar Ibnoaf Hospitals into peripherals with less. Capacity, was considered to be a plan to weaken public health services and outsource services to private sector. Another theme that was highlighted in hospitals included the profit-making aspect of the governmental sector in the form of drug supplying and profit-making retail. CONCLUSIONS: A change in health services after the enforcement of decentralisation was illustrated. Moreover, the incapacitation of public health systems and empowerment of the privatisation concept was the prevailing perception among stakeholders. Having contextualised in-depth studies and policy analysis in line with the global liberalisation and adjustment programmes is crucial for any health sector reform in Sudan.

Patients' and health system's delays in the diagnosis and treatment of new pulmonary tuberculosis patients in West Gojjam Zone, Northwest Ethiopia: a cross-sectional study.

BACKGROUND: Tuberculosis (TB) is a major public health concern in the developing world. Early diagnosis and prompt initiation of treatment is essential for effective TB control. The aim of this study was to determine the length and analyze associated factors of patients' and health system's delays in the diagnosis and treatment of new pulmonary TB (PTB) patients. METHODS: A cross-sectional study was conducted in 30 randomly selected public health facilities in West Gojjam Zone, Amhara Region, Ethiopia. Newly diagnosed PTB patients who were ≥15 years of age were consecutively enrolled in the study. Patients' delay (the time period from onset of TB symptoms to first presentation to a formal health provider) and health system's delay (the time period from first presentation to a formal health provider to first start of TB treatment) were measured. Median patients' and health system's delays were calculated. Mixed effect logistic regression was used to analyze predictors of patients' and health system's delays. RESULTS: Seven hundred six patients were enrolled in the study. The median patients' delay was 18 days (interquartile range [IQR]: 8-34 days) and the median health system's delay was 22 days (IQR: 4-88 days). Poor knowledge of TB (adjusted odds ratio [AOR], 2.33; 95 % confidence interval [CI], 1.34-4.05), first visit to non-formal health provider (AOR, 47.56; 95 % CI, 26.31-85.99), self-treatment (AOR, 10.11; 95 % CI, 4.53-22.56) and patients' age (≥45 years) (AOR, 2.99; 95 % CI, 1.14-7.81) were independent predictors of patients' delay. Smear-negative TB (AOR, 1.88; 95 % CI, 1.32-2.68) and first visit to public health centers (AOR, 2.22; 95 % CI, 1.52-3.25) and health posts (AOR, 5.86; 95 % CI, 1.40-24.39) were found to be independent predictors of health system's delay. CONCLUSIONS: The health system's delay in this study was long and contributed more than 50 % of the total delay. Better TB diagnostic tools to complement sputum smear microscopy are needed to early diagnose PTB cases at peripheral health facilities. In addition, due emphasis should be given to increase public awareness about symptoms and consequences of TB disease.

Assessment of health system challenges and opportunities for possible integration of diabetes mellitus and tuberculosis services in South-Eastern Amhara Region, Ethiopia: a qualitative study.

BACKGROUND: The double burden of tuberculosis (TB) and diabetes mellitus (DM) is a significant public health problem in low and middle income countries. However, despite the known synergy between the two disease conditions, services for TB and DM have separately been provided. The objective of this study was to explore health system challenges and opportunities for possible integration of DM and TB services. METHODS: This was a descriptive qualitative study which was conducted in South-Eastern Amhara Region, Ethiopia. Study participants included health workers (HWs), program managers and other stakeholders involved in TB and DM prevention and control activities. Purposive sampling was applied to select respondents. In order to capture diversity of opinions among participants, maximum variation sampling strategy was applied in the recruitment of study subjects. Data were collected by conducting four focus group discussions and 12 in-depth interviews. Collected data were transcribed verbatim and were thematically analyzed using NVivo 10 software program. RESULT: A total of 44 (12 in-depth interviews and 32 focus group discussion) participants were included in the study. The study participants identified a number of health system challenges and opportunities affecting the integration of TB-DM services. The main themes identified were: 1. Unavailability of system for continuity of DM care. 2. Inadequate knowledge and skills of health workers. 3. Frequent stockouts of DM supplies. 4. Patient's inability to pay for DM services. 5. Poor DM data management. 6. Less attention given to DM care. 7. Presence of a well-established TB control program up to the community level. 8. High level of interest and readiness among HWs, program managers and leaders at different levels of the health care delivery system. CONCLUSION: The study provided insights into potential health systems challenges and opportunities that need to be considered in the integration of TB-DM services. Piloting TB and DM integrated services in selected HFs of the study area is needed to assess feasibility for possible full scale integration of services for the two comorbid conditions.

Use of interferon gamma-based assay to diagnose tuberculosis infection in health care workers after short term exposure.

BACKGROUND: We intended to assess the risk for health care workers (HCWs) of acquiring M. tuberculosis infection after exposure to patients with sputum-smear positive pulmonary tuberculosis at three University Hospitals (Ullevål, Akershus, and Haukeland) in Norway. METHODS: We tested 155 exposed health care workers and 48 healthy controls both with a tuberculin skin test (Mantoux) and the T-SPOT.TB test, a recently developed interferon-gamma release assays based on the M. tuberculosis-specific ESAT-6 and CFP10 antigens, to investigate if this test might improve infection control measures. RESULTS: Among the 155 exposed HCWs tested in this study, 27 individuals were defined as newly infected cases by TST after recent exposure, while only 3 of these had a positive T-SPOT.TB test. The number of T-SPOT.TB positives represents 11% of the individuals defined as recently infected by TST after exposure (3/27) and 2% of the total number of exposed people tested (3/155). In addition, 15 individuals had been previously defined as infected by TST before exposure of whom 2 subjects were T-SPOT.TB positive. All individuals detected as T-SPOT.TB positive belonged to the TST positive group (> 15 mm), and the percentage concordance between T-SPOT.TB and TST, including both previously and newly infected subjects, was 12% (5/42). The 48 control participants used in the study were all T-SPOT.TB negative, but 3 of these subjects were TST positive. CONCLUSION: Our data indicate that the frequency of latent TB in the total cohort of HCWs is 3%, whereas the rate of transmission of TB to exposed individuals is approximately 2% and occurs through exposure periods of short duration. Thus, the risk of TB transmission to HCWs following TB exposure in a hospital setting in Norway is low, and improved screening approaches will benefit from the application of specific interferon-gamma release assays.

A systematic review of delay in the diagnosis and treatment of tuberculosis.

BACKGROUND: Early diagnosis and immediate initiation of treatment are essential for an effective tuberculosis (TB) control program. Delay in diagnosis is significant to both disease prognosis at the individual level and transmission within the community. Most transmissions occur between the onset of cough and initiation of treatment. METHODS: A systematic review of 58 studies addressing delay in diagnosis and treatment of TB was performed. We found different definitions of, for example, debut of symptoms, first appropriate health care provider, time to diagnosis, and start of treatment. Rather than excluding studies that failed to meet strict scientific criteria (like in a meta-analysis), we tried to extract the "solid findings" from all of them to arrive on a more global understanding of diagnostic delay in TB. RESULTS: The main factors associated with diagnostic delay included human immunodeficiency virus; coexistence of chronic cough and/or other lung diseases; negative sputum smear; extrapulmonary TB; rural residence; low access (geographical or sociopsychological barriers); initial visitation of a government low-level healthcare facility, private practitioner, or traditional healer; old age; poverty; female sex; alcoholism and substance abuse; history of immigration; low educational level; low awareness of TB; incomprehensive beliefs; self-treatment; and stigma. CONCLUSION: The core problem in delay of diagnosis and treatment seemed to be a vicious cycle of repeated visits at the same healthcare level, resulting in nonspecific antibiotic treatment and failure to access specialized TB services. Once generation of a specific diagnosis was in reach, TB treatment was initiated within a reasonable period of time.

Integrated Disease Surveillance and Response (IDSR) in Malawi: Implementation gaps and challenges for timely alert.

OBJECTIVE: The recent 2014 Ebola Virus Disease (EVD) outbreaks rang the bell to call upon global efforts to assist resource-constrained countries to strengthen public health surveillance system for early response. Malawi adopted the Integrated Disease Surveillance and Response (IDSR) strategy to develop its national surveillance system since 2002 and revised its guideline to fulfill the International Health Regulation (IHR) requirements in 2014. This study aimed to understand the state of IDSR implementation and differences between guideline and practice for future disease surveillance system strengthening. METHODS: This was a mixed-method research study. Quantitative data were to analyze completeness and timeliness of surveillance system performance from national District Health Information System 2 (DHIS2) during October 2014 to September 2016. Qualitative data were collected through interviews with 29 frontline health service providers from the selected district and 7 key informants of the IDSR system implementation and administration at district and national levels. FINDINGS: The current IDSR system showed relatively good completeness (73.1%) but poor timeliness (40.2%) of total expected monthly reports nationwide and zero weekly reports during the study period. Major implementation gaps were lack of weekly report and trainings. The challenges of IDSR implementation revealed through qualitative data included case identification, compiling reports for timely submission and inadequate resources. CONCLUSIONS: The differences between IDSR technical guideline and actual practice were huge. The developing information technology infrastructure in Malawi and emerging mobile health (mHealth) technology can be opportunities for the country to overcome these challenges and improve surveillance system to have better timeliness for the outbreaks and unusual events detection.

Applying tuberculosis management time to measure the tuberculosis infectious pool at a local level in Ethiopia.

BACKGROUND: Measuring the size of the infectious pool of tuberculosis (TB) is essential to understand the burden and monitor trends of TB control program performance. This study applied the concept of TB management time to estimate and compare the size of the TB infectious pool between 2009 and 2014 in West Gojjam Zone of Amhara Region, Ethiopia. METHODS: New sputum smear-positive and smear-negative pulmonary TB (PTB) and retreatment cases who attended 30 randomly selected public health facilities in West Gojjam Zone from October 2013 to October 2014 were consecutively enrolled in the study. In order to determine the infectious period, the TB management time (number of days from the onset of cough until start of anti-TB treatment) was computed for each patient category. The number of undiagnosed TB cases was estimated and hence the TB management time for the undiagnosed category was calculated. The total size of the TB infectious pool during the study period for the study zone was estimated as the annual number of infectious person days. RESULTS: New smear-positive and smear-negative PTB cases contributed 25,050 and 12,931 infectious person days per year to the TB infectious pool, respectively. The retreatment and presently undiagnosed cases contributed 8840 and 34,310 infectious person days per year, respectively. The total size of the TB infectious pool in West Gojjam Zone during the study period was estimated at 81,131 infectious person days per year or 3405 infectious person days per 100,000 population per year. Compared to a similar study done in 2009 in the study area, the current study showed reduction of the TB infectious pool by 244,279 infectious person days. CONCLUSIONS: TB management time is a simple and practical tool that may help to estimate and compare the changes in the size of the TB infectious pool at local level. It may also be used as an indicator to monitor the changes in TB control program performance.

Prevalence and associated factors of tuberculosis and diabetes mellitus comorbidity: A systematic review.

INTRODUCTION: The dual burden of tuberculosis (TB) and diabetes mellitus (DM) has become a major global public health concern. There is mounting evidence from different countries on the burden of TB and DM comorbidity. The objective of this systematic review was to summarize the existing evidence on prevalence and associated/risk factors of TBDM comorbidity at global and regional levels. METHODS: Ovid Medline, Embase, Global health, Cochrane library, Web of science and Scopus Elsevier databases were searched to identify eligible articles for the systematic review. Data were extracted using standardized excel form and pilot tested. Median with interquartile range (IQR) was used to estimate prevalence of TBDM comorbidity. Associated/risk factors that were identified from individual studies were thematically analyzed and described. RESULTS: The prevalence of DM among TB patients ranged from 1.9% to 45%. The overall median global prevalence was 16% (IQR 9.0%-25.3%) Similarly, the prevalence of TB among DM patients ranged from 0.38% to 14% and the overall median global prevalence was 4.1% (IQR 1.8%-6.2%). The highest prevalence of DM among TB patients is observed in the studied countries of Asia, North America and Oceania. On the contrary, the prevalence of TB among DM patients is low globally, but relatively higher in the studied countries of Asia and the African continents. Sex, older age, urban residence, tobacco smoking, sedentary lifestyle, poor glycemic control, having family history of DM and TB illness were among the variables identified as associated/risk factors for TBDM comorbidity. CONCLUSION: This systematic review revealed that there is a high burden of DM among TB patients at global level. On the contrary, the global prevalence of TB among DM patients is low. Assessing the magnitude and risk/associated factors of TBDM comorbidity at country/local level is crucial before making decisions to undertake TBDM integrated services.

Diabetes mellitus is associated with increased mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients in South-Eastern Amahra Region, Ethiopia.

BACKGROUND: There is growing evidence suggesting that diabetes mellitus (DM) affects disease presentation and treatment outcome in tuberculosis (TB) patients. This study aimed at investigating the role of DM on clinical presentations and treatment outcomes among newly diagnosed TB patients. METHODS: A prospective cohort study was conducted in South-Eastern Amhara Region, Ethiopia from September 2013 till March 2015. Study subjects were consecutively recruited from 44 randomly selected health facilities in the study area. Participants were categorized into two patient groups, namely, patients with TB and DM (TBDM) and TB patients without DM (TBNDM). Findings on clinical presentations and treatment outcomes were compared between the two patient groups. Cox proportional hazard regression analysis was applied to identify factors associated with death. RESULTS: Out of 1314 TB patients enrolled in the study, 109 (8.3 %) had coexisting DM. TBDM comorbidity [adjusted hazard ratio (AHR) 3.96; 95 % confidence interval (C.I.) (1.76-8.89)], and TB coinfection with human immunodeficiency virus (HIV) [AHR 2.59; 95 % C.I. (1.21-5.59)] were associated with increased death. TBDM and TBNDM patients did not show significant difference in clinical symptoms at baseline and during anti-TB treatment period. However, at the 2(nd) month of treatment, TBDM patients were more symptomatic compared to patients in the TBNDM group. CONCLUSIONS: The study showed that DM is associated with increased death during TB treatment. DM has no association with clinical presentation of TB except at the end of the intensive phase treatment. Routine screening of TB patients for DM is recommended for early diagnosis and treatment of patients with TBDM comorbidity.

Total Delay Is Associated with Unfavorable Treatment Outcome among Pulmonary Tuberculosis Patients in West Gojjam Zone, Northwest Ethiopia: A Prospective Cohort Study.

BACKGROUND: delay in diagnosis and treatment of tuberculosis (TB) may worsen the disease, increase mortality and enhance transmission in the community. This study aimed at assessing the association between total delay and unfavorable treatment outcome among newly diagnosed pulmonary TB (PTB) patients. METHODS: A prospective cohort study was conducted in West Gojjam Zone, Amhara Region of Ethiopia from October 2013 to May 2015. Newly diagnosed PTB patients who were ≥15 years of age were consecutively enrolled in the study from 30 randomly selected public health facilities. Total delay (the time period from onset of TB symptoms to first start of anti-TB treatment) was measured. Median total delay was calculated. Mixed effect logistics regression was used to analyze factors associated with unfavorable treatment outcome. RESULTS: Seven hundred six patients were enrolled in the study. The median total delay was 60 days. Patients with total delay of > 60 days were more likely to have unfavorable TB treatment outcome than patients with total delay of ≤ 60 days (adjusted odds ratio [AOR], 2.33; 95% confidence interval [CI], 1.04-5.26). Human immunodeficiency virus (HIV) positive TB patients were 8.46 times more likely to experience unfavorable treatment outcome than HIV negative TB patients (AOR, 8.46; 95% CI, 3.14-22.79). CONCLUSIONS: Long total delay and TB/HIV coinfection were associated with unfavorable treatment outcome. Targeted interventions that can reduce delay in diagnosis and treatment of TB, and early comprehensive management of TB/HIV coinfection are needed to reduce increased risk of unfavorable treatment outcome.

Prevalence and Associated Factors of Diabetes Mellitus among Tuberculosis Patients in South-Eastern Amhara Region, Ethiopia: A Cross Sectional Study.

BACKGROUND: The association between diabetes mellitus (DM) and tuberculosis (TB) is re-emerging worldwide. Recently, the prevalence of DM is increasing in resource poor countries where TB is of high burden. The objective of the current study was to determine the prevalence and analyze associated factors of TB and DM comorbidity in South-Eastern Amhara Region, Ethiopia. METHODS: This was a facility based cross-sectional study. All newly diagnosed TB patients attending selected health facilities in the study area were consecutively screened for DM. DM was diagnosed based on the World Health Organization diagnostic criteria. A pre-tested semi-structured questionnaire was used to collect socio-demographic, lifestyles and clinical data. Logistic regression analysis was performed to identify factors associated with TB and DM comorbidity. RESULT: Among a total of 1314 patients who participated in the study, the prevalence of DM was estimated at 109 (8.3%). Being female [odds ratio (OR) 1.70; 95% confidence interval (CI) (1.10-2.62)], patients age [41-64 years (OR 3.35; 95% CI (2.01-5.57), 65-89 years (OR 3.18; 95% CI (1.52-6.64)], being a pulmonary TB case [(OR 1.69; 95% CI 1.09-2.63)] and having a family history of DM [(OR 4.54; 95% CI (2.36-8.73)] were associated factors identified with TB and DM comorbidity. CONCLUSION: The prevalence of DM among TB patients in South-Eastern Amahra Region is high. Routine screening of TB patients for DM is recommended in the study area.

Routine diagnosis of intestinal tuberculosis and Crohn's disease in Southern India.

AIM: To investigate whether routinely measured clinical variables could aid in differentiating intestinal tuberculosis (ITB) from Crohn's disease (CD). METHODS: ITB and CD patients were prospectively included at four South Indian medical centres from October 2009 to July 2012. Routine investigations included case history, physical examination, blood biochemistry, ileocolonoscopy and histopathological examination of biopsies. Patients were followed-up after 2 and 6 mo of treatment. The diagnosis of ITB or CD was re-evaluated after 2 mo of antituberculous chemotherapy or immune suppressive therapy respectively, based on improvement in signs, symptoms and laboratory variables. This study was considered to be an exploratory analysis. Clinical, endoscopic and histopathological features recorded at the time of inclusion were subject to univariate analyses. Disease variables with sufficient number of recordings and P < 0.05 were entered into logistic regression models, adjusted for known confounders. Finally, we calculated the odds ratios with respective confidence intervals for variables associated with either ITB or CD. RESULTS: This study included 38 ITB and 37 CD patients. Overall, ITB patients had the lowest body mass index (19.6 vs 22.7, P = 0.01) and more commonly reported weight loss (73% vs 38%, P < 0.01), watery diarrhoea (64% vs 33%, P = 0.01) and rural domicile (58% vs 35%, P < 0.05). Endoscopy typically showed mucosal nodularity (17/31 vs 2/37, P < 0.01) and histopathology more frequently showed granulomas (10/30 vs 2/35, P < 0.01). The CD patients more frequently reported malaise (87% vs 64%, P = 0.03), nausea (84% vs 56%, P = 0.01), pain in the right lower abdominal quadrant on examination (90% vs 54%, P < 0.01) and urban domicile (65% vs 42%, P < 0.05). In CD, endoscopy typically showed involvement of multiple intestinal segments (27/37 vs 9/31, P < 0.01). Using logistic regression analysis we found weight loss and nodularity of the mucosa were independently associated with ITB, with adjusted odds ratios of 8.6 (95%CI: 2.1-35.6) and 18.9 (95%CI: 3.5-102.8) respectively. Right lower abdominal quadrant pain on examination and involvement of ≥ 3 intestinal segments were independently associated with CD with adjusted odds ratios of 10.1 (95%CI: 2.0-51.3) and 5.9 (95%CI: 1.7-20.6), respectively. CONCLUSION: Weight loss and mucosal nodularity were associated with ITB. Abdominal pain and excessive intestinal involvement were associated with CD. ITB and CD were equally common.

Transport of Ixodes ricinus infected with Borrelia species to Norway by northward-migrating passerine birds.

Birds are capable of transporting ticks and, consequently, tick-borne pathogens over long distances and across geographical barriers such as oceans and deserts. The purpose of this study was to assess the prevalence of Borrelia spp. in ticks transported by birds by using PCR. A total of 9768 northward-migrating passerine birds was examined for ticks at 4 bird observatories along the southern Norwegian coast during their spring migration in 2003-2005. Two of the bird observatories were located on islands where flagging revealed very few or no ticks (Akerøya and Store Færder), while the other 2 were located in areas with established dense tick populations: an island, Jomfruland (>100 ticks per hour of flagging) and a mainland locality, Lista (40 ticks in one hour of flagging). Borrelia spp. were found in 70 (13.6%) of 513 examined Ixodes ricinus nymphs (19 B. afzelii, 38 B. garinii, two B. turdi, and 11 B. valaisiana) and in 14 (8.1%) of 172 examined I. ricinus larvae (ten B. garinii, one B. turdi, and three B. valaisiana). This report is the first to identify B. turdi in Europe. Ticks collected from birds of the genus Turdus (T. merula, T. philomelos, and T. iliacus) had a higher prevalence of Borrelia spp. than ticks from the other passerine genera. Ticks that were cofeeding with a Borrelia-infected tick had an increased probability of being infected with the same Borrelia species. Ticks collected on birds from the south-western locality Lista were less likely to have Borrelia than ticks found on birds from the other, more eastern localities. The Turdus spp. are particularly important, both because they carry many ticks per bird and because ticks carried by these species have a higher prevalence of Borrelia. This higher prevalence may be related to Borrelia infection of the birds or transmission of Borrelia through cofeeding. The prevalence of the different Borrelia species in ticks collected from migratory birds may be related to migration routes.