SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies.

Novel coronavirus, SARS-CoV-2, is advancing at a staggering pace to devastate the health care system and foster concerns over public health. In contrast to the past outbreaks, coronaviruses are not clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection, they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid, and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations is yet to be known, the impact of these reprogramming is reflected in the hyperinflammatory responses, so called cytokine storm and the hindrance of the host immune defence system. The metabolic reprogramming during SARSCoV- 2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy sources by inhibiting the activation of glycolytic and hexosamine biosynthetic pathways can also augment antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy that can address the cross talks between the metabolic pathways might be more effective than a single approach, and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help exploit the cellular machinery and devise a therapeutic strategy that promotes resistance to viral infection and can augment body's antivirulence mechanisms. This review may cast light on the possibilities of targeting altered metabolic pathways to defend against virus infection in a new perspective.

Trends in the annual risk of tuberculous infection in India.

SETTING: Twenty-four districts in India. OBJECTIVES: To evaluate trends in annual risk of tuberculous infection (ARTI) in each of four geographically defined zones in the country. STUDY DESIGN: Two rounds of house-based tuberculin surveys were conducted 8-9 years apart among children aged 1-9 years in statistically selected clusters during 2000-2003 and 2009-2010 (Surveys I and II). Altogether, 184,992 children were tested with 1 tuberculin unit (TU) of purified protein derivative (PPD) RT23 with Tween 80 in Survey I and 69,496 children with 2TU dose of PPD in Survey II. The maximum transverse diameter of induration was measured about 72 h after test administration. ARTI was computed from the prevalence of infection estimated using the mirror-image method. RESULTS: Estimated ARTI rates in different zones varied between 1.1% and 1.9% in Survey I and 0.6% and 1.2% in Survey II. The ARTI declined by respectively 6.1% and 11.7% per year in the north and west zones; no decline was observed in the south and east zones. National level estimates were respectively 1.5% and 1.0%, with a decline of 4.5% per year in the intervening period. CONCLUSION: Although a decline in ARTI was observed in two of the four zones and at national level, the current ARTI of about 1% in three zones suggests that further intensification of TB control activities is required.

Selected risk factors associated with pulmonary tuberculosis among Saharia tribe of Madhya Pradesh, central India.

Tuberculosis (TB) is a major public health problem among the Saharia, a marginalized tribal group in Madhya Pradesh state, central India. However, there is no information on the risk factors associated with the development of TB disease in this community. A cross-sectional TB prevalence survey was conducted among the Saharia residing in Sheopur district of Madhya Pradesh. Information on tobacco smoking and alcohol consumption was collected from all the individuals. Persons aged ≥45 years, males, smokers and alcohol consumers had higher risks of developing TB disease. There is an urgent need to develop and implement culturally appropriate awareness raising activities to target smoking and alcohol consumption to support the efforts to control TB in this community.

Yield of culture of Mycobacterium tuberculosis complex in sputum samples transported from tribal areas.

BACKGROUND: There is little information on the recovery of Mycobacterium tuberculosis complex from sputum samples collected in the field for bacteriological examination. SETTING: Tribal areas in the State of Madhya Pradesh, in central India. METHODS: Sputum specimens collected from subjects with chest symptoms in a disease prevalence survey were refrigerated until transportation to the laboratory. The specimens were processed for microscopy and culture. The samples were grouped based on the delay in processing for culture from the day of collection into three groups: 0-3, 4-7 and ≥8 days, and the recovery of M. tuberculosis complex in these groups was analysed. The statistical analysis was performed using χ(2) test. RESULTS: Of the 3651 processed specimens, 114 were positive for M. tuberculosis complex by culture and 96 by smear microscopy. The differences in the proportion of 'smear-positive, culture-positive', 'smear-positive, culture-negative' and 'smear-negative, culture-positive' samples between the three groups were not significant. CONCLUSION: In difficult-to-reach areas with limited resources, refrigeration of sputum specimens until they are transported for processing at a reference laboratory for culture seems not to significantly affect the recovery of M. tuberculosis complex isolates.

Annual risk of tuberculosis infection among the tribal children of Jhabua, Madhya Pradesh.

A cross sectional tuberculin survey was undertaken to estimate the Annual Risk of Tuberculosis Infection (ARTI) amongst tribal children aged 1-9 years in Jhabua district, Madhya Pradesh, India. Of the 1056 test-read children, 774 (73.3%) had no BCG scar. The prevalence of infection was estimated as 6.3% (95% CI: 4.8-7.7) and ARTI as 1.2% (95% CI: 0.9-1.5). The findings suggest that the tuberculosis situation in the tribal population of Jhabua district is not that different from the situation among the non-tribal population in the country. However, there is a need to further intensify tuberculosis control measures in the area.

Prevalence of pulmonary tuberculosis amongst the Baigas--a primitive tribe of Madhya Pradesh, Central India.

BACKGROUND: A community-based cross-sectional tuberculosis (TB) disease prevalence survey was undertaken amongst the Baiga primitive tribal community of Baiga Chak in central India. MATERIAL AND METHODS: A population of 2,359 was covered under the study. Sputum samples were collected from chest symptomatics and examined for smear microscopy and culture. RESULTS: Overall prevalence of PTB was 146 (95% C.I: 0-318) per 100,000 population. CONCLUSION: The findings suggest that TB is not a major public health problem amongst this tribal group. However, there is still the need to maintain and further strengthen TB control measures on a sustained and long term basis in the area.

Why do tuberculosis suspects bypass local services to attend tuberculosis sanatorium?

BACKGROUND: The Government Hospital of Thoracic Medicine (GHTM), Tambaram, in Kanchipuram district (formerly known as tuberculosis [TB] sanatorium), Tamil Nadu, draws patients from all over India although RNTCP services have been in place country-wide for a number of years. OBJECTIVE: To document the reasons for patients with chest symptoms attending GHTM, Tambaram. MATERIALS AND METHODS: In a prospective observational study, on a simple random sample basis, TB suspects attending the out-patient department of GHTM during the period January-March, 2006, were interviewed using a semi-structured interview schedule. Information on demographic, socio-economic characteristics and reasons for attending GHTM for health care was collected. RESULTS: A total of 2,023 respondents attended GHTM during the study period; 56% were males, 67% were aged <45 years, 63% were literates and the average annual family income was Rs 25,000. Multiple reasons for attending GHTM were given: popularity of the centre (82%), perceived availability of good treatment (52%), referral by earlier treated patients (36%), expectation of specialized care (22%), referred by treating physicians (13%), and came for inpatient care (11%). CONCLUSION: Despite the availability of local RNTCP health services, many patients with chest symptoms made use of GHTM services due to the reputation of the former "TB sanatorium" in the community. The findings suggest that there is a need to improve community awareness of the availability of free diagnostic and treatment facilities locally under RNTCP.

Prevalence of pulmonary tuberculosis among the Bharia, a primitive tribe of Madhya Pradesh, central India.

A cross-sectional survey was undertaken to estimate the prevalence of pulmonary tuberculosis (TB) among the primitive Bharia tribe of Madhya Pradesh, India. Virtually the entire community in Patalkot valley of Chhindwara District was covered. Individuals aged > or =15 years were questioned about chest symptoms relating to TB. Sputum samples were collected and examined by smear microscopy and culture. The overall prevalence of pulmonary TB was found to be 432 per 100 000 population-not dissimilar to that seen in the wider population in India. There is, however, an urgent need to strengthen TB services in the area to improve access for this group.

Assessment of X-ray readers in TB prevalence surveys.

A prevalence study was carried out a rural community in Tiruvallur district in Tami Nadu to standardize the method of assessing an X-ray reader in tuberculosis (TB) prevalence surveys by means of different measures of agreement between the reader and a Standard Reader (SR). The exercise on assessing the X-ray readers was carried out on two occasions; one involving three trainee readers (R1, R2, and R3), and the other involving one trainee reader (R4). The extent of agreement was estimated using Kappa statistics (K), over-diagnosis, under-diagnosis, crude agreement and prevalence adjusted bias adjusted kappa (PABAK). The overall performance of readers R1, R2, and R3 was not satisfactory in terms of K (21, 34 and 14%) in the first assessment. The K, over-diagnosis and under-diagnosis were estimated to be 61, 28 and 4% for R1, 63, 18 and 4% for R2 and 58, 31 and 5% for R3 in the final assessment. This suggested that R2 performed well compared to the other two readers. The K was 68% for R4 in the first assessment. As the over-diagnosis was to the extent of 40%, the trainee reader underwent one more assessment. The K was 64% which was as good as before, but there was no improvement in the over-diagnosis (43.5%) in the second assessment. Based on the performance, only one reader (R2) was certified as qualified for X-ray reading in the first occasion while the reader (R4) assessed in the second occasion was not qualified. These findings were subject to the inherent variation in the SR's readings against which the readers were assessed.

Attenuation of toll-like receptor expression and function in latent tuberculosis by coexistent filarial infection with restoration following antifilarial chemotherapy.

Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen-stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans.

Human type 1 and 17 responses in latent tuberculosis are modulated by coincident filarial infection through cytotoxic T lymphocyte antigen-4 and programmed death-1.

Mycobacterium tuberculosis and filarial coinfection is highly prevalent, and the presence of a tissue-invasive helminth may modulate the predominant type 1 T helper (Th1; interferon [IFN]-gamma-mediated) response needed to control M. tuberculosis infection. By analyzing the cellular responses to mycobacterial antigens in patients who had latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with M. tuberculosis infection significantly diminishes M. tuberculosis-specific Th1 (interleukin [IL]-12 and IFN-gamma) and type 17 T helper (Th17; IL-23 and IL-17) responses related to increased expression of cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1. Blockade of CTLA-4 restored production of both IFN-gamma and IL-17, whereas PD-1 blockade restored IFN-gamma production only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific Th1 and Th17 responses in latent tuberculosis, suggesting a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans.

Weight gain in patients with tuberculosis treated under directly observed treatment short-course (DOTS).

UNLABELLED: SET UP: One Tuberculosis Unit (TU) in Tiruvallur district, Tamil Nadu, India where Tuberculosis (TB) patients treated under Directly Observed Treatment Short Course (DOTS) programme. OBJECTIVE: To identify the effects of weight gain among TB patients at the end of treatment on different factors such as socio-economic and demographic characteristics, smoking and drinking habits, treatment under supervision, the type of DOTS centres and problems in taking drugs. METHODS: TB patients registered between May 1999 and December 2004 formed the study population. Multiple regression method was used for the analysis. RESULTS: Among 1557 smear-positive TB patients registered under DOTS programme, the changes in weight ranged from a loss of 4 kgs to a gain of 20 kgs at the end of TB treatment; the average change in weight was 3.22 kgs. The gain in weight at the end of treatment was associated with age (<45 years), DOT at government centres, no problems in taking drugs as reported by patients and cure rate. CONCLUSION: The findings showed that there is an association between gain in weight with DOT at government centres and cure of patients.

Impact of advocacy on the tuberculosis management practices of private practitioners in Chennai City, India.

BACKGROUND: Innovative schemes to ensure the participation of private practitioners (PPs) in the Revised National Tuberculosis Control Programme (RNTCP) are necessary to identify and treat all patients with tuberculosis (TB). We developed a novel public-private mix (PPM) model to encourage PPs to practise DOTS and participate in the RNTCP while retaining their patients. METHODS: The Resource Group for Education and Advocacy for Community Health (REACH) developed and implemented the programme in partnership with the Chennai local health authority and the Tuberculosis Research Centre, Chennai, India. PPs were sensitised to the RNTCP and DOTS through a one-to-one approach or group meetings, and were assisted in referring patients. Surveys were carried out at baseline and at the completion of the study to assess changes in attitudes and practices. RESULTS: Six hundred PPs underwent sensitisation about the RNTCP, after which the proportion of PPs adopting DOTS increased significantly (P < 0.001), and the majority (72.8%) used sputum testing for diagnosing TB. The proportion of PPs who used X-ray alone for diagnosis declined to 16.0% from a baseline of 45.4%. CONCLUSIONS: This PPM model, which emphasises sustained advocacy for DOTS and allows PPs to retain private patients, looks promising and needs to be tested at other sites.

DOTS reaches socially marginalized population in the community: a study from a rural area of South India.

We report here that the Directly Observed Treatment, Short course (DOTS) is reaching all tuberculosis patients in the community irrespective of social classification based on the analysis from the tuberculosis prevalence survey and programme performance during 1999-2003 from a rural area in Tamilnadu, South India. New smear- positive cases treated under a DOTS programme were classified in two groups namely; scheduled caste living in colony and other population. The prevalence of smear- positive cases among the scheduled caste population was 1.9 times higher than the other population and this was reflected in the notification also. The successful treatment outcome was also similar in these two groups (75% and 78% respectively; overall 77%). From these findings it is concluded that people living in colony have equal access to DOTS as those in the village.

Phenol ammonium sulphate basic fuchsin staining of sputum in pot for the detection of acid-fast bacilli.

BACKGROUND & OBJECTIVES: Improper practices of making direct smears of sputum for detection of acid-fast bacilli (AFB) and of disposing sputum cups are hazardous. The present study was undertaken with the objective to stain sputum samples in their containers by 'phenol (10%) ammonium sulphate (4%) basic fuchsin (2%) solution' and to decolourize and counterstain their smears for detection of AFB- (henceforth called pot method) and to compare the smear results of pot method with the standard Ziehl-Neelsen (ZN) method. METHODS: A total of 575 selected sputum samples from pulmonary tuberculosis patients were stained by the standard ZN and pot methods and the proportions of AFB positive smears were compared. RESULTS: Of the 575 samples, 126 were AFB positive for both the staining methods and the difference was not statistically significant. Pot method missed 9 ZN positive smears (8 scanty and one 1+) and ZN method missed 9 pot positive smears (9 scanty) and the difference was not significant. High grade smears (3+) were seen more in pot method (42) than in ZN method (25) and the difference was significant. INTERPRETATION & CONCLUSION: Our findings showed that pot method was comparable to standard ZN method and had many advantages. Pot method can be explored further for the detection of AFB in sputum samples obtained from pulmonary tuberculosis suspects.

Annual risk of tuberculosis infection among tribal population of central India.

OBJECTIVE: To estimate the annual risk of tuberculosis infection (ARTI) among tribal children of Madhya Pradesh, central India. METHODS: Community-based, cross-sectional tuberculin survey among children aged 1-9 years in the tribal population of Madhya Pradesh. Multistage stratified cluster sampling was used to select a representative random sample of villages predominated by tribal population from selected districts. A total of 4802 children were tuberculin-tested with 1TU of PPD RT 23 and the reaction sizes read after 72 h. RESULTS: A total of 3062 (64%) children had no BCG scar. The frequency distribution of children by reaction sizes indicated a fair mode at 18 mm in the right hand side of the distribution. By mirror-image technique, the prevalence of infection among children with no recognizable BCG scar was estimated as 6.8% (95% CI: 4.8-8.9%). The ARTI was computed as 1.3% (0.9-1.7%). The corresponding figures for children irrespective of scar status were 7.1% (95% CI: 5.5-8.8%) and 1.3% (1.0-1.7%) respectively. CONCLUSIONS: The risk of tuberculosis infection in tribal population of Madhya Pradesh, central India is not different from other areas of the country. There is, however, a need to further intensify tuberculosis control measures on a sustained and long-term basis.

Evaluation of different types of chest symptoms for diagnosing pulmonary tuberculosis cases in community surveys.

BACKGROUND: Prevalence of tuberculosis (TB) is an important epidemiological index to measure the load of the disease in a community. A series of disease surveys were undertaken in rural community in Tiruvallur district in Tamilnadu, south India OBJECTIVE: To investigate the yield of pulmonary tuberculosis (TB) cases by different symptoms status and suggest predominant symptoms for detection of cases in the community based surveys. METHODS: Three disease surveys were conducted during 1999-2006, in a random sample of 82,000 adults aged > or = 15 years to estimate the prevalence and incidence of pulmonary TB. All subjects were screened for chest symptoms and chest radiography. Sputum examination was done among those who were either symptomatic or abnormal on X-ray or both. Cases observed through symptom inquiry were included for analysis. RESULTS: In survey-I, 65.6% had cough of > or = 14 days and yielded 79.1% of the total cases. In surveys II and III, symptomatic subjects with cough contributed 69.5% and 69.2% of the cases respectively. In survey I, 26.8% had symptoms without cough but with at least chest pain > or = 1 month contributed 8.4% of total cases. The corresponding proportions in subsequent surveys were 29.3, 11.5%; and 23.4, 11.2% respectively. The number of symptomatics without cough and chest pain but with fever > or = 1 month was negligible. CONCLUSION: The relative importance of cough as a predominant symptom was reiterated. The yield of pulmonary TB cases from symptomatics having fever of > or = 1 month was negligible. Fever may be excluded from the definition of symptomatics for screening the population in community surveys.

Annual risk of tuberculosis infection in Chennai city.

AIM: To study the proportion of children infected with Mycobacterium Tuberculosis in Chennai city. METHODOLOGY: A cluster sampling methodology was adopted to select an estimated sample size of 7000 children from five corporation zones selected systematically from ten zones of the city. A total of 7098 children aged 1-9 years were subjected to Mantoux and test read; 1897 (27%) from slum area and 5201 (73%) from non-slum area. RESULTS: The prevalence of infection among children without BCG scar was estimated to be 10.5 % (ARTI of 2.0%) and was similar to that among children irrespective of scar status. The prevalence of infection was higher among children in slum areas (11.1%; ARTI 2.1%) compared to non-slum areas (8.9%; ARTI 1.7%); but the difference was not statistically different. CONCLUSION: The tuberculosis situation in Chennai as measured by risk of infection was higher in urban city area than rural areas and comparable to that found in other cities as reported from earlier studies. This information can be used as baseline information for monitoring the epidemiological trends in Chennai city in future.