Introduction

1.1 Overview

Tuberculosis is a common and infectious communicable disease that is caused by mycobacterium tuberculosis. It is of two principle kinds: pulmonary TB, which usually attacks the lungs, and extra-pulmonary TB, which attacks any part of the body, such as: the lymphatic, pleural, bone and/or joint, genitourinary, miliary, peritoneal, meninges and/or central nervous system (CNS), and all other sites combined. Pulmonary TB sometimes combined with extra pulmonary tuberculosis (Parimon, 2008; Sreeramareddy et al., 2008; Friedman, 2001).

Tuberculosis is spread in form of droplets which are expelled when the infected persons cough, sneeze, speak, or sing. Close, prolonged, frequent, or intense contacts are the main ways that leads to 22% of the infection rate. Other resources include: foreign-born from areas where TB is common, residents and employees living in plagued congregate settings, health care workers who serve severely infected clients, low-income populations, highly inflicted racial or ethnic minority populations, children exposed to severely infected adults, and persons who inject illicit drugs.

Extra pulmonary TB that occurs outside the lungs may spread through lymphatic or hematogenous dissemination to any tract or through coughing and swallowing to the gastrointestinal tract. Such a type of bacteria may remain dormant for years at a particular site before causing the disease. Since extra pulmonary TB can affect virtually all organs, it has a wide variety of clinical manifestations. A matter which causes difficulty and delay in its diagnosis (Mehta, 1991; Gonzalez et al., 2003). Though, it is said to be more often diagnosed in women and young patients (Rieder et al., 1990; Gonzalez et al., 2003; Yang et al., 2004; Noertjojo et al., 2002; Cowie and Sharpe, 1997; Antony et al., 1995; Chan-Yeung et al.,2002). In the United States, extra pulmonary TB is associated with ethnic minorities and with those born in other countries (Rieder et al., 1990) while in Asia, lymphatic TB occupies the front position of the risky infectious diseases (Cowie and Sharpe, 1997, 1998; Moudgil and Leitch, 1994; Nisar et al., 1991; Ormerod, et al., 1991). A study of Somali TB patients in Minnesota showed frequent lymphatic TB as well (Kempainen, et al., 2001). In HIV-infected patients, the frequency of extra pulmonary TB depends on the degree of decrease in cellular immunity (Huebner and Castro, 1995; Barnes, et.al., 1991). While in patients with <100 CD4 cells/mL, extra pulmonary and disseminated TB counts for 70% of all forms of TB (Jones, et al., 1993). The materials needed for culture confirmation of extra pulmonary TB is much more difficult than that for culture confirmation of pulmonary TB (Gonzalez, et al., 2003).

1.2 Economic and Social Effect of Tuberculosis

Statistically speaking, Mycobacterium tuberculosis infects one-third of the world's population and is the most common single death causing agent in young adults (WHO, 2008). Globally, it accounts for 2.5% of the other diseases. However, the consequences of tuberculosis (TB) on society are huge. Worldwide, one person out of three is infected with Mycobacterium tuberculosis, i.e. two billion people in total. Currently, it holds the seventh place in the global ranking of the causes of death. (Dye, 1999; Smith, 2004).

Economically speaking, TB hinders socioeconomic development for the high percentage of the disease, 75%, afflict the productive age group that ranges between 15-54 years. Furthermore, ninety-five per cent of all cases and 99% of deaths occur in developing countries, with the greatest burden in sub- Saharan Africa and South East Asia (Dye, 2006; World Health Organization, 2006a).

Despite the availability of Effective drugs for more than 50 years, every 15 seconds, someone dies from TB. Besides, the percentage of TB infection is every second of every day (Dye, 2005; WHO, 2000). In light of this, Dye (1999) and Smith (2004) add that unless intensive efforts are made, it is likely to maintain that position through to 2020 and it is likely for a person with active TB to infect an average of 10 to 15 other people every year.

The total Budget for TB control in 22 severely-infected countries in 2006 equals US$ 1.6 billion, taking into consideration the cost of the health system staff, the infrastructure used for TB control, in addition to the requirements of the National Tuberculosis Control Programme which is less than that of 2002 which soared to US$ 876 million. However, the Russian Federation and South Africa occupy the front position as far as TB costs are concerned, where their costs amounted US$ 810 million. However, even though the health systems managed to control the growing number of TB patients in 2006, TB financial costs in 2006 would have been the same as for the National Tuberculosis Control Programme budgets, i.e. US$ 141 million. Furthermore, such costs and such funding gaps are liable to be increased to US$ 2.0 billion, and US$ 180 million, respectively when all 74 infected countries are included. Globally, these 74 countries represent 89 % of TB cases (Dye, 2006; World Health Organization, 2006a). On the other hand, WHO estimates that 9.27 million new cases of TB occurred in 2007 (139 per 100 000 population), compared with 9.24 million new cases (140 per 100 000 population) in 2006 and with 44% or 4.1 million (61 per 100 000 population), were new smear positive cases.

As far as the expected cost for diagnosing and curing this disease is concerned, it is of three kinds: the direct, indirect and the intangible costs, and as stated below:

1.2.1 Direct Costs

Direct or immediate costs for diagnosing and treating are of importance for poor families. (Lubeck, 2003; Verstappen, 2004; Drummond et al., 2005) state, in this respect, that direct costs include the costs of medical care and related items, such as: the expenses of visiting doctors, laboratory and radiological examinations, hospital costs, medications, transportation to and from the doctors, and special aids.

1.2.2 Indirect Costs

A great economic loss occurs as a result of "indirect" costs, which involve the cost stemming from losing employees, traveling to health facilities, selling assets to afford TB treatment, and in particular, losing productivity due to illness and premature death (Smith, 2004; Floyd, 2003; World Health Organization, 2005a). In light of this, Johannesson (1996) indicates that indirect costs are "those resulting from the loss of function in one's usual activity, including work disability, sick-leave or reduced productivity".

In calculating the loss of productivity, the two commonly used methods are the human capital and the friction cost approach. The human capital approach evaluates the individual's productivity by the market price; that is the potential gross salary of the individual, including all of the employer's contributions. While in case of self-employed persons, the gross personal income includes the statutory insurance expenses or as Lofland et al. (2001) puts it, it takes a societal approach. The friction cost approach assumes that the disabled person is replaced by a currently unemployed person during the friction period, where the latter is the time during which the sick person is replaced. Hence, friction costs include all the expenses related to replacing that worker (ibid.).

The estimated cost of TB treatment in patients with susceptible tuberculosis in developed countries ranges from US$ 276 to US$ 1546 and for multi-drug resistant tuberculosis (MDR-TB) ranges from USD 1000 to 10000. (Wyss & Lorenz, 2001, and WHO 2000). Determining the approximate costs for effective tuberculosis control is an important factor in specifying the actual expenditures required for treating tuberculosis. A matter that could be achieved by taking into consideration both the direct and indirect costs of tuberculosis.

1.2.3 Intangible Costs

Lubeck (2003) and Xie et al. (2008) maintain that intangible costs can be defined as the pain and suffering of a patient because of the disease. It includes a reduction in the physical function, an increased psychological distress, and a reduced social function. Intangible costs can be measured either by HRQoL questionnaires or alternatively by a contingent evaluation method which is based on "eliciting the levels of willingness in paying".

Lienhardt et al. (2001) add that tuberculosis has a severe impact on the impoverishment of patients and their households. The major factors which lead to impoverishment involve the following: the inability to work due to illness, the direct and indirect costs of accessing diagnosis and treatment, and the repeated visits to different care providers, which are associated with providers and patient's delays.

DOTS have the potentiality to reduce the economic and social effect of TB for patients and their households. However, few studies have explicitly examined this issue. The study in Uganda by Saunderson (1995) found that under DOTS, patient costs were reduced and they were able to start working again quickly.

In South India, Muniyandi et al. (2008) conducted a comparative study to calculate the costs of treating TB patients, using DOTS programme with those who were treated without using such a programme. The total number of patients was 896, divided as such (455 for DOTS and 441 for non-DOTS). Throughout the study, it was found that the direct cost for patients registered in DOTS areas, and for the mean pre-treatment was significantly lower than that in non-DOTS areas (Rs 874 vs. Rs 1,064) and that the mean direct costs during the treatment were also lower than that of the former (Rs 227 vs. Rs 250).

Pre-treatment indirect costs were nil in Rs 951 in the DOTS area compared to Rs 1,895 in the non-DOTS area. Throughout treatment, the indirect costs were significantly less in DOTS than in those of the non-DOTS (Rs 825 DOTS vs. Rs 1,821 non DOTS). As for the total mean cost of pre-treatment direct cost, it was lower in DOTS, Rs 1,762 than in non-DOTS area, Rs 2,903. The total mean of the direct costs during the treatment was also lower in DOTS, Rs 1,014, in comparison to Rs 2,069 in non-DOTS. Generally speaking, the indirect costs were significantly lower in the DOTS area than in non-DOTs ones.

Sreeramareddy et.al. (2008) conducted a retrospective study for about 474 patients in a tertiary care hospital that lies in Western Nepal for the purpose of comparing demographic, life-style and clinical characteristics between EPTB and PTB patients. The study found that the ratio of males to females was 1.07 (119/111) in EPTB and 2.29 in PTB (170/74), and that the median age of EPTB patients (29.5 years) is much lower than that of PTB patients, (47.5 years). Further, the study stated that, in the past, smoking and immunosuppressive drugs like steroids or anti-cancer drugs, diabetes and TB were mostly and directly related to PTB.

Studies from a number of developing-countries revealed that the poor have much less access to TB and DOTS programmes than the non-poor, to the extent that they can be excluded from TB care (Singh et al., 2002; Balasubramanian et al., 2004). Cohen et al. (1999) carried out three studies to examine the association of several markers of social status (unemployment, perceived and observed social status) with the host resistance to upper respiratory infections. The study found that unemployment and lower social status were associated with the increased susceptibility to infection. Such an association proves the fact that the grave impact of this disease occurs in the lowest social status groups. Thus, the further the increase in social status, the more decreases in susceptibility.

Portero, et al. (2002) noticed that there is a relationship between being healthily uneducated and the percentage of TB infection among the general population of Metro Manila, Philippines. That is, a lower score was found to represent the general knowledge about TB while a higher score was independently associated with college education. On the other hand, the low monthly-paid persons were characterized by having no TB knowledge; no intention of seeking health care and by no self-treatment of TB.

Schoeman et al. (1991) studied the relationship between the socioeconomic factors and pulmonary TB. By measuring variables, like: demographic details, general living conditions, household ownership of luxury items, and weekly consumption of four proteins (meat, fish, chicken and cheese). They concluded that no significant differences were found between cases and controls on most of the variables, and that the overall significant differences were on the pattern of language groups, employment and meat and chicken consumption. Such a tendency was observed for more employed cases than for the controls, who are of primary school education. However, no conclusive evidence was found on the association between socioeconomic factors and the risk of developing TB.

Gustafson et al. (2004) studied the impact of demographic, socioeconomic and cultural risk factors on active TB in Guinea, Bissau. They found that Bissau has a very high incidence of intra-thoracic TB. Factors as the human immunodeficiency virus (HIV), increasing age, male sex, ethnicity, adult crowding, family structure, and poor housing conditions were independent risk factors for TB. Apart from HIV prevention, TB control programmes need to emphasize risk factors, such as: the socioeconomic inequality, ethnic differences, crowding, and gender.

Souza et al. (2000) identified that socio-demographic risk factors are statistically associated with TB in Brazil, within "defined population bases" (i.e. populations living in areas with well-defined boundaries). A matter which makes it possible to construct different levels of aggregation, including census tracts, neighborhoods, and sanitary districts. The results, further, showed that the distribution of such a disease at the census-tract level is not aggregated randomly. The results also involved the need for additional ways of stratifying this population and expressing different collective levels TB risks. The results, furthermore, indicated that there were high percentages of households without satisfactory sanitary installations and without regular garbage collection, in addition to noticeable percentages of illiteracy among persons aged between 10-14 years and among extremely limited schooling heads of family.

Floyd et al. (1997) conducted a study in rural South Africa to compare the cost-effectiveness of (DOT) with conventionally delivered treatment for tuberculosis. Conventionally, the patients were stayed in the hospital for the first two months of treatment to ensure compliance with treatment during the intensive phase. But, throughout their study, they found that the directly observed treatment was 2.8 times cheaper to deliver than that of the conventional treatment (US 4740.90 compared with US$ 2047.70) and that it was more cost-effective, costing US$ 890.50 per cured patient compared with either US$2095.60 (best case) or US$3700.40 (worst case) of the conventional treatment.

The analytical study of Cost-effectiveness was done by Sanderson (1995) in Uganda to estimate the total costs borne by the patient and the health service for different treatment program designs. The study concentrated on two regimens (designs) of treatment: the first one is currently used and consists of two monthly hospitalized initial phase then four to ten months continuation phase. The other regimen consists of four non-hospitalized months, weekly supervision and of blister usage in the initial phase while the continuation phase is as the current used regimen.

The study found that the design based on an ambulatory treatment of patients without hospitalization is costlier than that depending on hospitalization during the initial phase (current regimen) which equals £ 115.23 and £ 190.09, respectively. The study also measured the cost for patients to be approximately 70% of the cost of the current used regimen (i.e., before diagnosing, during hospital stay, the lost work time and the social cost).

Another study of cost effectiveness was carried out by David & Daniel (1999) in California during 1995 to compare between self-administration therapy (SAT) and directly observed treatment (DOT) for patients of less risky TB. They estimated that the rate of treatment default was 1.7%. The study found that SAT has more cost effectiveness than DOT. The total cost of SAT is less than DOT by US$ 1.83 million, excluding the cost of patients out of pocket money, the time of work lost, diagnosis and out of hospitalization.

Muniyandi et al. (2005) conducted another study to see the economic impact of TB in Tamilnadu, India during June and December 2000, to assess the expenditures incurred due to TB whether direct medical, non-medical, indirect and the total costs before and during the treatment and to specify the effect of such a disease on employment. The study arrived at the following fact that the median direct, indirect and total costs for 343 patients who completed their treatment successfully were Rs 340. During treatment, the direct costs, Rs 100, were more than 50% from patients who did not get any indirect costs in both pre treatment, and during treatment periods. Moreover, the total costs were Rs 1398. In other words, patients have lost about 12%, i.e. more than 60 workdays.

In (2009) Kik et al. conducted another comparative study to compare the direct and indirect costs of pulmonary and extra pulmonary 60 immigrant TB patients in Netherlands, and specifically, at the 14 Municipal Health Services (MHSs) and the two specialized TB hospitals from April 2007 to October 2007. In the course of the study, they did not observe any significant differences between the characteristics of the interviewed patients of PTB and ETB though ETB patients tended to be older than PTB patients. The expenditures of patients varied widely. For instance, the direct costs during the entire TB illness averaged €353 (median €190); the total direct costs of patients ranged from €0 to €3961; and the costs during the pre-diagnostic period were slightly higher for patients with ETB (mean €10, sd 18.8) than that with PTB (mean €3, sd 7.4, ). Most of the costs were incurred if patients were hospitalized, and in case of indirect costs, the average patients lose 81 days of their normal productivity due to TB infection (i.e. a median of 60 days) where ETB patients, on average, lose much time during the pre-diagnostic period than those of PTB patients.

Dejonghe et al. (1992) evaluated the direct cost effectiveness of standard and short-course treatments for the smear positive TB patient in Malawi, Mozambique and Tanzania and found that short-course chemotherapy with hospitalization is approximately 23% cheaper according to the heath services perspectives than the standard treatment and that by implementing the ambulatory short-course of treatment, the cost of treatment will be reduced to 35%, 65%, and 50%, in Malawi, Mozambique, and Tanzania, respectively.

Brown et al. (1991) estimated, in the united states, the total expenditures of health care for the patient, inpatient diagnosis and treatment, screening, preventive therapy, contact investigations, surveillance and for the outbreak investigations of tuberculosis. Throughout the study, which involved 26, 283 cases, they estimated that 90% of the patients were given an outpatient treatment (23,654 TB cases) and that the direct medical expenditure for TB was approximately US$ 703.1 million. From that, only US$ 423.8 million represented the cost of inpatient care whereas US$ 182.3 million represented the outpatient care. The study depended on estimation to count the total costs for drug resistant (10.7%) and for multi-drug resistant tuberculosis (3.5%) while the indirect cost of illness was excluded.

Wyse & Lorenz (2001) conducted a study, in Dar es Salaam, Tanzania, on the costs of tuberculosis for households and health care donors. This study included one hundred ninety-one patients with a treatment period ranging from 8-to-12 months. They found that the average costs to a patient range from US $ 186 to US $ 1457 (including costs such as the following: x-ray examinations, laboratory, consultation, drug, hospitalization, transportation and productive loss costs) and that the average costs to the health care donors per patient was only US $ 90 (including programme management, laboratory unite, drug and ambulatory care cost). The known major types of costs in the study were the costs of drugs, costs transportation and, in particular, the costs due to the loss of work force.

A cost effectiveness study, in Pakistan, was conducted by Khan et. al. (2001); the study lasted from Sep. 1996 until June 1998 for the purpose of finding out the most cost effective strategy for the implementation of direct observed treatment (DOT). Throughout the study, the patients were divided into three different groups according to the type of the DOT used strategy, such as: self administration of medication, DOT by family members or DOT by health care workers. The results illustrated that the type of self-administration DOT was themost cost-effective. Its costs soar high to US $ 164 per patient cured compared to the other strategies as DOT with family, and DOT with healthcare worker where their costs were US$ 172 and US$ 310, respectively.

A pharmacoeconmic evaluation of tuberculosis was conducted by Elamin et.al. (2008) in Penang, Malaysia. The number of patients was 202 with a treatment period ranging form 6-to-12 months. The study found that the average cost to the healthcare providers per patient was only US $ 189.5 (including x-ray examination, laboratory tests, consultation cost, drug and supplies, health staff time, hospitalization costs, stationary, and over head cost). Furthermore, the average costs to the patients was US $ 726.90 (including meals, transportation and the time away from work). The major types of costs documented in the study were drug and supplies, transportation and, in particular, the cost due to the loss of work forces

Further cost-effectiveness study was carried out by Islam et al. (2002) in Bangladesh to compare the cost-effectiveness of TB programme run by the Rural Advancement Committee (RAC), which used community health workers (CHWs), with that of the government TB programme which did not use CHWs. Such a study identified a total of 186 and 185 TB patients over one year to find that the application of CHWs was more cost-effective than government area, which obtained a cure rate at 84%, i.e. US$ 64 per patient compared with 82% cure rate, i.e. US$ 96 per patient in the governmental areas.

Rajeswari et al. (1999) conducted a study on the socioeconomic impact of TB on patients and families in India to assess the expenditures involved in tuberculosis diagnosis and treatment; the effect of tuberculosis on patient's family and to estimate the loss of income due to work disability. The study included that a total of 304 patients, who received their treatment from private practitioners, governmental and non-governmental hospitals. The expenditure cost included direct medical cost, such as: consultation fees and the money spent on investigation and drugs; direct non-medical cost, such as the money spent on transportation, loading, special food and on persons accompanying the patients; and indirect cost, as the loss of wage and the decreased earning ability due to illness. They found that the direct cost in the three different types of health facilities was US$ 38.5, US$ 48.5 and US$ 253.00, and that the total cost of TB treatment was US$ 147.50, US$ 169.50 and US$ 368.50 in the governmental hospital, non-governmental hospital and private practitioners, respectively.

1.3 Health Related Quality Of Life (HRQL)

Carr et al. (1996) stated that the broad-ranging concept, the quality of life (QoL), incorporates health states, satisfaction with work, leisure time, level of independence, social relationships, and environment. The World Health Organization (WHO) defined QOL as the ability of individuals to perceive their position in life within the cultural contextual and the valuable systems in which they live by in accordance with their goals, expectations, standards and concerns (Anonymous 1995). According to Khanna and Tsevat (2007), HRQoL is a multi-dimensional concept that associates the physical, emotional, and social components of an individual with his/her medical conditions or treatment).

In recent decades, the interest of measuring HRQoL has increased noticeably due to advances in medical science and technology and to the increased number of people who live contentedly with chronic diseases and disabilities. According to the patients' perspective, the change in the morbidity profile evoked the need of evaluating the outcome of different treatments.

Measuring HRQoL can be done either by disease-specific tools or generic measurement tools. The generic instruments allow comparisons between patient groups with different diagnoses, whereas the disease-specific instruments give information about only one certain disease and its effect on health. Disease-specific instruments are, however, more sensitive to the important differences in health status. They are; therefore, successfully used for measuring results of specific treatments. A well-known example of a disease-specific instrument is the questionnaire of Rheumatoid Arthritis Quality of Life (RaQoL). It is the first patient-completed instrument, especially designed to be used with RA patients (de Jong et al. 1997). Other example of a disease-specific instrument is the questionnaire of Tuberculosis Quality of Life (SF-12 Questionnaire by Dhingra and Rajpal 2003).

The generic instruments are divided into two kinds: profile and single index score measures, as illustrated below:

  1. Profile measures describe the health state according to various physical and emotional dimensions, such as physical functioning, bodily pain, general health, social functioning, and other dimensions. A well-known example of it is the widely used a Health Status Survey Questionnaire resulted from a Medical Outcomes Study of a Short Form with 36 items, (SF-36).
  2. Ware and Sherbourne (1992) mentioned that SF-36 is a well-validated generic health status measure used in health surveys of both general and various populations with different diseases. The 36 items in the questionnaire are grouped into 8 multi sub-scale items that measure the physical functioning; role limitations due to physical problems and bodily pains; general health perceptions; vitality; social functioning; mental health; and role limitations due to emotional problems. For each subscale, there is a score that calculates values from 0 to 100, where the low scores indicate poor health.

    Chamla (2004) prospectively measured active TB patients' HRQL at the start point, middle, and at the end point of the treatment. During the treatment, role physical, vitality and mental health scores decreased after the initial 2 months, but showed an overall improvement at the end of the treatment while all the other subscale scores showed a gradual increase throughout the treatment. After the anti-TB treatment, the study observed a significant improvement in all physical health subscales of the SF-36 (physical problems and bodily pains; general health, p < 0.05), besides two mental health subscales role limitations due to emotional problems and social functioning (p < 0.05) improved significantly. The study also observed that, at the end of the treatment, active TB patients still significantly scored lower at role physical, vitality and mental health subscales compared to general population comparisons. Generally speaking, physical health subscales were more affected than mental ones. Furthermore they found that younger people tended to have better HRQL than older ones.

    Two studies, in Canada at the Montreal Chest Institute, a TB clinic, were conducted by Dion et al. (2002, and 2004); the studies compared, in three consecutive interviews, between patients who had already begun treating active tuberculosis (three consecutive interviews during the intensive phase), people with LTBI and people had previously been treated from TB disease, the studies noticed that the active TB patients scored significantly lower in SF-36 physical Component Scores, but not in Mental Component Scores, when compared to people with LTBI and those with previously treated TB disease.

    Wang et al. (1998) maintained that active TB patients reported lower scores (p < 0.01) across all SF-36 subscales than the healthy non-TB people, whose role of physical and role of mental are most affected. Guo et al. (2008, 1998) stated that, in comparison to those with LTBI, people with active TB scored significantly lower at all SF-36 subscales. In contrast, SF-36 scores among people with LTBI before taking the preventative therapy were very similar to that of U.S. norm references. In addition they found that older people tended to have poorer HRQL than younger ones.

    Marra et al. (2008) identified areas of HRQL that are affected by LTBI and active TB disease, the study included the patients with recently diagnosed active TB (104) or LTBI (102)patients , the Short Form-36 (SF-36) at baseline, 3 months, and 6 months were administered. The study analyzed the differences in HRQoL of both Latent TB and Active TB infection and discovered that, in comparison to those with LTBI, people with active TB scored significantly lower at all SF-36 subscales, in the onset of treatment. In contrast, SF-36 scores among people with LTBI before the preventative therapy were very similar to that of U.S. and after 6 months of drug therapy, the study noted a significant HRQL improvement in active TB patients throughout the 6 months of treatment, using SF-36. Although anti-TB treatment was generally improved HRQL, active TB patients still had poorer HRQL in Physical Component Scores and Mental Component Scores at the end of the treatment, compared to the LTBI and general population. The study added that, after the preventive treatment, Mental Component Scores among people with LTBI declined significantly, while Physical Component Scores stayed unchanged.

    Study in the Ankara, Turkey was conducted by Aydin and Ulusahin (2001); they compared the TB patients with COPD patients and the study found that TB patients had a lower prevalence of depression and anxiety and a lower level of disability. The study assumed that the chronic duration of COPD and the older age of the COPD patients may lead to a higher prevalence of psychological impairments, and that with multi-drug resistant, TB patients reported to have the worst disability level.

    Yang et al. (2003) indicated that pulmonary TB patients showed more psychological symptoms and a lower degree of social support in comparison to healthy controls. Moreover they observed that males were more likely to have better health than females.

    Duyan et al. (2005) found that the best HRQL correlated with variables like: the higher income, education, better housing conditions, better social security, and with closer family's and friends' relationships. Further addition the study found that there were no significant associations between gender, age and HRQL in TB patients

    HRQoL assessment study for pulmonary TB and LTBI patients in Tarrant County in the United State was performed by Pasipanodya et al. (2007); they measured HRQL among pulmonary TB, who completed at least 20 weeks of the treatment period. They discovered that, in comparison to those with LTBI, treated TB patients had lower scores and that lung functions and/or those born in the United States (against foreign born) tended to have better HRQL outcomes. Moreover, no gender and smoking difference were noted.

    Rekha et al. (2009) evaluated HRQoL of pulmonary TB in Chennai, India; the study noted that the HRQoL in TB patients in terms of symptom, activity and impact including the overall scores was worse in status when compared to that of the general population. Further, the study concluded that the females were the worst in status and that the male smokers had a low HRQoL.

    Muniyandi et al. (2007) assessed HRQL of the previous sample of TB patients for one year after successfully treatment completion. They saw that 40% of these people reported persistent symptoms, such as breathlessness, cough, chest pain, and occasional fever. They further calculated three SF-36 component scores: the physical, mental, and the social well-being to arrive at the fact that there was no gender difference on physical well-being score. However, females scored much lower at mental and social well-being scores while younger people and older ones had only lower physical and mental well-being scores. They also offered U.S. general population norms for the three component scores and concluded that TB patients' HRQL came back to its normal level after one year achievement of the treatment.

    Letrait (1996) stated that apart from the physical symptoms, a patient with tuberculosis faces several physiological, psychological, financial and social problems. These problems impair the quality of his/her life and have a great impact on his/her well being. It has been recognized that the quality of life indices, which focus on patients' own perception of disease, provide additional information that cannot be found from conventional clinical and functional measurements.

  3. The single index score instruments produce a single value (utility score) of 0-to- 1 scale that provides an overall picture of the level of HRQoL and that changes in it. Utility values are necessary for calculating the Quality-Adjusted Life Years (QALYs), developed to combine the quantity and quality of life into a single measure.

SF 12 (Short Form Health Survey)

Jenkinson (1997) said that Short Form Health Survey, SF-12, is an instrument of choice, where a short generic measure provides summary information on the physical and mental health status. Such a device is able to produce the two summary scales originally developed from the SF-36 with considerable accuracy and with far less respondent effect.

Study in New Delhi Tuberculosis Centre, India conducted by Dhingra and Rajpal (2003, 2005), by using Short Form (DR- 12) at baseline, four weeks and eight weeks of treatment, The study observed that there was a gradual improvement on DR- 12 scores in active TB patients over the course of the treatment. In general, the symptoms scores showed better improvement than socio-psychological and exercise adaptation scores. They added that there was a significant difference between the scores of pulmonary and extra-pulmonary tuberculosis patients (higher in extra-pulmonary cases) both in Symptom Scores and in Total HRQL Scores at the start point of treatment. Moreover, sputum negative patients showed a higher Symptom Score than the sputum positive patients.

In India, Singh et al. (2004) evaluated the impairment of HRQL for 100 patients (of 15 years & older) with tuberculosis during their treatment at 0 week, 4 weeks & 8 weeks by using a HRQL questionnaire. The Questionnaire was based on symptoms (score I), physiological, psychological & social interaction of the patients (score II). The study observed that there was a perceptible increase in the HRQL score at week 4 & 8 in all categories of patients and in patients, who did not convert sputum negative at the end of the intensive phase though the latter's increase was low as compared to those who turned sputum negative. Finally, an improvement was also noticed in both male & female patients with pulmonary or extra pulmonary disease.

1.4 Epidemiology of tuberculosis in Yemen

Tuberculosis is still one of the major problems in Yemen and Yemen was considering one of the high burden countries in the region for long time based on latest evaluation of TB which had done by National-Wide Survey of the Tuberculin Testing among school children (Annual report of NTCP 2007).

According to the report NTCP 2007, ARI= (0.86%) which is equivalent of occurring (43 NSS+)/100,000 Population each year. The annual expected incidence of NSS+ is =8480, and same number of other forms of Tuberculosis. The most recent estimated of tuberculosis in Yemen published by WHO (2007) shown that; the annual incidence of NSS+TB cases= (37/100,000 Population), which means =( 7297 NSS+TB cases/Year), and for all forms of TB cases=(82/100,000 Population ), while the prevalence is 136/ 100,000 Population, mortality (death /100,000 Population /Year =10), HIV+ among new adult TB cases= 0.8%) and the new cases of Multi-drug resistant/ 2004= (3.1%) and in previously treated cases= 9.4%.

The majority of tuberculosis patients in Yemen are in the period of 15-54 years of age as shown in figure 1.1 and the pulmonary tuberculosis represented 72 % while the extra pulmonary represented 28% most of them in Sana'a city 24%. (NTCP report 2007)

1.5 Transmission and Pathogenesis of Tuberculosis

As it stated earlier, the bacterial disease, tuberculosis (TB), is transmitted by particles, or droplet nuclei that are expelled when persons who have pulmonary TB sneeze, cough, speak or sing (Brewer and Heymann, 2004; Bjune, 2005; CDC, 2000; Gandy & Zumla, 2002; Feja, 1999).

Droplet nuclei which contain one to 10 bacilli whose diameter is roughly 10 µm are expelled through coughing, and suspend in the air to be later transported by air currents. Normal air currents can keep them airborne for prolonged periods of time and spread them throughout rooms or buildings. Some of these droplet nuclei, usually those larger than 10 µm, are inhaled and anchored in the upper respiratory tract (Wells, 1995).

The effective droplet nucleus is very small; measuring 5 µm or less. Despite small, it is able to avoid the mucus and ciliary system action and produce the anchorage in bronchioles and respiratory alveoli. Being small in size allows them to remain suspended in the air for prolonged periods of time. (Friedman, 2001; CDC, 2000; WHO 1999).

TB transmission occurs with greater prevalence in poorly ven­tilated and crowded spaces (Hawker et al., 1999; Beggs et al., 2003; Elender et al., 1998 and Valin et al., 2005). A sputum smear-positive individual with pulmonary TB is four to six times more conta­gious than a smear-negative case (Menzies, 1999). However, sputum smear-negative, culture-positive patients with pulmonary TB are also infectious to others (Hernandez-Garduno, 2004; Behr, 1992). According to Jerant et al. (2000); White & Williman (2001); and WHO (1999), environmental factors that suit TB transmissions include the following:

  1. The exposure of susceptible individuals to an infectious person in a relatively small, enclosed space
  2. Inadequate ventilation that results in either insufficient dilution or in the removal of infectious droplet nuclei
  3. The recirculation of air containing infectious droplet nuclei
  4. The duration of exposure
  5. The susceptibility of the exposed person.

Correa (1997), Starke (1996), and Vallejo (1994) all maintained that five to 200 inhaled bacilli are enough to be successfully infected. After inhalation, the bacilli are usually installed in the mid lung zone to move then to the distal and sub pleural respiratory bronchioles or alveoli. Subsequently, alveolar macrophages phagocytose the inhaled bacilli. However, these first macrophages are unable to kill mycobacteria; accordingly, the bacilli continue their replication inside these cells. As a result, logarithmic multiplications of the mycobacteria take place within the macrophage at the primary infection site. Then, the infected macrophages transport to the regional lymph nodes to disseminate the lymphohematogenous of the mycobacteria to other lymph nodes and organs, such as: kidneys, epiphyses of long bones, vertebral bodies, and juxtaependymal meninges that are adjacent to the subarachnoid space, and, occasionally, to the apical posterior areas of the lungs. In addition to whatever mentioned, chemotactic factors, released by the macrophages, attract the circulating monocytes to the infection site, and lead them to be mature macrophages with an increased capacity to ingest and kill free bacteria.

Correa (1997); Friedman (2001); and CDC (2000) noticed that two or three weeks after the initial M. tuberculosis infection, a cell-mediated immune response is fully established. While CD4+ T helper cells activate the macrophages to kill the intracellular bacteria and finally to motivate the formation of epithelioid granuloma, CD8+ suppressor T cells lyses of the infected macrophages, which resulted in the formation of caseous granulomas with central necrosis. Due to the fact that mycobacteria are not able to grow under the adverse conditions of the extracellular environment, most infections are controlled by the host immune system and the only evidence of a real and effective infection is a positive tuberculin skin test TST.

However, the initial pulmonary infection site, which denominates "primary complex or Ghon focus" and its adjacent lymph nodes, sometimes, reach a sufficient size that activates the development of radiographically demonstrable necrosis and calcification (Feja 2005, Schluger 1994).

1.6 Diagnosis of Tuberculosis

For proper and complete medical evaluation of TB diagnosis, the following steps have to be taken into consideration:

1.6.1 Determining the Medical History

One should obtain from the patient a complete history of the possible exposures to people with TB, Multidrug-Resistant TB (MDR-TB), past history of TB, previous positive tuberculin skin test, and previous history of treatment either for TB infection or any disease. An adequate clinical history should look for information about household, immigration from high prevalence area, and about the medical factors which motivate factors for TB disease (e.g. diabetes mellitus, HIV infection, injection drug users and homeless people). (American Thoracic Society (2000), American Thoracic Society/Centers for Disease Control and Prevention (2001), Correa (1997), Feja (2005), Jacobs (1993), Taylor (2005), Vallejo (1994).

1.6.2 Examining the Physical Symptoms

Physical examination is an essential part in evaluating, and obtaining the history of clinical signs and symptoms of pulmonary TB, which may include prolonged and productive coughs over two weeks duration, hoarseness, chest pain, or hemoptysis. Systemic symptoms of TB may involve unexplainable weight loss, fever, night sweats, appetite loss, easy fatigability, or chills.

1.6.3 Examining the Bacteriological Aspect

Such a step implies adopting the following examinations of:

1.6.3.1 Sputum Smear

Bacteriological examination of sputum is referred to as acid fast bacilli (AFB). Such an examination is considered the only way in which the diagnosis of pulmonary tuberculosis can be confirmed. Whenever tuberculosis is suspected, three specimens of sputum should, at least, be collected and examined by microscopy and the examined samples be preferably obtained within two days.

1.6.3.2 Sputum culture

Timothy (2006) stated that the culture of tubercle bacilli is a regarded as a confirmation step that is necessary for carrying out the sensitivity test that is in turn essential for monitoring the initial and acquired drug resistance to anti-tuberculosis drugs.

1.6.4 Examining TB Radiographically

Chest x-ray screening has been used for active case finding for the last seventy years Golub (2005). WHO (1994), CDC (2000) and Friedman (2001), mentioned that the x-ray diagnosis of tuberculosis is unreliable because other chest diseases may resemble tuberculosis on x-ray, and because pulmonary TB may show many forms of radiographic abnormalities.

1.6.5 Adopting Tuberculin Skin Test (TST)

A tuberculin skin test can be done by using the Mantoux method. Such a test is utilized to diagnose Latent TB Infection (LTBI) (Laura, 2007). Although this test is considered the best-studied test available to diagnose TB infection, it is not useful in diagnosing active TB disease, but rather in detecting the presence of TB infection. A positive TST does not necessarily signify active TB; it may be falsely negative in up to 20% of clients with active TB disease. Further, diagnostic tests (e.g. CXR, sputum for AFB smear, culture) should be carried out before diagnosing active TB. False positive reactions to the TST may result from the exposure to non tuberculosis mycobacteria (NTM). A negative reaction to the TST does not exclude the diagnosis of active TB disease or LTBI. Some persons may have a false negative reaction to the TST if they are tested too soon to TB exposure. In general, it takes 2 to 12 weeks after the initial infection of person's immune system to respond to the tuberculin antigen (delayed hypersensitivity reaction).

1.7 Treatment of Tuberculosis

1.7.1 History of TB Treatment

Before discovering specific antibiotics for TB treatment, the mortality of patients with pulmonary disease (disease of the lungs) was about 50%. The introduction of anti-tuberculosis drugs in the 1950s and the development of the various drug regimens meant that by 1980s, there was a 98% chance of cure. However, such a treatment has to be continued with good quality drugs for six months to ensure the completion of the therapy.

The present TB chemotherapy treatment is one of the most spectacular achievements in medicine. The first trials of Tuberculosis treatment began when Robert Koch (1882) discovered a staining technique that enabled him to see Mycobacterium tuberculosis. Since then, the scientist started to find drugs that are effective for such organisms. Below are the names of scientists with their invented drugs:

  1. Cantan (1885) discovered that inhaling the cultures of nonpathogenic bacteria could diminish the quantity of Mycobacterium tuberculosis in patient sputum.
  2. Babe (1888) found that the growth of bacteria bacilli could be inhibited by products of Gram-ve and Gram+ bacteria.
  3. Streptomycin was discovered in USA in 1944, and was soon brought to clinic use. It was considered the first specific anti-tuberculosis drug, but after few months of treatments the bacteria developed a resistance to streptomycin.
  4. Scientists in Europe continued working to find a cure for TB. They succeeded in developing para-aminosalycilic acid (PAS), which was brought into use in the late 1946s. By combining the two drugs, streptomycin and PAS in the regimen, the emergence of drug resistant bacteria was largely prevented and the cure became the norm.
  5. In 1951, there discovered isoniazed, pyrazinamide (1954), cycloserine (1955), ethambutol (1962) and rifampicin (1963).

1.7.2 Treatment of Latent Tuberculosis Infection (LTBI)

The purpose of treating asymptomatic infection is to prevent the development of active disease in the future. Such a treatment has other nomenclatures, such as: preventive therapy, chemoprophylaxis or latent TB treatment. Treating latent TB with Isoniazid (10 mg/kg/day or, at most, 300 mg/day) for six to nine months is indicated in every adult person susceptible to develop an active disease (International Union Against Tuberculosis and Lung Disease, 1994; Horsburgh, 2004; Castelo-Filho, 2004; Hopewell, 2006).

Such a treatment reduces the risk of developing the disease from endogenous reactivation, but it does not protect the patient from exogenous exposure. Therefore, when there is a possibility for recent new exposures to the tubercle bacillus, the patient must extend the treatment of latent TB (when receiving Isoniazid) or the instauration of a new treatment (when the previous one has already been discontinued).

The candidates for treating latent TB infection are:

  • household contacts of AFB smear-positive pulmonary TB patients, who have not recently been vaccinated with BCG, have TST in duration>10 mm; or and who have BCG vaccination within the previous two years with TST in duration > 15 mm;
  • individuals with TST conversion (a positive test with >10 mm in duration after a previously negative test, which had been applied 12 months earlier)
  • HIV-infected individuals with a reactive TST of > 5 mm;
  • HIV-infected individuals that report close contact with a smear-positive TB patient, regardless of the TST response; and
  • Individuals with a chest X-ray image consistent of residual TB, and without a history of previous anti-TB treatment.

In every case, and before starting the preventive chemotherapy with Isoniazid, the physician should confirm the absence of active TB disease. A step can be done by noticing the following:

F the chest X-ray should be normal; and

F the individual should be asymptomatic and should before beginning with the preventive chemotherapy exclude active TB, either pulmonary or extra pulmonary, particularly, in patients with moderate/severe immunodeficiency. Moreover, appropriate follow-up for the patient is necessary to ensure the supplement of a regular drug and at least 70% adherence to the preventive treatment regimen.

Rose (1992); Jordan (2001) noticed that risk-benefit analyses demonstrated cost effective benefits for Isoniazid preventive therapy in low risk reactors, and a substantial cost effective benefits in higher risk reactors, in addition to another type of benefits, substantial long-term public health, that is mentioned by Salpeter (1993). However, the overall effectiveness of Isoniazid preventive therapy in low or middle income countries has not been well-established.

1.7.3 Treatment regimens

Isoniazid (H)

Isoniazid is the most widely used anti-tuberculosis drug. It is given in the dose of 5 mg per kg body weight per day up to maximum 300 mg per day. It can be safely in pregnant women. A major side effect, hepatitis, develop in about 0.5 % of cases, if hepatitis is suspected or jaundice is observed stop treatment.

Rifampicin

Rifampicin is very potent, relatively non toxic drug. The daily dose for children and adults is 10 mg per kg body weight up to 600 mg per day. It can be safely in pregnant women. When given in recommended dosage, rifampicin dose not cause any side effect with great frequency, particulary during continuous daily administration.

One of the major side effects of rifampicin is hepatitis, although this is rare. Alcoholism, pre-existing liver diseases or the simultaneous administration of other hepatotoxic agents seem to increase the risk. The development of jaundice requires discontinuation of the drug.

Pyrazinamide

Pyrazinamide is most active during 2(3) months of therapy. The daily dose for adult is 20- 30 mg per kg body weight and for children 30-40 mg per kg body weight up to maximum 2500 mg. it may be used safely in pregnant women. The most serious side effect of pyrazinamide is hepatitis. Joint pains and occasional attack of gout, due to the diminished execretion and accumulation of uric acid may occur less frequently.

Isoniazid/thioacetazone

Thioacetazone may help prevent the emergence of resistance to other drug such as isoniazid. And therefore administered in combination with isoniazid. The daily dose is 2.5 mg per kg body weight for adults and children up to maximum of 150 mg per day. Hepatitis the major side effect occurs as with isoniazid alone. Cutaneous reaction in patients treated with medication (due to thioacetazone) may be more serious than other drugs. Exfoliative dermatitis or Stevens-Johnson syndrome may occur and can be fatal.

Streptomycin

Streptomycin has strong effect on the elimination of tubercle bacilli in cavities of the lungs. The daily dose is 15 mg per kg body weight for adult 20 mg per kg body weight for children, up to maximum of one gram. The main toxic side effect of streptomycin is vestibular damage. The risk increases with the dose and age.

Ethambutol

The primary use of ethambutol is to prevent emergency of resistance to the drugs. The daily dose in the first two months of chemotherapy is 25 mg per kg body weight in adults and 15 mg per kg body weight in children. When administrated for more than two months, the dose should be reduced to 15 mg per kg body weight per day. Ethambutol may be produce impairment of vision; a decrease in visual acuity, blurring and red-green color blindness.

1.7.4 Regimens

1.7.4.1 Regimen for positive pulmonary

New cases of AFB smear positive pulmonary tuberculosis and other newly diagnosed seriously ill patients sever forms of tuberculosis. This regimen includes patients with tuberculosis meningitis, disseminated tuberculosis, tuberculosis pericarditis, peritonitis bilateral or extensive pleurisy, spinal disease with neurological complications, smear negative pulmonary tuberculosis with extensive parenchymal involvement, intestinal or genito-urinary tuberculosis.

The regimen consists of:

Initial (intensive) phase: 2HRZS(E); i.e., isoniazed, rifampicin, pyrazinamide and either streptomycin or ethambutol, given daily under strict direct observation for 2 months (8 weeks). When the patient has completed the Initial phase 2 months and the sputum smear is negative the continuous phase is started. If the sputum smear is positive at two months, the initial phase of 4 drugs daily is continued for other four week s under strict observation. After this the continuation phase is started, regardless of sputum smear examination results.

Continuation phase: 6HT, e.g. isoniazed and thioacetazone daily for six months. For the patients who have serious adverse reactions (such as Stevens-Johnson syndrome, exfoliative dermatitis) ethambutol may be substituted for thioacetazone. Patients should come to the health facility every four week to collect their drugs for self administration at home.

1.7.4.2 Regimen of extra pulmonary and negative pulmonary

Initial intensive phase: 2HTS (E), i.e., isoniazid, thioacetazone and either streptomycin or ethambutol, given daily for two months. Patients should come to healthy facility every month to collect their drugs for self administration at home.

Continuation phase: 10 HT i.e., isoniazid and thioacetazone daily for 10 months. Patients should come to healthy facility every month to collect their drugs for self administration at home.

1.6.5 Re-Treatment of TB

The regimen according to WHO (1997) should be given to patients afflicted with tuberculosis diseases after completing the standard regimen (2 months of isoniazed, rifampicin, pyrizanamide and streptomycin or ethambutol then 6 months of isoniazed and thioacetazone). Re-treating TB involves passing through two phases:

  • Initial (Intensive Phase): this phase requires using 2HRZES/1HRZE, i.e. rifampicin, isoniazid, pyrazinamide and ethambutol, which is supplemented with streptomycin for the first two months. Then, the same drug is used again, but this time with no streptomycin. The dose should be taken daily for about one month and under direct strict observation. When the patient completes the initial phase which consists of 2 months and when the sputum smear is negative, the continuous phase is started. If the sputum smear is positive throughout the three months, the initial phase of treatment with four daily oral drugs lasts for other four weeks. If the patient is still smear- positive at the end of the fourth month, all drugs are stopped for 2-3 days, and a sputum specimen is sent to the laboratory for culture and for sensitivity testing. The patient should, then, start the continuation phase and refer to a specialist if possible.
  • Continuation Phase: the second phase demands using 5HRE, i.e., 5 months of isoniazid, rifampicin and ethambutol, which are given daily under direct strict observation. If the patient remains positive after the completion of the continuation phase, s/he is no longer eligible for this regimen. That is to say, this patient will be considered as a chronic case and will be dealt with accordingly.

1.7.6 Treatment of Drug-Resistant Tuberculosis

Tubercle bacteria developed resistance to the most effective drugs or at least to rifampicin and isoniazid, anti-TB drugs, or the so called Multi-drug-resistant TB. Such a process consists of two phases:

  • Initial Phase: this phase involves taking the following for three months: streptomycin, kanamycin or mikacin, pyrzinamide, quinolones (ofloxacin or ciprofloxacin), ethambutol or cycloserine.
  • Continuation Phase: in this phase three drugs should be used for 18-24 months, such as: ethionamide, quinolone, ethambutol or cycloserin:

1.7.7 Directly Observed Treatment (DOTS)

In 1994, the internationally recommended control strategy, later named DOTS, was launched. Hence, the abbreviation, DOTS, stands for Directly Observed Treatment, Short-course, and its key components include:

  • government commitment;
  • case detection by predominantly passive case finding;
  • standardized short-course chemotherapy for, at least, all confirmed sputum;
  • AFB smear-positive cases, provided under proper case management conditions;
  • a system of regular drug supply; and
  • a monitoring system for program supervision and evaluation.

Supplying drugs for 6 months for DOTS costs less than US$ 10 in some parts of the world. The World Bank ranked the strategy of DOTS as one of the "most cost-effective of all health interventions". Countries that employ DOTS are able to avoid an expected increase in drug resistance, such as the case in Cuba and Nepal, where levels of drug resistance showed a remarkable declination (World Health Organization 1994, World Health Organization 2002c). A total of 183 countries and territories implemented DOTS strategy in 2004. By the end of 2004, 83% of the world's population lived in DOTS-covered countries. DOTS programs notified 4.4 million new cases and relapsed TB cases in 2004, of which only 2.1 millions were new AFB smear-positive. In total, 21.5 million TB patients, and 10.7 million AFB smear-positive patients were treated in DOTS programs over 10 years ranging from 1995-2004 (Sharma 2006, World Health Organization 2006a).

Globally, the case detection rate by DOTS programs increased almost linearly from 11% in 1995 to 28% in 2000, and then were accelerated to 45% in 2003. If 7% of the global increase of detection between 2002 and 2003 was maintained, it would have reached approximately 60% by 2005, of which only 10% was below target. Comparing different parts of the world in 2003, it was found that case detection was the highest in Latin American (48%) and Western Pacific regions (50%), and the lowest was in Eastern Europe (22%). The recent acceleration has been mostly due to the rapid implementation in India, where case detection increased from 1.7% in 1998 to 47% in 2003. Whereas in China, case detection increased from 30% in 2002 to 43% in 2003. India and China together accounted for 63% of the increase in DOTS case-notification between 2002 and 2003. Hence, supporting agencies like: growing coverage, governments, donors, and others began asking for any piece of evidence that DOTS has on an expected epidemiologic impact (De Cock, 1999; World Health Organization, 2002b; World Health Organization, 2002c; Dye, 2005; Frieden, 2005; Sharma, 2006; World Health Organization, 2006a).

The global success rate of DOTS treatment has been high (77%) since the first observed cohort in 1994. In 1998, it remained above 80%, even though the cohort size increased 6 folds to 1.4 million patients. There is, however, much variation among regions. The success of treatment exceeded 85% in the Western Pacific region, largely because China reported a 93% success rate. Clearly, the biggest failure of DOTS was in Africa, where rates of TB continued to rise. In 2002, the African region registered less than 75% cure rates while death rates were as high as 8% in patients co-infected with M. tuberculosis and HIV. Whether this statistic indicates a failure of DOTS, or is the result of the rapid spread of the HIV epidemic is still debatable. Eastern Europe, another region plagued by poor health systems and by an expanding HIV epidemic, witnessed continuing increases in TB incidence rates throughout the 1990s, though the increase now seems to have peaked. Increases in the incidence rates of the disease are 274. A Global effect of TB was also noted in Central Asian countries, where death rates in DOTS recipients remained stable at 5%. However, both Eastern Europe and Central Asia represent hotspots of MDR-TB (Dye, 2005; Frieden, 2005; Sharma, 2006; and World Health Organization, 2006a).

Although the decline in TB has almost been avoided by good chemotherapy programs in countries such as Chile, Cuba, and Uruguay, there have only been few recent and unequivocal demonstrations of the impact of DOTS in severely plagued countries, as it happened in Peru and China. In Peru, the rate of pulmonary TB started decreasing annually by 6% with DOTS implementation in 1991. In 13 provinces of China that implemented DOTS, the prevalence rate of culture-positive TB was cut by 30% between 1990 and 2000 (Dye, 2005; World Health Organization, 2006a).

Although the substantial expansion and success with DOTS, most countries will probably not trespass the aspiration of the United Nations Millennium Development Goals in halving the prevalence of TB and its death rates between 1990 and 2015. Further, innovative steps should be taken into consideration when aspiring to control TB globally. The main objectives are: continuing DOTS expansion with more funding and oversight, building an existing DOTS programs to pursue DOTS-Plus, increasing funding on research to improve diagnosing, curing, and vaccining, re-visiting strategies of chemoprophylaxis and active case finding, and using DOTS to strengthen the infrastructure of public-sector and community- based health programs and insurance schemes (Sharma, 2006; World Health Organization, 2006a).

In Yemen, the government lined the policy of the National TB Control programme (NTP) with that of WHO TB control strategy of Direct Observed Treatment, short course (DOTS), where patients were observed by nurses when swallowing their medication in the initial phase of treatment, and when missing their clinic appointments, nurses will call them to come, otherwise, home visits will be done.

1.7.8 Adherence to TB Treatment

To ensure adherence and therapy completion, all patients must be treated under directly observed therapy (DOTS). Poor adherence to TB treatment can lead to relapse, transmission of the disease for more people and to the development of drug resistance. (Cabrera et.al., 2002; CDC, 1994 and Oza, 2000). Moreover, to insure following-up, patients should be healthily educated about TB diseases, methods of diagnosis, ways of transmission, treatment and prevention. (Cabrera et.al. 2002).

1.8 Study problem statement

In Yemen, no studies or even reports on the cost of tuberculosis treatment and HRQoL were conducted. So, the study will enable estimating the public health expenditures on tuberculosis treatments, investing its results by using an effective and accurate financial policy for the tuberculosis control, it also may help in the assessment of economic burden of tuberculosis in capital city Sana'a, allocation of resources and sets of priorities for tuberculosis control activities, give estimation for the total budget needed for National Tuberculosis Control Programme and encourage the health authorities to pay for prevention and early detection of tuberculosis infection before progression to disease in order to save large amount of money needed for treatment of tuberculosis diseases.

Another focus of our study was to assess the HRQoL of patients with pulmonary and extra pulmonary and to evaluate any change in HRQoL during treatment.

1.9 Aims of the Study

Objective General

  1. Assessment economic burden of tuberculosis in Sana'a, Yemen, for the patient and the payer
  2. Evaluate the health related quality of life for tuberculosis patients

Objective Specific

  1. To determine the socio-demographic, clinical and laboratory aspects of tuberculosis patients in Sana'a TB centers.
  2. To estimate the public health expenditures on treatment of pulmonary and extra pulmonary tuberculosis
  3. To identify the economic impact of treatment of pulmonary and extra pulmonary tuberculosis in Sana'a, Yemen
  4. To encourage health authorities to pay for prevention and early detection of tuberculosis infection before progression to disease in order to save large amount of money in treating it
  5. To identify the factors associated with HRQoL among TB patients
  6. To evaluate the impairment of HRQL in order to get a responsive change in the quality of life and to follow up the patient during treatment

1.10 Significance of the study

  1. Evaluation of cost of this disease helps the policy makers and planners to justify continued allocation of resources for their programmes
  2. Providing government with good data concerning the cost of tuberculosis diseases in countries previously financed from other donor agencies
  3. Discovery of the people at risk for tuberculosis in capital city Sana'a
  4. Assessment of the possible cost saving via prevention activities (BCG vaccination, prophylaxis treatment).
  5. Evaluation of the future expenditure by determination of the current expenditure
  6. Appreciation of avoiding of productivity loss and premature death by the early detection and treatment.
  7. Assessment any change in HRQoL during treatment to quantify the impairment of quality of life in patient.
  8. Provide important information that cannot be obtained from conventional clinical and functional measurements among tuberculosis patients.

Methodology

2.1 Design of the Study

Prospective prevalence-based pharmacoeconomic evaluations were used in this study. The study total cost stems from two sources: direct and indirect costs. Direct medical cost includes the cost of prescribing medication, diagnostic laboratory tests, x-ray films, reagents and supplies for X-ray departments and the cost of the time taken by health professional workers. Indirect medical cost includes the cost of transporting to and from center, telephone bills, electric and water bills. During this period, the rate of the estimated cost of building consumption, vehicles and other pieces of furniture is excluded while of the time away from work is counted for 48 patients. Indirect cost is calculated by multiplying the average cost of the time lost due to illness with the average of daily earning. Intangible cost, on the other hand, which involves the cost of pain, suffering and anxiety, Intangible costs was measured by HRQoL questionnaires. Calculation of all costs according to the societal perspective in which all expenditures on the disease (direct and indirect) are considered.

A descriptive study is designed to evaluate treatment of pulmonary and extra pulmonary tuberculosis in governmental health facilities in Sana'a. The present study also aims to evaluate and measure prospectively the impairment of HRQL in pulmonary and extra pulmonary TB in patients by using a questionnaire, based on a linguistic validation process. Patients with tuberculosis aged 15-70 years, who registered at the pulmonary and extra pulmonary TB centers between March 2008 and May 2009, were included in the study. 341 consecutive patients were included in the study were available for follow up analysis. Pre-tested questionnaire regarding socio-demographic data, perception about his/her QoL using SF-12. This questionnaire contained question relating to symptoms (Symptoms score - Score I) as well as the life activities (Score II) related to their interest in work, house hold activities and exercise. And finally social activities (Score III) related to mental status, and social adaptability.

2. 2 Sample Size and Sampling Procedures

The first 341 patients will be met during an expected time of eight month interviewed for pulmonary and twelve months for extra pulmonary. The study includes all patients with suspected or confirmed pulmonary and extra pulmonary tuberculosis; who were investigated and recorded in medical records during March 2008 until August 2009. The total number of subjects to be evaluated is 390 pulmonary and extra pulmonary tuberculosis patients, based on several parameters. And according to exclusion and inclusion criteria, 49 patients were excluded from study. Fifteen (15) of them transferred to other health facilities, (4) four defaulters, (2) two died and the rest of them not completed the Health related quality of life Questionnaire for the following months.

Demographic, clinical data and pharmacoeconomic analysis will be carried out for 320 pulmonary and extra pulmonary tuberculosis patients. Health related quality of life Questionnaire carried out for 341 pulmonary and extra pulmonary tuberculosis patients

2. 3 Location and Time of the Study

The republic of Yemen is located on the south west of the Arabian Peninsula occupying 555.000 km and having a population of about (19,607,345) according to the last census on December 2004. Sana'a city is one of twenty two cities in Yemen. It is situated in the north and has a population of (1,747,834). It is selected for this study for its high TB prevalence as compared to other cities. Sana'a TB Center is selected to be the sample location of the study because it is characterized by being a large and rich medical TB centre with caseload, data availability, consultants, and with a good recording and reporting system which takes into consideration, before treating, demographic information like: the patient's name, gender, BCG vaccination status, full address, telephone number, medical history of patient's family, social status (smoking and working) and patients' past medical history.

2. 4 Ethical Considerations

Prior to the data collection process, the study was approved by the local committee in Ministry of Health to conduct this study directly in the TB centers. Accordingly, every patient will be informed about the objectives of the study and consented by a verbal interview.

2. 5 Study Population

The study populations consist of all tuberculosis patients, who started a new course of tuberculosis treatment at TB Sana'a center from March 1, 2008 until August 10, 2009. All Patients pulmonary and extra pulmonary was visited the center during working hours to take their medication. It was estimated that the pulmonary TB patients come eight months during the treatment period, so s/he comes 14 times to pharmacy (because in the first two months, checking should be weekly and after that it becomes once per month). While in case of extra pulmonary, the duration of treatment is 12 month, so s/he comes 12 times to pharmacy. Patients transferred from the Sana'a TB center to complete their treatment in other health center, defaulted patients , Subjects with major comorbidity (HIV, malignancy, diabetes, underlying cardiorespiratory disease, rheumatic disease, psychiatric disease), or if the patient die were excluded from the study.

2.6 Data Collection

The instruments were used for data collection consist of:

  1. Data collection form for demographic data, clinical data and economic burden of pulmonary & extra pulmonary TB for patients
  2. Check list for economic burden for the payer
  3. Questionnaire about HQRL (SF12- Questionnaire).

Clinical data will be collected from medical records of tuberculosis patient. Other data which include demographic, socioeconomic, economic burden and HQRL will be collected by direct interview using structured questionnaire. The cost data will be collected from x-ray department laboratory department, chest clinic, financial management department and other related departments. Demographic was collected as patient's name, gender, BCG vaccination status, full address, telephone number, medical history of patient's family, social status (smoking and working) and patients past medical history. Data monthly income was collected. Data about education status also collected according to education level follow: literacy, primary level, secondary level, university level.

Clinical data was categorized as: pulmonary and extra pulmonary tuberculosis, clinical signs and symptoms associated with tuberculosis (cough, loss of weight, loss of appetite, fever, and haemoptysis). Clinical investigations include x-ray examination for TB patient throughout the duration of medication. And laboratory test that carried out as initial steps of diagnosis or during treatment period to monitor the patient (acid fast bacilli test, sputum culture)

The drug regimen prescribed according to the type of TB disease, if susceptible positive pulmonary tuberculosis, the initial (intensive) phase: 2HRZS (E); i.e., isoniazed, Rifampicin, pyrazinamide and either streptomycin or ethambutol, given one time daily for 2 months( 8 weeks), patients in this intensive phase should come to the health facility every week to collect their drugs. Continuation phase: 6HT, e.g. isoniazed and thioacetazone daily for six months, patients should come to the health facility every four week to collect their drugs for self administration at home in this phase. While the regimen of extra pulmonary and negative pulmonary was the initial intensive phase: 2HTS(E), i.e., isoniazid, thioacetazone and either streptomycin or ethambutol, patients should come to collect their drugs every month from TB center for self administration at home.

Continuation phase: 10 HT i.e., isoniazid and thioacetazone daily for 10 months. Patients should come to healthy facility every month to collect their drugs for self administration at home.

Cost will be obtained from different departments in center included in study and indirect cost to the patient will be estimated by interviewing 48 patients. Cost of transportation for patient and his/her caregiver will be estimated according to the public transportation rate standard government rate.

2.7 Data Analysis

Statistically package for the social sciences (SPSS) will be employed for data analysis. All descriptive statistics and appropriate inferential statistics such as chi Square to compare economic burden between pulmonary and extra pulmonary patients, Mann-Whitney U to compare HQRL between pulmonary and extra pulmonary patients and Paired T-test and Wilcoxon's nonparametric rank sum test was used to assess differences between groups of subjects in the first day of treatment, at the end of first month and at the end of second month. Statistical significance level was 0.05 with confidence intervals of 95%. In addition the data were analyzed using pharmacoeconomic methods.

Discussion

4.1 A Profile Study

The study included three hundred ninety patients (390) were undergone to be evaluated; only 15 fifteen out of them, i.e., (3.8%) were transferred to other health facilities, (4) four patients were defaulters (1%), (2) two patients were died (0.5%) and the rest of them, i.e., (7.2%) of the sample no longer wished to participate in the surveys for the following months.

The study profile was lower than the findings gained by Muniyandi et al. (2005) indicated that 20% of the patients were defaulters, 2.6% failed to be treated and 7.6% died. Elamin et al. (2004), on the other hand, found that 3.4% of the patients were defaulters, 2.2% dead patients and 13.4% were transferred patients, while Wally et al. (2001) found the 27% were defaulters and 3.5% died. Finally, Zwarenstien et. al. (1998) found that in terms of transferred and dead patients, the percentage were 10.0 % and 0.9%, respectively.

4.2 Demographic Analysis

After analyzing each demographic factor separately, a comparison was done between pulmonary tuberculosis patients and extra pulmonary tuberculosis patients as far as the demographic data are concerned. Then, both groups were classified into two groups in accordance with the results of the diagnosis and the decision of doctors: pulmonary tuberculosis (i.e., patients, who commonly had a cough and abnormal chest radiography due to the infection of the lungs) and extra pulmonary tuberculosis (i.e., those that took a longer duration of treatment).

This study showed that the females constituted the majority of the patients whether in pulmonary tuberculosis (54%) or extra pulmonary tuberculosis (62%); a result that was consistent with that found by Peto et al. (2009), Bukharie et al. (2009), Sreeramareddy et al. (2008), Musellim et al. (2005) & Cailhol et al. (2005), Gonzalez et al. (2003), Noertjojo et al. (2002), Harries (1995), Rieder (1990). They reported that females occupy the first place as far as extra pulmonary tuberculosis is concerned; a reason explained by Ullah et al., (2008) as that female's preponderance is elusive, but it might be the biological sex differences and socio-cultural risk factors related to gender roles are the main reasons that made women more susceptible to the disease. In man-dominated society, women are even more pathetic from the socioeconomic viewpoint. Moreover, mothers' who feed their kids on the expense of their own nutrition is usually done out of their emotional feelings towards them. This differential access to food by females may be an additional factor that relatively leads them to be more malnutrition than males (Ullah et al., 2002).

Other likely socio-cultural factors may include high female's illiteracy, economic dependency and her poor access to health care. Females' infection with extra pulmonary tuberculosis usually occurs in the reproductive age group ranging between 15-45; a matter that emphasizes the fact that such endocrine factor might also play a role. In a study performed as far back as 1940, it was found that females' infection with extra pulmonary tuberculosis was associated with hormonal changes (Thompson 1940).

The reproductive burden in females associated with pregnancy, parturition, abortion and lactation might be other factors that lead to their infection, especially, early marriages, teen-parenting, multi-gravidity with less time interval between successive pregnancies and lactational stress might all impair immunity and lead to tuberculosis. In a study conducted in India, by Olakowski (1973), it was found that females had up to 130% risk of progressing from tuberculosis infection to a disease round the ages from 10 and 44 years.

This study, however, was not agreed upon by Kik et al. (2009), Elamin et al. (2004) , Islam et al. (2000) and Rajeswari et al. (2005), who indicated that the majority of the patients were males, figuring out (63%) (74.2%), (71%) and 66% respectively.

The present study noticed that there is strong association between pulmonary tuberculosis & extra pulmonary tuberculosis and age. The median age of extra pulmonary tuberculosis patients was (30 years) while in pulmonary tuberculosis was (28 years). The present study is consistent with Sreeramareddy et al. (2008) in regard with extra pulmonary tuberculosis patients (aged 28.5 years) and disproportionately with pulmonary tuberculosis patients (aged 47 years). The study by Peto et al. (2009) found no strong connection between extra pulmonary tuberculosis and age.

A matter that was proved to be so by the current study, which says that smoking is associated with pulmonary tuberculosis. A finding that made this study is on the same line with other studies, such as those of Sreeramareddy et al. (2008), Bates, et al. (2007). Another report associates smoking with the relapse of tuberculosis emphasizing the fact that smokers are less likely to have isolated extra pulmonary tuberculosis (Chiang, 2007). Therefore, the history of smoking motivates a high degree of suspicion for active tuberculosis; a piece of information useful for pointing the patients with tuberculosis (Sreeramareddy et al., 2008).

The current study reported that the male smokers occupied the top position whether in pulmonary or extra pulmonary tuberculosis, as indicated in the following percentages, respectively: (63.5%) and (57.8%). Such a result was in the same line with that carried out in Turkey by Musellim et al. (2005), whose male smokers amounted 64.9%. Leung et al. (2003), on the other hand, in a study carried out in Hong Kong, reported that smoking rate reached 22% in healthy controls and 56% in tuberculosis, patients and that extra pulmonary tuberculosis was higher among non-smokers. Gajalakshmi et al. (2003), added that the relationship between smoking and mortality causes increases the percentage of tuberculosis, morality.

Another study, in India, by Kollapan and Gopi (2002), proved that there is a relationship between smoking and pulmonary tuberculosis in Indian males; where their percentages was 75% in pulmonary tuberculosis cases and 55% in controls, who had a smoking habit. As the number of cigarettes and the smoking periods increase, the rate of tuberculosis, increases. In this respect, Lam et al. (2001), associated between smoking and causes of mortality; they saw that the risk of mortality in males only increased with smoking. These findings suggested that females were relatively protected against the effects of smoking on the lungs.

Finally, Altet et al. (1996), examines how passive smoking increased the risk of tuberculosis among children. Despite the obvious facts and all research findings regarding smoking effects on health, especially, the lungs, the situation in Yemen is still worse; there is no health education campaign, or any rules to control sales cigarettes; a matter that popularized such an important public health problem.

In terms of age distribution, the study found that the majority of tuberculosis patients were within the economically productive age group that ranges between 15-54 (WHO, 2000), who registered a percentage as high as (89%) in pulmonary tuberculosis whereas (93%) was for extra pulmonary tuberculosis. This was similarly reported by Wyss et al. (2001), Tupasi et al. (2003) and Walley et al. (2001), who found that tuberculosis patients within this age group were 86.9%, 85.9% and 85.2%, respectively. On the other hand, a finding by Ullah et al. (2008), Elamin et al. (2004) and Lyawoo (2003) showed a lower proportion of with patients falling within the age in question, figuring out 70%, 66.2% and 67.7%, respectively.

As far as the educational status of patients is concerned, they were classified into three different categories: low educational level, which refers to the primary and secondary school; high educational level, i.e., patients in university level; and no educational level, which denotes patients who did not have any type of formal education. This study found that the tuberculosis patients with low educational level amounted (52%) and (49%) in pulmonary tuberculosis and extra pulmonary tuberculosis, sequentially, a result that differs from that of Elamin et al. (2004) and Guwatudde et al. (2003), who found that tuberculosis patients with low educational level amounted 88% and 74.5% respectively. Those with nil education soared as high as (37%) and (42%) in pulmonary tuberculosis and extra pulmonary tuberculosis, respectively. Furthermore, highly educated TB patients registered (11%) in pulmonary tuberculosis and (10%) in extra pulmonary tuberculosis. They were 17 in pulmonary tuberculosis and 15 in extra pulmonary tuberculosis.

There were also 82 and 76 tuberculosis patients with low educational level in pulmonary tuberculosis and extra pulmonary tuberculosis, sequentially. Furthermore, there were 60 and 65 with nil education in pulmonary tuberculosis and extra pulmonary tuberculosis respectively. The number of these two types of patients was approximately equal to the number of patients with no incomes, (272 patients). Therefore, the study was complied with report by WHO (2000), Cohen et al. (1999) and with Kik et al (2009) to confirm that tuberculosis patients were vulnerable groups and unemployed.

The majority of patients were either of the type of nil education, or of school education or housewives. The study found that 85% of patients were not employed, a result that was not consistent with the finding of Elamin et al. (2004) and Zwarenstein et al. (1998), who found that tuberculosis patients who were not employed constituted 53.0% and 62%, respectively. This high unemployment attributed to the high percentage of nil and low education was the main reason that made Yemen to be considered the poorest country.

The highest tuberculosis cases were in Alsabeen area (30% pulmonary tuberculosis patients and 33% extra pulmonary tuberculosis patients). Next, came Alsafia area, where the percentages of tuberculosis were 20% for both pulmonary tuberculosis and extra pulmonary tuberculosis patients. This was attributed to the fact that tuberculosis health centers were near to these areas and the population density was high in these areas compared to other areas.

The vaccination status among tuberculosis patients registered (46%) for pulmonary tuberculosis patients and (47%) for extra pulmonary tuberculosis patients. The present study showed a strong correlation among vaccination, education and employment in case of pulmonary tuberculosis and extra pulmonary tuberculosis patients. This confirmed the fact that tuberculosis is the disease of the poor and of people of low education level.

In addition, the present study showed that females with extra pulmonary tuberculosis had less vaccination than males. The high percentage of nil vaccination attributed to the high percentage of illiteracy and of low education among females, and to the less attention paid on the part of females in comparison with that of males. Furthermore, the percentage of females in Yemen is more than males.

4.3 Clinical, x-ray and laboratory test analysis

Cough was shown as a common predominant symptom for tuberculosis patients studied. Pulmonary tuberculosis was seen to represent the highest type of tuberculosis which was mainly diagnosed with productive and with a long period of coughing in addition to multi-symptoms, whereas extra pulmonary tuberculosis which was mainly diagnosed with loss of weight and loss of appetite.

In regard with x-ray analysis, the study illustrated that more films were used for patients with pulmonary tuberculosis, compared with patients with extra pulmonary tuberculosis. That was because pulmonary tuberculosis improvement can be easily observed through chest x-ray (lung abnormality). While extra pulmonary tuberculosis required other laboratory examinations to follow up and to monitor the patients.

Laboratory test data demonstrated that acid fast bacilli test was the predominant test done for pulmonary tuberculosis patients (more than six times per patients). It was used either to confirm the availability of tuberculosis disease, to decide the time of the negative conversion or to estimate the outcomes of treatment course.

In terms of place of diagnosis, the study found the extra pulmonary tuberculosis patients looked for private hospital and clinics more than pulmonary tuberculosis patients; this was attributed to the fact that extra pulmonary tuberculosis can affect virtually all organs; it has a wide variety of clinical manifestations, which cause diagnosis difficulty (Gonzalez, et al. 2003& Mehta, et al., 1991). Or in other words, the clinic signs are not specific and so arouse high suspicious on the part of physician (Bukharie et al., 2009). Accordingly, extra pulmonary tuberculosis patients need to be continuously examined until getting the right diagnosis of their condition whether in private hospitals or in private clinics; besides one should take into consideration that there is no special care allotted for such a type of patients and that there have no facilities provided by the governmental hospitals.

4.4 Treatment Analysis

Many research findings arrived at the fact that drug regimens are of three types in accordance with their different treatment duration. As for WHO and Yemen Control Programme Guidelines, it was stated that three anti-tuberculosis category were used for treating TB. Besides, the number of consultation visits was 14 and 12 times for pulmonary tuberculosis patients and extra pulmonary tuberculosis patients, respectively. The study showed that more physician visit done by pulmonary tuberculosis patients; who frequently consult the medical center for the purpose of treatment; therefore more follow up and supervision for those patients was required.

4.5 Pharmacoeconomic Analysis

In the present study, the majority of the facts are based on actual expenditures paid for tuberculosis treatment. The average cost was taken into consideration in all the calculation of tuberculosis treatment regimens because they best reflect the real expenditure and therefore, it is of grave importance for both policymakers and health planners. Then, the total cost of tuberculosis was grouped into two main categories: first was the cost to the health services, which included the cost of anti-tuberculosis drugs, x-ray staff time, pharmacy staff time, TB center staff time, electric, water and telephone bills; while the annual consumption rate of the building, x-ray machine, microscope, in addition to other equipments that were excluded from the study. Second was the cost to the patients that included transporting to and from TB centers to their homes in addition to the cost of the time being away from work either because they were seeking treatment or were disable to work.

Launching from the fact that people in Yemen are very poor, NTCP carried out a strategy to reduce the incurred such types of costs, by which drugs were being weekly distributed to patients from the nearest health unites, when they are in the initial phase and monthly in a continuous phase in case of pulmonary tuberculosis while in case of extra pulmonary tuberculosis the patients take their drug only monthly from the TB center. All costs were calculated in Yemen currency (YR) and was, then, converted to the united state dollar at the 2009 exchange rate where US$1.00= YR 200.

4.5.1 Direct Medical Costs

The current study noticed that the large proportion of anti-TB drugs direct cost was (12.5%) & (38.2%) out of the total costs and costs of health services, respectively. and that the cost pulmonary tuberculosis patients was equivalent to US$ 20.2. Whereas in the case of extra pulmonary tuberculosis, the anti-tuberculosis drugs constituted (9.3%) & (78%) from the total costs and costs of health services, respectively, and the cost per patient was equivalent to US$ 30.2. The percentage of health service cost was higher in extra pulmonary tuberculosis than in pulmonary tuberculosis in terms of drug cost; because the extra pulmonary tuberculosis did not do the laboratory test and x-ray examination in the TB center, for they came to such center after they have already done their diagnosis, furthermore the cost and long period of use drug for extra pulmonary tuberculosis was more than of pulmonary tuberculosis.

A Similar finding was arrived at by Islam (2002), when he compared the drug cost to the total expenditures (37.8%). Slightly a higher cost was found by Wyss (2001) when he compared drug cost compared with the health services (44.4%). On the other hand the present study was consistent with Wyss (2001) and Sanderson (1995) in terms of the proportion of the drug cost compared with the total cost of treatment, which constitutes 7% and 10.7%, respectively.

Slightly a lower cost was found in other studies which had greatly concentrated on the aspect of costs; such a study was carried out by Elamin et al. (2008). The latter found that a large proportion of direct medical costs out of the total costs of illness were associated with anti-tuberculosis drugs figuring out (32.4%) from the total cost of illness, besides, the cost per patient was equivalent to US$ 61.44. and Muniyandi et al. (2005), which found the drug costs with total expenditure was (25%). A similar finding was reached by Sanderson (1995) entailing that there were additional costs associated with streptomycin drug (water for injection and syringe) and therefore, additional costs were incurred.

A higher cost, which was associated with x-ray services per patient in the TB center, was US$ 18, i.e., it constituted 11.2% and 34.1% from the total costs and costs of health services, respectively. In a comparison with the previous study conducted by Elamin et al. (2008), they found that the highest cost, US$ 28.6, constituted 3.1% and 15.1% from the total costs and costs of health services, respectively. The study by Wyss (2001) found that only US$ 3.60 was paid for this service per patient and that the high percentage of x-ray cost was in the present study; although the cost of a film and its reagent was lower than any other studies. This attributed to the fact that TB center did only the AFB test, while other studies included many other tests in addition to the AFB.

The study found that cost of laboratory tests per treated patient was US$ 5.4 and constituted 3.3% and 10.2% from the total costs and costs of health services, respectively. Elamin et al. (2008) stated that a higher cost was that of the laboratory tests per treated patient, which was $ 28.50, and which constituted 3.1% and 15.2% of the total costs and costs of government health services, respectively. Islam et al. (2002) showed a lower cost laboratory examination, US$ 2.19 that constituted 2.8% and 3.7% from the total costs and costs to the health services, respectively.

The present study showed the total direct expenditures for pulmonary tuberculosis was US$ 52.8 per pulmonary tuberculosis patient and for extra pulmonary tuberculosis was US$ 38.7 per extra pulmonary tuberculosis patient. The study was consistent with finding by Muniyandi et al. (2005) which found the total direct expenditures was US$30 to US$43 according to the category of treatment. On other hand very high expenditure was found in the study conducted in Haiti by Jacquet et al. (2006), which found the total direct expenditures for pulmonary tuberculosis was US$ 432 per tuberculosis patient, while in other study by Elamin et al. (2006), they found that the total direct expenditures for pulmonary tuberculosis was US$ 189.50.

4.5.2 Indirect Medical Costs

Implementing TB patients' treatment using the direct observation strategy helps decongesting TB center and increases the capacity to manage with the widespread increasing demand of having tuberculosis care centers. For that reason, pulmonary tuberculosis patients should visit the center either weekly (in the initial phase) or monthly (in the continuous phase) while extra pulmonary tuberculosis patients should visit it monthly to take their medicines. Accordingly, the cost associated with transporting to and from TB centers constituted 30.4% & 21.1% for pulmonary tuberculosis and 33. %2& 29.1% for extra pulmonary tuberculosis in terms of the cost to the patient and the total cost of treatment, respectively.

The high expenditure on transportation was found in a study conducted by Elamin et al. (2008). The study found that transportation constituted 71.0 % and 56.5%, to the patient and the total cost of treatment, respectively. A very low cost on transportation was found in a study carried out by Wyss (2001), where the cost of transportation constituted only 3.5% and 3% for the cost to the patient and the total cost of treatment, respectively. Floyd (1997) added that visits for directly observed treatment constituted 14% of the total cost.

4.5.3 Indirect Cost

The indirect cost consisted of the loss of time off work due to illness. Such a cost was estimated using a special designed data-collection form, whereby patients were asked to give information about their employment status; the amount of time lost if he was ill, and of his monthly salary when being healthy. The study found that the cost associated with the loss of productivity in pulmonary tuberculosis patients was (US$ 73.2), which constitutes 67.5% to the patient cost and 46.7% the total cost. While in case of extra pulmonary tuberculosis patients, it was equivalent to (US$ 51.9), which constitutes 18.2% to the patient cost and 16.1% the total cost.

The low percentage cost was associated with the loss of productivity in extra pulmonary tuberculosis patients, due to high cost of tests done for extra pulmonary tuberculosis patients outside TB center, to figure out (55.6%). Furthermore, the cost of transportation for extra pulmonary tuberculosis patients was (28.6%). This was due to the fact that extra pulmonary tuberculosis patients should come to the TB center to take his/her medication monthly while pulmonary tuberculosis patients could take his medication from the center near his home.

The cost of this study was very low if compared to the finding of Muniyandi et al. (2007), Sanderson (1995) and Wyss (2001), which found that the highest cost for the loss of the ability to work was US$112, US$ 162; and between US$ 154 and USD 1384 respectively, and different explanations are possible for this low cost in this study. African countries, for instance, found that the cost associated with the loss of productivity was high due to the fact that patients may take longer time treating themselves by using religious practitioners, herbal medicines and divining, instead of coming cross hospitals and using the medicine offered by them (Wyss et al., 2001).

Slightly higher to the findings of the present study was that done by Guwatudde et al. (2003), where the costs to the patients constituted approximately 80% of the total costs of the treatment. The cost of this study was very low if compared to the finding by kik et al. (2009), where the indirect cost associated with the loss productivity was € 2608 per patient.

The study carried out by Elamin et al. (2008) was consistent to the present study, particularly, in the case of extra pulmonary tuberculosis; the study found that the cost associated with the loss of productivity was constituted 16.3% of the patient cost and 12.9% of the total cost of tuberculosis.

4.5.5 Total Costs of Tuberculosis

Among the findings of the current study was that the total cost of tuberculosis treatment was US$ 161.2 and USD 322.8 for pulmonary tuberculosis and extra pulmonary tuberculosis patients, respectively. Such a cost was very much lower than that found by WHO (2000) in developed countries (US$ 2,000-US$ 21,000). Elamin et al. (2008) found that in Malaysia the total cost was US$ 916.4, and a study in South Africa showed that the total cost was US$ 890.50.

Other studies in India by Rajeswari et al. (1999) which found the total cost wasUS$171, Sanderson (1995), in Uganda showed the total cost of tuberculosis treatment was (US$ 403.20) and Khan et al. (2002) stated that the cost in Pakistan was (US$ 310.0), which was close to the findings of the Present study.

The costs to the patients of the present study were 67.2% & 87% for pulmonary tuberculosis & extra pulmonary tuberculosis, respectively. A matter that was similar to the previous studies conducted by Sanderson (1995), Elamin (2008) and Wyss et al. (2001). The latter found that the cost to the patients were approximately 70%, 79.5% and 84.2%. Such a cost, to the patients, looks very high although an alternative treatment design was applied to reduce the cost of transportation incurred by patients during the treatment period. However, there are still other options to reduce the cost through the early tuberculosis diagnosis and detection, which helps avoid the loss of time away from work due to illness. Continuous health education and counseling were freely done by the staff members of TB center; a matter that played a very important and effective role in improving patient's compliance to the treatment.

According to NTCP report in 2007, there were 3537 cases of positive pulmonary tuberculosis; 2369 cases of extra pulmonary tuberculosis and 2196 cases of negative pulmonary tuberculosis; by multiplying these number by the average cost of tuberculosis per patients (US$ 156.7; US$ 327.95 and US$ 230.6), respectively. That is to say the estimated cost of positive pulmonary tuberculosis, extra pulmonary tuberculosis and negative pulmonary tuberculosis in Yemen will be (US$ 554248, US$ 776914 and US$ 506397.6), respectively.

The TB Scoring of Health Related Quality of Life (HRQL)

4.6 Patients and Methods

The purpose of this study is to evaluate the health related quality of life and to identify the factors associated with it among TB patients. Out of 390 consecutive patients in the study, only about 341 were available for follow up analysis, especially, after excluding the following major diseases that lead to co-morbidity (such as HIV, malignancy, diabetes, underlying cardio-respiratory disease, rheumatic disease, psychiatric disease) to eliminate their interference with HRQoL of tuberculosis patients. There are several reasons, which explain why HRQL measurement is useful in TB study. Many HRQL domains are affected by TB, mainly by its symptoms, in addition to life activities and social domains. There are numerous tuberculosis-related problems that become more severe with this disease. The questionnaires used in this study are well known and well-characterized. The current research includes disease-specific instruments, SF-12 specific questionnaire, which offers information to help understand the unique experiences among TB patients and to enable conducting a comparison with the pulmonary tuberculosis patients and extra pulmonary tuberculosis patients (Dhingra and Rajpal et al.(2003& 2005) and Singh et al. (2004)).

HRQL is measured at baseline, and is repeated after one month of the follow up, and at the end of the intensive phase treatment (i.e., after two months of the follow up). The repeated measurement is feasible for two reasons: First, it helps separating the transient and maintaining effects of TB treatment. Second, it offers a piece of evidence about the validity of the questionnaire, especially, when the changes of the medical intervention of patients' quality of life meet the expectations. For example, SF-12 questionnaires are valid and reliable as the Arabic version, where the reliability of scales reaches a=0.71. The original English scale was, then, translated and adapted to the Arabic scale in accordance to guidelines (Fayers and Machin 2007)

4.7 HRQoL of Patients with Pulmonary & Extra Pulmonary Tuberculosis

Little information is published in regard with HRQL assessment of tuberculosis, besides, less information could be found in light of the comparison between HRQL in both pulmonary and extra pulmonary tuberculosis participants. However, there are few studies by Dhingra and Rajpal et al. (2003& 2005), Singh et al. (2004) and Dhuria et al. (2009) that involve a comparison between HRQoL of pulmonary and extra pulmonary tuberculosis participants. This study assesses the effect of TB on QOL in terms of treatment. The findings of the study indicate that, before treatment, patients with pulmonary tuberculosis have significantly lower mean scores than extra pulmonary tuberculosis as far as symptoms scores and the total scores of the second month of the follow up are concerned. This finding coincides with the findings obtained by Dhingra and Rajpal et al. (2003& 2005); Singh et al. (2004); and Dhuria et al. (2009).

The worst domain affected is life activity score II followed by the social activity domain, score III. Similar results were shown in studies conducted, at the New Delhi TB Centre, by Dhingra and Rajpal (2003&2005) and Singh et al. (2004). However, Dhuria et al. (2009) a study in the United States by Hansel et al. (2004) and in Russian by Guryleva et al. (2002) reported that the most affected domain was the physical domain.

4.7.1 HRQoL of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis during the Period of Treatment

The HRQoL score of pulmonary tuberculosis & extra pulmonary tuberculosis patients showed a gradual increase during the treatment period; a matter that indicates the positive effect of medical intervention on patients' quality of life. The patterns observed in the present study are: the bodily pain (symptoms score), which has a rapid positive response, and life and social activity scores, which showed less gradual increases. This is due to the fact that bodily pain is the best in detecting the impact of medical interventions (Chamla et al., 2004). In this study, and specifically, at the onset of the course of treatment, participants with pulmonary tuberculosis had bigger deficits in HRQL than extra pulmonary tuberculosis However, after one month of drug therapy; participants with pulmonary tuberculosis and extra pulmonary tuberculosis displayed clear marks of improvements in most HRQL domains. The domains that improved in pulmonary tuberculosis and extra pulmonary tuberculosis participants were symptoms, life activity and social activity scores; and the maximum improvement was seen in the symptoms (bodily pain). Similar results reported by Dhingra and Rajpal (2003&2005) and Singh et al. (2004), they found, also, that the scores were higher in extra pulmonary patients than pulmonary tuberculosis patients.

In present study, and particularly after the completion of the intensive phase, the mean symptoms, life activities and social activities scores were 87.3, 54.9 and 74.7 in case of pulmonary tuberculosis while in case of extra pulmonary tuberculosis; they were 92.9, 59.6 and 77.0 in scale of 100. Such results are in consistent with that of an Indian study conducted by Muniyandi et.al. (2007) they explicated that after a year of successfully treating TB, the physical, mental and social well-being scores were 74, 68 and 84. Furthrtmore, after comparing these scores with those of US general population, 81, 77 and 85 on a scale of 100, it appeared that the scores of both studies were somehow similar to one another. Similar observations reported in China stated that the mean physical wellbeing scores were not different from those of the controls at the end of treatment (Chamla 2004).

4.8 HRQoL of Pulmonary TB Depending on Sputum Status

There was a better significance of HRQoL in negative pulmonary tuberculosis than in positive pulmonary tuberculosis at the end of the second month of the follow-up, of score I. On the other hand, there was a higher significance of HRQoL in positive pulmonary tuberculosis than in negative pulmonary tuberculosis at the end of the first month of the follow-up of score II, and at the total HRQoL scores of the first day. Dinghra and Rajpal (2003& 2005) explicated that the sputum negative patients showed a higher Symptom Score than the sputum positive patients.

4.9 HRQoL of Pulmonary Tuberculosis Patients according to the Outcomes at the End of Intensive Phase

The study maintained that there was an association between HRQoL scores at the end of the second month and pulmonary tuberculosis patients, who converted from sputum positive to sputum negative at the end of the intensive phase in all the domains. Dinghra and Rajpal (2003& 2005) showed that the patients who converted from sputum positive to sputum negative had higher scores than patients who did not convert, at the end of the intensive phase.

4.10 Socio-economic Impact of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis On The Hrqol

4.10.1 Socio-economic Impact of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis on the HRQoL Depending on Gender

The present study observed that life activity domain and social domain in EPTB women were more affected than in men, but not affected in case of pulmonary tuberculosis. Many previous studies, such as Dhuria et al. (2009), Rekha et al. (2009), Muniyandi et al. (2007), Chamla (2004), Nyamatihi et al. (2005) and Yang et al. (2003) reported that a decrease in HRQoL scores was associated with female. On other hand, Duyan et al. (2005) and Jotam et al. (2007) found no association between gender and HRQL in tuberculosis patients. In Pakistan, for instance, Liefooghe et al. (1995) stated that despite the fact that both male and female patients with tuberculosis face social and economic problems, still female patients were highly affected, and that the impact of TB on women was so obvious. Other researchers, as Hudelson (1996), Khan et al. (2000) and Rajeswari (2005) added that what placed women in a socially precarious position was the proven fact that fear and stigma associated with tuberculosis deeply affected women more than on men. That was why, Women with tuberculosis were likely to be divorced or to accept a second wife for their husbands. Such an observed gender difference in the present or previous studies may reflect cultural and social misunderstandings about the disease.

4.10.2 HRQoL of Pulmonary and Extra pulmonary Tuberculosis Patients Depending on Age

The current study stated that there was no association between SF-12 and age, either in pulmonary tuberculosis patients or extra pulmonary tuberculosis patients in all domains, a finding which had been arrived at by Duyan et al. (2005) On the other hand, Wang et al. (1998), Chamla (2004), Muniyandi et al. (2007), Guo et al. (2008, 1998) and Dhuria et al. (2009) found that younger people tended to have better HRQL than older ones.

4.10.3 HRQoL of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis Patients Depending on Education Level

The study indicated that an association was between HRQoL scores and education in pulmonary tuberculosis patients at score II (life activities), score III (social activities), and the total score. On the other hand, such an association was, also, found with educated extra pulmonary tuberculosis patients, but only at score II (life activities), a fact that was proved to be true by Muniyandi et al. (2007) and Duyan et al. (2005).

4.10.4 HRQoL of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis Patients Depending on Smoking Status

There was no association between HRQoL scores and pulmonary tuberculosis patients due to smoking. The study identified, also, no association was between HRQoL scores and smoking in extra pulmonary tuberculosis patients. A result which contradicted what was found by Muniyandi et al. (2007) and Rekha et al.(2009), who proved the opposite.

4.10.5 HRQoL of Pulmonary Tuberculosis & Extra Pulmonary Tuberculosis Patients Depending on Marital Status

The study clarified that there was an association between the HRQoL of score II and marital status in pulmonary tuberculosis patients, accompanied with a significant difference in the total score at the first day, and the second month of the follow-up score III. Moreover, association was between HRQoL scores and marital status in extra pulmonary tuberculosis patients at the first day and the second month of the follow-up score, and that the HRQoL of married extra pulmonary tuberculosis patients had higher HRQoL scores at the first day, the first month of the follow-up, and the second month of the follow-up score III. Finally, the married extra pulmonary tuberculosis patients had higher HRQoL scores at the first day total score, the first month total score and the second month total score. Dhuria et al. (2009) has reported that such HRQL scores increase with married tuberculosis patients.

4.10.6 HRQoL of PTB & EPTB Patients Depending on Employment Status

The study illustrated that there was an association between HRQoL scores and employment in pulmonary tuberculosis patients, in case of score II. A similar association was found in extra pulmonary tuberculosis patients, but this time in regard with score I, score II, score III and the total score. Such a finding was consistent with that reached by Muniyandi et al (2007), Duyan et al. (2005) and Dhuria et al. (2009).

4.11 Score II of HRQoL and Socioeconomic impact

Nothing is published regarding HRQL assessment in TB and life activity scores. The study showed that there was associations between HRQoL of score II in pulmonary tuberculosis patients and the impact of the following socioeconomic factors, like (education, marital status, and employment). On the other hand, no association was found between HRQoL of score II in pulmonary tuberculosis patients and the impact of socioeconomic factors, like (smoking, gender and age).Concerning extra pulmonary tuberculosis patients, it was noticed that there was an association between HRQoL of score II with socioeconomic factors, like (marital status, gender, age and employment), and that there was no association between HRQoL of score II in extra pulmonary tuberculosis patients and socioeconomic factors, as (education and smoking).

4.12 HRQoL for Exercise of Score II and socio economic impact

Nothing published in regard with HRQL assessment in tuberculosis and exercise. The study showed that in case of pulmonary tuberculosis that there was no association between exercise and the following socio-economic terms: (education, employment status, smoking, marital status and gender) while in case of extra pulmonary tuberculosis patients, the association was between exercise and socio-economic terms, as (education, employment status, smoking, marital status and gender). Any decrease in exercise score was connected with an increase in the age factor in pulmonary tuberculosis patients. While there was not such an association between exercise score and age groups in extra pulmonary tuberculosis patients.

To sum up, at the beginning of therapy, PTB applicants have significantly lower HRQL than extra pulmonary tuberculosis. The deficits in their HRQL are only a matter of symptoms. But, after two months of the treatment using drug and microbiological cures, large improvements in most HRQL are achieved so that pulmonary tuberculosis and extra pulmonary tuberculosis applicants will have similar HRQL, and that pulmonary tuberculosis will no longer come to the TB center for the purpose of follow-up. In addition, 7.2% of both pulmonary tuberculosis and extra pulmonary tuberculosis groups will no longer continue participating in the survey after the second month of their treatment.