PART – A (General Particulars)

1. Proposed Project Title: Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

2. Principal Investigator: Dr. Md. Anisur Rahman(Detail curriculum vitae is annexed) Professor & Head, Department of

Epidemiology NIPSOM

3. Co-investigator(s): (A copy of the curriculum vitae and list of publications in respect of each collaborating investigator is annexed)

1. Dr. Md. Rizwanul KarimAsst. professor, Department of Epidemiology,NIPSOM

2 Dr. Ummul Khair AlamMedical Officer, Population Dynamics,NIPSOM.

4. Place of the study / Institution(s) : Sixteen Upzilla DOTS centers.

5. Sponsoring / collaborating agency: Bangladesh Medical Research Council

6. Duration: 6 (six) Months.

7. Date of Commencement: As soon as fund will be available.

8. Date of Completion: Within six months from the date of starting.

9. Total Cost: Tk.- 5,00,000/-

10. Other Support for Proposed Research: Nil (Font different)

(1) Is this research project being Yes No supported by any other source?

(2) Has an application for funding of Yes No

(3) Is this project been submitted to any Yes Noother organization(s)?

If 'Yes' to 10(1) or 10(2) above, please indicate the organization(s) and amount of funds.

11. Date of Submission: /10/2013

12. Signature of Principal Investigator: ________________________Dr. Md. Anisur Rahman

13. Signature of Co-Investigator(s) : ________________________Dr. Md. Rizwanul Karim

________________________Dr. Ummul Khair Alam

14. Endorsement of the Institute Head:

Signature:

Prof. Dr. Saroj Kumar MazumderDesignation: Director, National Institute of Preventive and Social Medicine. (NIPSOM)

Official Seal:

PART-B

PRINCIPAL INVESTIGATOR(S) INFORMATION SHEET

1. (i) Name: Dr. Md. Anisur Rahman

(ii) Designation: Professor & Head, Department of Epidemiology, NIPSOM

(iii) Official Address with telephone: Professor & Head, EpidemiologyNational Institute of Preventive and Social MedicinePhone. O1199880233 ,Email: anisnipsom@yahoo.com

(iv) Present Residential Address with telephone: Flat no.B2, House no. 10, Road 13/A, Sector 6, Uttara, Dhaka.

2. Academic background

Name of the degree

Year Institute Board Remarks

SSC 1976 Rangpur Zilla School Rajshahi 1stHSC 1978 Titumir Govt. College Dhaka 1stMBBS 1985 SSMC Dhaka PassedMPH Epidemiology

1991 NIPSOM Dhaka Passed

3. Field Experience:

List is attached (it is in the resume of the principal investigator)

4. (a) Research ExperienceList is attached (it is in the resume of the principal investigator)(b) Other Experiences: List is attached (it is in the resume of the principal investigator)

5. Percentage of time to be devoted to this project: 30%

6. Number of Scientific Publications: List is attached (it is in the resume of the principal investigator)

PART - C

1. Proposed Project Title:

Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

2. Executive summary:

Tuberculosis (TB) has been a public health issue for many years and remains the major

cause of death from a single infectious agent among adults in developing countries. TB

remains one of the leading causes of adult mortality and morbidity in Bangladesh.

Bangladesh ranks sixth among higher TB burden countries where extra-pulmonary TB

patients were 12% of all TB cases in 2008. Age, education, income, occupation, race,

sex, malnutrition (Vit D deficiency), HIV positivity, diabetes, renal disease, drinking

unpasteurized milk, all are thought to be important predictors of extra-pulmonary

tuberculosis. A case control study will be conducted in sixteen upazillas of Bangladesh.

A total of 588 samples ( 294 cases and 294 controls) will be recruited from the treatment

register of the DOTS centers of the selected upazillas. Sociodemographic, household

characteristics, contact with index TB cases and disease profile will be collected by a

interviewer administered semistructured questionnaire. Statistical tests (2) will be

performed to determine the association between exposure and outcome variables

comparing cases and controls. Crude odds ratios (OR) and 95% confidence intervals (CI)

will be estimated in the univariate analysis. Important predictors (p = <0.05) of univariate

analysis will be included in a backward elimination logistic regression model to identify

independent predictors. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries, but appropriate studies to investigate this are lacking. This study will be carried out to predict important risk

indicators for EPTB that are distinctive from risk indicators for PTB. As a result, more

attention will be paid to address EPTB cases and strategy will be formulated to combat

EPTB focusing more emphasis on those factors.

Part – D

Introduction

Background

Tuberculosis (TB) remains a major global public health problem. It is the second

greatest contributor among infectious diseases to adult mortality, causing

approximately two million deaths a year worldwide. It is estimated that about one

third of the world’s population is infected with Mycobacterium tuberculosis.1, 2

Tuberculosis continues to cause a large burden of disease in the world, enhanced by

poverty, poor public health, nutritional status and increasing HIV/AIDS prevalence

and thus TB continues to be a persistent challenge for global health and

development.3 The South East Asia Region (SEAR) with an estimated 4.88 million

prevalent cases carries one third of the global burden of TB. The control of TB in the

Region is affected by variations in the quality and coverage of various TB control

interventions, population demographics, urbanization, changes in the socio-economic

standards, HIV and more recently, emerging drug resistance.4 Extrapulmonary

involvement occurs in one fifth of all TB cases; 60% of patients with extrapulmonary

manifestations of TB have no evidence of pulmonary infection on chest radiographs

or sputum culture.5

Tuberculosis is a major public health problem in Bangladesh since long. Till date TB

remains one of the leading cause of adult mortality and morbidity and preventable

death in Bangladesh. With a population of 150 million, Bangladesh ranks sixth

among higher TB burden countries. Almost half of the population is infected with

TB. Extra-pulmonary TB patients were 11% in 2007 and 12% in 2008.6 A total of 147

342 cases were diagnosed in 2007. Most of the extra-pulmonary cases were female.

New smear negative and extra-pulmonary cases were 15.7% and 10.9% respectively.

Proportions of extra-pulmonary and new smear negative cases reported from

metropolitan cities and by Chest Disease Clinics were higher compared to upazilas.

This is due to limited diagnostic facilities available at upazila level to detect smear

negative or extra-pulmonary cases.7

Research questionWhat are the differences in the distribution of risk indicators between pulmonary and

extrapulmonary tuberculosis?

General objectiveTo find out the differences in the distribution of risk indicators between pulmonary

and extrapulmonary tuberculosis

Specific objectives

1. To assess the sociodemographic characteristics differences between

pulmonary and extrapulmonary tuberculosis.

2. To find out the differences in household-characteristics between pulmonary

and extrapulmonary tuberculosis.

3. To identify the kitchen environment status of pulmonary and extrapulmonary

tuberculosis.

4. To find out the differences in contact related and lifestyle variables between

pulmonary and extrapulmonary tuberculosis.

5. To predict the differencs in the distribution of risk indicators for pulmonary

and extrapulmonary tuberculosis.

Justification of the studyDifferences in the likelihood of extra-pulmonary TB have been observed in various

studies among TB patients by demographic characteristics. Moreover, diagnosis of

extra-pulmonary TB cases was not so much successful. As a result a huge number of

extra-pulmonary tuberculosis patients were undiagnosed.6

Recent studies have suggested that the sites of extra-pulmonary TB may be

according to geographic location and population. Clinical manifestations of TB are

variable and depend on a number of factors that are related to microbe, the host and

the environment.8 Studies have examined the role of host related factors on the risk of

development of EPTB. Risk factors for EPTB in Bangladesh may be different to

those in low-burden countries, but appropriate studies to investigate this is lacking.

This study will be carried out to identify possible risk indicators for EPTB that are

distinctive from risk indicators for PTB. As a result, more attention will be paid to

address EPTB cases and strategy will be formulated to combat EPTB giving more

emphasis on those factors.

Literature review

There are several studies regarding risk factors of pulmonary and extra-pulmonary

tuberculosis. Studies in Bangladesh related to extra-pulmonary tuberculosis and

related risk factors are very limited. Studies carried out in different parts of the world

are viewed thoroughly to find out what others have learnt and reported relevant to

extra-pulmonary tuberculosis.

Extra-pulmonary tuberculosis may affect any organ or tissue, most commonly found

in mediastinal lymphnodes, larynx, cervical lymphnodes, pleurae, meninges, central

nervous system, spine, bones and joints, kidneys, pericardium, intestines, peritoneum

and skin. Less common extra-pulmonary involvement is eye, nasopharynx and

adrenal gland.9

Clinical features:

A patient with pulmonary tuberculosis presents with one or more following

symptoms in addition to cough:

Respiratory symptoms- shortness of breath, chest pain, coughing up of blood

General symptoms- loss of weight, loss of appetite, fever, night sweats

Sign and symptoms of extra-pulmonary tuberculosis depend on the site involved.

Most common examples are:

TB lymphadenitis: swelling of lymphnodes

Pleural effusion: fever, chest pain, shortness of breath

Joint TB: pain and swelling of joints

Spinal TB : radiological findings with or without loss of function

Meningitis: headache, fever, neck stiffness and subsequent mental confusion

Gastro-intestinal TB: abdominal pain, chronic diarrhea, sub-acute obstruction,

passage of blood in stool and right iliac fossa mass.

Genito-urinary TB : urinary frequency, dysurea, hematuria and loin pain

Burden of tuberculosis

Bangladesh Situation

Tuberculosis is a major public health problem in Bangladesh since long. Till date TB

remains one of the leading cause of adult mortality and morbidity and preventable

death in Bangladesh. With a population of 150 million, Bangladesh ranks sixth

among the highest TB burden countries. Almost half of the population is infected

with TB. In 2008, the estimated prevalence and incidence rates of all forms of

tuberculosis were respectively 387 and 223 per 100 000 population.

Situation of extra- pulmonary tuberculosis

EP-TB: Global Situation

In 2008, 5.7 million eases of TB (new cases and relapse) were notified to NTPs, out

of which 2.7 million were new positive cases, 2.0 million new smear- negative

pulmonary cases (or cases for which smear status was unknown) and 0.8 million new

were extra-pulmonary TB Global case notification of extra- pulmonary cases in 2008

was 7, 85,272 Among them high burden countries contributes 5,76,402 cases. 1 In

2007, total case notification of tuberculosis in South East Asia region was 22,02,149

Out of these, 2,95,866 were extra-pulmonary cases (13.5%).10

EP-TB: Bangladesh situation

In Bangladesh, though the pulmonary case detection rate continues to improve, the

extra-pulmonary case detection had not yet been met. The proportion of extra-

pulmonary tuberculosis is lower, There is no prevalence rate of extra-pulmonary

tuberculosis in Bangladesh. The percentage of extra-pulmonary tuberculosis cases

among total case notification were 11% in 2007 and 12% in 2008.6 Proportions of

extra-pulmonary cases reported from metropolitan cities and by CDCs were higher

compared to upazilas. This is due to limited diagnostic facilities available at upazila

level to detect extra-pulmonary cases.4

Risk factors for TB

Role of background characteristics

Younger age and female gender were found as independent risk factors for EPTB,

relative to PTB.11, 12 Females tended to be more likely to have any form of extra-

pulmonary tuberculosis than males, except pleural tuberculosis. The strength of this

association was strongest in the age range 25-64 yrs and less pronounced amongst the

oldest patients. 13 This sex difference in rates of EPTB has been previously attributed

to various factors such as cigarette smoking, genetic and hormonal factors, iron

status, alcohol consumption, delay in diagnosis and associated disease.14

The other reasons for female disease preponderance may be the social exclusion of

younger women who are generally homebound and have poorer nutritional status than

their male counterparts, social stigma associated with TB which discourages women

from seeking early medical care, and Vitamin D deficiency due to poor dietary intake

as well as inadequate exposure to sunlight because of poor housing and the culture of

wearing burqas. Several studies showed Pakistani women to have low levels of serum

25-hydroxyvitamin D. There is a growing evidence of a strong association between

TB and Vitamin D deficiency.15

A prospective study was conducted by Shafi Ullah et al to assess its frequency in

various organ systems of the body and to evaluate the role of demographic factors

like sex and age in its causation. High female preponderance was noted with M: F

ratio of 1:2. Mean age was 35 years and 70% of the patients were in the age group 15-

45 years. Lymph modes were most common site of EPTB, involved in 66.4% of the

cases. They concluded that EPTB has high rates in females in their reproductive age.

The other likely socio-cultural factors could be high female illiteracy, female

economic dependency and their poor access to health care. Thus, in their

environments, female gender and age between 15-45 years are two important

predisposing factors for EPTB.16

Socio-economic condition and TB

Analytic epidemiological study showed women, non-Hispanic blacks, and HIV-

positive persons to have a significantly higher risk for extra pulmonary tuberculosis

than men, non-Hispanic whites, and HIV-negative persons.17 EPTB is reported to be

more often diagnosed in females and in young patients. Almost one-third of the

tuberculosis cases in Yemen were extra-pulmonary (28%) was associated with

poverty and that most of the extra pulmonary tuberculosis patients came from rural

areas.

Multivariate assessment of host factors showed that risk o TB was increased with

variation in occupational status. Assessment of environmental factors showed an

increased risk with household crowding, history of household exposure to a known

TB case, as well as amongst the Jola ethnic group.18

Smoking

Smokers incur a 2 to 4 fold increased risk of invasive respiratory disease. Perhaps the

greatest public health impact of smoking on infection is the increased risk of

tuberculosis, a particular problem in under developed countries where smoking rates

are increasing rapidly. 19 A higher proportion of culture confirmed TB cases was

found among ever smokers (current and ex-smokers) than never-smokers. Pulmonary

involvement was more prevalent among ever smokers than never smokers and the

reverse was true for extra-pulmonary involvement.20 Female and age were associated

with EPTB, while alcohol abuse, smoking habit, contact with PTB patients and BCG

vaccination had a protective effect. 21

Common sites of EPTB

Lymph node tuberculosis comprised the greatest number of EPTB Cases in almost all

studies.22-25 The central nervous system was the next most frequent site of EPTB

involvement, followed in descending order by skeletal, pleural, abdominal, cutaneous,

genitourinary, pericardial, miliary, and breast tuberculosis.23 Miliary tuberculosis

developed in infants, lymphadenitis and meningitis in preschool children, and pleural

effusion and skeletal tuberculosis in older children.24 The distribution of different

types of EPTB differed significantly among age groups. Meningeal and bone and or

joint TB were more commonly observed among the male patients, while lymphatic,

genitourinary, and peritoneal TB cases were more frequently seen among females. 25

Study found that a higher number of extra pulmonary tuberculosis patients were

diagnosed in private hospitals and clinics than the pulmonary tuberculosis patients

which might be attributed to the fact that extra pulmonary tuberculosis presents more

diagnostic and therapeutic problems than pulmonary tuberculosis which are less

familiar to most of the Clinicians.26 Patients with bilateral lung involvement were

more likely to have extrapulmonary involvement, with an adjusted odds ratio (OR) of

4.21 (95% confidence interval [CI], 1.82-9.72), while patients with cavitary lesions

(adjusted OR, 0.37; 95% CI, 0.16-0.84), and with higher levels of serum albumin

(adjusted OR, 0.45; 95% CI, 0.25-0.78) had less frequent involvement. Clinicians

should be aware of the possibility of extrapulmonary involvement in TB patients with

bilateral lung involvement without cavity formation or lower levels of serum

albumin.27 Study suggests that in a significant number of patients with EPTB fever is

absent, ESR is normal and MT is negative. So, over reliance on these clinical and

laboratory data may lead to failure to diagnose EPTB.28

Age, education, income, occupation, race, sex, malnutrition (Vit D deficiency), HIV

positivity, diabetes, renal disease, drinking unpasteurized milk, all are thought to be

important predictors of extra-pulmonary tuberculosis. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries, but appropriate studies to investigate this are lacking. The present study

will also help us to gain insight into the demographic and social characteristics of

EPTB cases in Bangladesh thereby will extend the knowledgebase of EPTB based on

which better TB control strategies can be developed.

4. Materials and Methods

4.1 Study design

This will be a case control study

4.2 Study period

A total period of the study will be from January to June 2012.

4.3 Place of the study

DOTS centers of eighteen upazillas of Dhaka division.

4.4 Study population

Selection of cases and controls:

The samples will be classified as either EPTB (cases) or PTB(controls). Patients whose disease involved organs or tissues outside the thorax, excluding those patients who also had pulmonary involvement, are considered to have cases of extrapulmonary tuberculosis and will be classified as case patients. EPTB cases will encompass lymphatic,

genitourinary, bone and/or joint, meningeal, peritoneal, gastrointestinal, cutaneous

and unclassified cases. EPTB cases that will involve >1 EPTB disease site will be

classified according to the major site. Patients in whom the sites of disease is

exclusively intrathoracic, (i.e., confined to lungs, pleura, and intrathoracic lymph

nodes) are considered to have cases of pulmonary tuberculosis and will be classified

as control patients.

.Tuberculous pleuritis will not be classified as EPTB because pleura is believed to be

involved by direct invasion from frequently accompanying pulmonary parenchymal

TB or hypersensitivity reaction by M. tuberculosis rather than blood stream

dissemination.

Cases of disseminated TB and cases with concurrent EPTB-PTB will be excluded

from our principal analysis, because they are not distinctly classifiable as either EPTB

or PTB. In order to determine the possible ramifications of this definition of EPTB,

we will perform a separate analysis that will be compared disseminated and

concurrent EPTB-PTB with EPTB only and with PTB only. In addition, we will

perform a separate analysis in which disseminated and concurrent EPTB will be

added to our existing EPTB classification. The presence of extra-pulmonary

involvement in patients with pulmonary TB will be based on either of the following

criteria:

1) Demonstration of acid-fast bacilli or the growth of Mycobac-terium tuberculosis

from tissue;

2) Presence of granulomas with or without caseation necrosis in tissue;

3) Positive polymerase chain reaction (PCR) results for the DNA of M.

tuberculosis from tissues; or

4) A clinical diagnosis by duty physicians based on symptoms, laboratory,

radiographic findings, and treatment response to anti-TB medications.

Addresses of the cases and controls will be noted from the DOTS center registers

with a view to trace study subjects at home for exploration of exposure information.

4.5 Sample size

The study will enroll 294 people per group, for a total of 588 people. ( using SPSS

Sample power software; IBM). With this sample size, there is an 80% likelihood that

the study will yield a statistically significant result, and allow us to conclude that the

percentage of subjects in 'selected exposure' is different for PTB than for EPTB. The

sample size of 294 is based on the assumption that groups differ by 10 percentage

points. The test will be 2-tailed, which means that an effect in either direction will be

interpreted. Based on these same parameters and assumptions the study will enable us

to report the difference in proportions with a precision (95.0% confidence level) of

approximately plus/minus 0.07 points. Specifically, an observed difference of 0.10

would be reported with a 95.0% confidence interval of 0.03 to 0.17. In computing the

sample size to be 294 we assume that there will be no missing data. If the actual rate

of missing data is 2%, we would need a sample size of 300 per group. We used an

alpha of 0.05, which is often the default value, in computing the required sample size

of 294 per group.

4.6 Sampling technique

Convenient sampling technique will be adopted due to scarcity of the cases. All

available cases and one control (age sex matched) for each case will be recruited

within the data collection period. The cases and controls will be selected from DOTS

treatment registers who enrolled in the last 5 months and meet the selection criteria.

4.7 Data collection instrument

Data collection instruments will be a pre-tested structured questionnaire and a check

list.

4.8 Data collection technique

Firstly an official letter will be issued from MBDC to the UH&FO of the selected

upazillas with a copy to Civil Surgeon of the corresponding district informing the

study purpose. Another letter will be sent to the executives of the BRAC and Damien

foundation requesting necessary assistance in the field. Six data collectors will be

trained on several setting before collecting data. They will be guided and assisted by

the local NGO program officer and GOV assigned Tuberculosis and Leprosy Clinic

Assistant (TLCA). Data will be collected through face to face interview of the

household at their residence by using the questionnaire. Addresses of the respondents

will be taken from the DOTS centers treatment registers with a view to trace study

subjects at home for exploring exposure information. Before the interview, the detail

of the study will be explained to the eligible respondents. Informed verbal consent

will be obtained from every respondent and interviews will be held in private. The

characteristics of the head of the household will be obtained by interviewing head and

in case of children necessary information will be primarily collected from the mother

of the children. To ensure quality control, proper attention through direct supervision

will be given by the research investigators. A research officer will continuously

supervise the data collection and the research investigator will also make regular on-

site field checks. In addition, all the questionnaires will be checked for consistency

and completeness by the investigators. A subset of questionnaires will be re-checked

in the field for validity.

4.9 Data processing and analysis

After data collection, each questionnaire will be checked for completeness and

consistency. The data will be entered into computer with the help of Software

“Statistical Package for Social Sciences” (SPSS) for windows version 19.0.

Univariate comparisons between the group with pulmonary TB and the group with

extrapulmonary involvement will be performed using Pearson’s chi-square test or

Fisher’s exact test for categorical variables and Student’s t-test for continuous

variables. Using variables with p values of <0.20 from the univariate comparisons,

multiple logistic regression models will be constructed to identify predictors of the

presence of extra pulmonary involvement. In logistic regression, backward

elimination will be used to select variables to be maintained in the final model, using

a p value of <0.05 as the criterion for statistical significance of associations. The area

under the receiver operator characteristic (ROC) curve will be used to evaluate the

performance of the models. Adjusted odds ratios and 95% CI will be reported.

Study factors

Key variables

Sociodemographic variable

AgeSexReligionEducation of the respondentOccupation of the respondentParent’s educationParent’s occupationAverage monthly IncomeTotal family membersFamily typeFamily mobilityResidence typeArea of residence

Household characteristics

House ownershipFloor materialWall materialRoof materialNo of bedroomsArea of bedroomsCrowdingNo of external windowsWindow materialWindow Opening statusType of latrineDrinking water sourceSource of lighting

Kitchen environment

Kitchen positionKitchen distanceKitchen ventilationStove typeFuel typeCooking time

Contact information

Type of contactContact relationContact regularityFrequency of contact

Lifestyle related variables

Smoking statusNo. of smoker in the familySharing same room with smokerSharing same bed with smokerTime of start smokingTime of quit smokingNo of sticks smoked per dayNonsmoking tobacco useAddiction type

Disease related variables

Type of TBType of symptomsSite of extrapulmonary TBTime of first appearance of symptomsMethod of diagnosisTime of DiagnosisPlace of diagnosisSmear test result

Miscellaneous

BCG vaccinationFood security status

5. Utilization of results/ policy implications

The present study will be conducted to gain insight into the demographic and social

characteristics of EPTB cases in Bangladesh thereby will extend the knowledgebase

of EPTB based on which better TB control strategies can be developed.

6. Facilities

(Resources, equipment, chemicals, subjects (human, animal) etc. Required for the

study):

6.1. Facilities Available

Infra-structure of government health service centre will be used for management of

the research project. In addition, the institutional facilities of the principal investigator

and co-investigators will be used for conduction of the study.

6.2. Additional Facilities Required

Manpower: - Two research Officer,

- Six data collectors

7. Approval of the Head of the Department/Institute

Approved

8. Flow chart

Study period: 1st Week of January to 4th Week of June; 2013-2014

SL no

Activities Period of studyMonth January February March April May JuneWeek 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

1 Proposal Development and acceptance

2 Literature Review

3 Selection of study area

4 Planning and Designing

5 Preparation of Research Instrument

6 Pre Test

7 Data Collection

8 Data Analysis, Interpretation

9 Report Writing

10 Report Submission

9. Ethical considerations

Prior conducting the study, ethical clearance will be taken from the NIPSOM Ethical

Review Committee. The study will neither include any invasive procedure nor any

private issue and no drug will be tested. Before initiation of the interview a brief

introduction on the aims and objectives of the study will be presented to the

respondents. They will be informed about their full right to participate or refuse to

participate in the study. A complete assurance will be given that all information

provided by them will be kept confidential and their names or anything which can

identify them and only will be disseminated and published for public interest. After

completion of these procedures the interview will be started with their due

permission. The research will be conducted in full accord with ethical principles.

10. Dissemination policy

With the proper permission of funding agency the study findings will be disseminated

through seminar and discussion meeting with policy makers. Attempts will also be

taken to publish the data in international journals.

References

1. World Health Organization (WHO); Global tuberculosis control, WHO report 2009.

2. Sudre P, Tendam G and Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Organ 1992, 70:149-59.

3. Behavioral barriers in tuberculosis control….Silvia Waisbord the CHANGE Project Academy for Education development. SEA-TB3.

4. Tuberculosis in the South-East Asia Region- The Regional Report: 2008, WHO Project No : SE ICP TUB. New Delhi.

5. Herchline TE. Tuberculosis. http://emedicine.medscape.com/article/230802-overview.

last updated 9 Dec; 2011.

6. World Health Organization (WHO). SEARO: Tuberculosis Control in the South East Asia Region. WHO report 2009.

7. Tuberculosis Control in Bangladesh, Annual Report 2008,NTP.

8. American Thoracic society: Diagnostic Standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000; 161:1376-95.

9. Guideline, National Tuberculosis control Programme, Bangladesh, 4th edition.

10. World Health Organization (WHO). SEARO: Tuberculosis Control in the South east Aswia Region. WHO report 2008.

11. Sreeramareddy CT, Panduru KV, Verma SC, Joshi HS and Bates MN. Comparison of pulmonary and extra-pulmonary tuberculosis in Nepal- a hospital based retrospective study. BMC Infec Dis 2008 Jan; 248:8.

12. Al-Otaibi F and El Hazmi MM. Extra-pulmonary tuberculosis in Saudi Arabia. Indian J Pathol Microbiol. 2010 Apr-Jun;53(2):227-31.

13. Forssbohm M, Zwahein M, Loddenkemper R and Rieder H.L. Demographic characteristics of patients with extrapulmonary tuberculosis in Germany. Euro Respir J 2007; 31(1): 99-105.

14. Cailhol j, Decludt B and Che D. Sociodemographic factors that contribute to the development of extrapulmonary tuberculosis were identified. Journal of Clinical Epidemiology 58 (2005) 1066–1071.

15. Chandir S , Hussain H, Salahuddin N, Amir M, Ali F, Lotia I and Khan AJ. Extrapulmonary tuberculosis: a retrospective review of 194 cases at a tertiary care hospital in Karachi, Pakistan. J Pak Med Assoc. 2010 Feb;60(2):105-9.

16. Ullah S, Shah SH, Rehman AU. Kamal A, Begum N and Khan G. Extra-pulmonary tuberculosis in Lady Reading Hospital Peshwar, NWFP, Pakistan: Survey of biopsy results. J Ayub Med Coll Abbottabad. 2008 Apr-Jun; 20(2): 43-6.

17. Yang Z, Kong Y, Wilson F, Foxman B, Fowler B, Fowler AH, Marrs CF, Cave MD and Bates JH. Identification of risk factors for extra-pulmonary tuberculosis. Clin Infect Dis 2004;38:199-205.

18. Hill P, Sillah DJ, Donkor SA, Out J, Adegbola RA and Lienhardt C. Risk factors for pulmonary tuberculosis: a clinic based case control study in The Gambia, BMC Public Health 2006;6:156.

19. Arcavi L, Neal L and Benowitz MD. Cigarette smoking and infection.2004;164:2206-2216.

20. Leung CC, Li T and Lam TH et al. Smoking and tuberculosis among elderly in Hong Kong. Am J Respir Crit care Med 2004; 170: 1027-1033.

21. Garcia-Rodrigueza JF, Alvarez-Diaza H, Lorenzo-Garciab MV, Mari˜no-Callejoa A, Fernandez-Rialc A and Sesma-Sanchezc P. Extrapulmonary tuberculosis: epidemiology and risk factors Enferm Infecc Microbiol Clin. 2011;29(7):502–509.

22. Ilgazli A , Boyaci H, Basyigit I and Yildiz F. Extrapulmonary tuberculosis: clinical and epidemiologic spectrum of 636 cases. Arch Med Res. 2004 Sep-Oct;35(5):435-41.

23. Fader T, Parks J, Khan N, Manning R, Stokes S and Nasir NA. Extrapulmonary tuberculosis in Kabul, Afghanistan:A hospital-based retrospective review. International Journal of Infectious Diseases. 2010;14, e102—e110

24. Maltezou H C, Spyridis P and Kafetzis D A. Extra-pulmonary tuberculosis in children.Arch Dis Child 2000;83:342–346.

25. Gunal S, Yang Z, Agarwal M, Koroglu M, Kazgan Z and Durmaz R. Demographic and microbial characteristics of extrapulmonary tuberculosis cases diagnosed in Malatya, Turkey, 2001-2007. BMC Public Health 2011, 11:154.

26. Othman GQ, Ibrahim MIM and Rajaa YA. Comparison of clinical and sociodemographical factors in pulmonary and extrapulmonary tuberculosis patient in Yemen.Journal of Clinical and Diagnostic Research. 2011 April, Vol-5(2):191-195.

27. Kim MJ, Kim HR, Hwang SS, Kim YW, Han SK, Shim YS, and Yim JJ. Prevalence and Its Predictors of Extrapulmonary Involvement in Patients with Pulmonary Tuberculosis. J Korean Med Sci. 2009; 24: 237-41.

28. Hussain MW, Haque MA, Banu SA, Ekram SA and Rahman MF. Extrapulmonary Tuberculosis: Experience in Rajshahi Chest Disease Clinic and Chest Disease Hospital. The Journal of Teachers Association, RMC, Rajshahi. TAJ 2004; 17(1) : 16-19.

PART – DBudget

I. Total Budget: Tk 500, 000 (Five lacs only)Sl. No.   Item

Unit cost Number

Months/ times BDT Sub-total

1 Personnel cost           1.1 Principal Investigator (PI) 5000 1 6 30000    1.2 Co-Investigator (Co-I) 4000 2 4 32000    1.3 Research Officer (RO) 12000 2 3 72000    1.4 Support Staff (MLSS) 1000 1 6 6000 140000

2 Field Expenses             2.1

 Honorarium for Resource Person for Training of RO, Volunteers

450 

3 

3 

4050 

   

    and data collectors            2.2 Cost of Data Collection 6000 6 2 72000    2.3 Local supervision cost 1000 4 3 12000    2.4 Compensation for research 150 600 1 90000      Participants         178050

3 Supplies and Materials  Not Applicable  4 Patient Cost   Not Applicable       

5Travel Cost            

  5.1 Non-local field cost for PI & Co-I 3000 3 1 9000    5.2 Non-local field cost for RO 1000 1 4 4000    5.3 Local field cost for PI & Co-I 300 3 20 18000  

  5.4Local field cost for RO/ Data collectors 150 1 100 15000 46000

6 Office Stationeries             6.1 Toner 6000 1 1 6000    6.2 Offset paper 500 6 1 3000  

  6.3Bag/Pen/pencil/eraser/measuring tape/ umbrella etc.

Lump sum     14000 23000

7 Data processing and computer charges           

  7.1 Data entry, coding, cleaningLump sum     25000  

  7.2 Data analysisLump sum     25000 50000

8 Printing and reproduction/dissemination           

  8.1 Printing of questionnaireLump sum     6,000  

  8.2 Report preparation/ printingLump sum     12000  

  8.3 PhotocopyLump sum     6000 24000

9  9.1 DisseminationLump sum     10000 10000

10Miscellaneous (Telephone, internet, postage etc.)        8950 8950

11 VAT & Income Tax (4%)        20000 20000Grand Total BDT 500000.00

[Taka five lacs only]

National Institute of Preventive and Social Medicine Directorate General of Health Services

Application for Ethical Clearance

1. Principal Investigator(s): Dr. Md. Anisur Rahman

Professor & Head, Dept. of Epidemiology.National Institute of Preventive and Social Medicine (NIPSOM)

2. Co-Investigator(s): Dr. Md. Rizwanul KarimAsst. Professor, Department of Epidemiology, NIPSOM

Dr. Ummul Khair AlamMedical Officer, Population Dynamics,NIPSOM.

3. Place of the Study/Institution(s): Sixteen Upzilla DOTS centers

4. Title of Study: Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

5. Type of Study: Case control study

6. Duration: 6 (six) Months

7. Total Cost: Tk.500,000/=

8. Funding Agency: Bangladesh Medical Research Council (BMRC)

Circle the appropriate answer to each of the following (If not Applicable write NA)

1. Source of Population :

(a) Ill Subjects Yes No

(b) Non* Ill Subjects Yes No

(c) Minors or persons Yes No under guardianship

2. Does the study involve :

(a) Physical risks Yes No to the subjects

(b) Social Risks Yes No

(c) Psychological Yes No risks to subjects

(d) Discomfort to Yes No subjects

(e) Invasion of the Yes No body

(f) Invasion of Yes No Privacy

(g) Disclosure of Yes No information damaging to

subject or others

3. Does the study involve :

(a) Use of records, Yes No (hospital, medical, death, birth or other)

(b) Use of fetal tissue Yes No or abortus

(c) Use of organs or Yes No body fluids

4. Are subjects clearly informed about:

(a) Nature and Yes No purposes of study

(b) Procedures to be Yes No followed including

alternatives used

(c) Physical risks Not applicable

(d) Private questions Yes No (e) Invasion of the Not applicable Body

(f) Benefits to be Yes No derived

(g) Right to refuse Yes No to participate or to withdraw from study

(h) Confidential Yes No handling of data

(i) Compensation Yes No where there are risks or

loss of working time or privacy is involved in any particular procedure

5. Will signed consent form/verbal consent be required :

(a) From Subjects Yes No

(b) From parent or Not applicable guardian (if subjects

are minors)

6. Will precautions be Yes No taken to protect

anonymity of subjects

The Ethical Review Committee (ERC)

TB remains one of the leading causes of adult mortality and morbidity in Bangladesh that

causing persistent crisis in health and development. Bangladesh ranks sixth among higher

TB burden countries where extra-pulmonary TB patients were 12% of all TB cases in

2008. Age, education, income, occupation, race, sex, malnutrition (Vit D deficiency),

HIV positivity, diabetes, renal disease, drinking unpasteurized milk, all are thought to be

important predictors of extra-pulmonary tuberculosis. A case control study will be

conducted in eighteen upazillas of Dhaka division. A total of 588 samples (294 cases and

294 controls) will be recruited from the treatment register of the DOTS centers of the

selected upazillas. Sociodemographic and disease profile will be collected by a

interviewer administered semistructured questionnaire. Before the interview, the detail of

the study will be explained to the eligible respondents. Informed verbal consent will be

obtained from every respondent and interviews will be held in private. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries. This study will help us identifying the risk factors that predispose to EPTB And will lead policymakers adopting targeted strategies to prevent it and decrease its national burden.

Documents submitted herewith to committee:

Umbrella proposal

Proposal Summary

Abstract for Ethical Review Committee as per attachment

Informed consent form for subjects

Procedure for maintaining confidentiality

Interview schedule and checklist

We agree to obtain approval of the Ethical Review Committee for any changes involving the rights and welfare of subjects or any changes of the Methodology before making any such changes.

Principal Investigator Other Investigator (s)

Predicting risk indicators for Pulmonary and Extra-pulmonary

Tuberculosis in rural areasThese issues will be kept in concern while conducting research process:

1. Any group whose ability to give voluntary informed consent assumes questionable will not be included

2. No potential risks exists in designing this study3. By following under mentioned steps confidentiality will be maintained:

Research data will be coded Data will be stored in a locked cabinets Only research personnel will be allowed to access data. There is no physical, psychological, social and legal risk. During physical examination, proper consent will be taken. For safeguarding confidentiality and protecting anonymity each of the patient will be given

a special ID no. A signed informed consent will be taken from the patient/patient’s guardians convincing

that privacy of the patient will be maintained and he/she will be compensated for loss of work time if they wants

A data collection sheet should (enclosed) be prepared for which a short interview of 25-30 minutes will be required

No drug will be used for this study No experimental new drug will be administrated No placebo will be used here Use of hospital records (outdoor) will be needed to fill up the patient’s data sheet.

4. Consent form will be a written statement5. A brief interview regarding study variables will be collected from the participants.6. The study result will accrue the benefit to the society by providing information regarding

exploration and identification of important risk factors and their distribution among pulmonary and extra-pulmonary tuberculosis cases in rural areas of Bangladesh.

7. No experimental drug, placebo will be used.

Principal Investigator

INFORM CONSENT FORM FOR SUBJECTS

Title of research study: Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas-----------------------------------------------------------------------------------------------Name of Participant:-----------------------------------------------------------------------------------------------Name of Investigator:

-----------------------------------------------------------------------------------------------

1. I consent to participate in the research titled “Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas”, the particulars of which-including details of interviews and questionnaires have been explained to me. A written copy of the information has been given to me to keep.

2. I authorize the researcher to use with me the interviews and questionnaires referred to under (1) above.

3. I acknowledge that:a. The possible effects of the interviews and questionnaires have been explained to

me to my satisfactionb. I have been informed that I am free to withdraw from the research at any time

without explanation or prejudice and to withdraw any unprocessed data previously supplied;

c. The project is for the purpose of research d. I have been informed that the confidentiality of the information I provide will be

safeguarded subject to any legal requirementse. I have been informed regarding the interviews. I have also been informed that

because of the number of people to be interviews is small; it is possible that someone may still be able to identify me on the basis of any references to personal information that might allow someone to guess my identity. However, I will be referred by pseudonym or identified by a different name in any publications arising from the research.

Signature Date-----------------------------------------------------------------------------------------

(Participant)

Signature Date-----------------------------------------------------------------------------------------

(Witness to consent)

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