NUTRITION AND TUBERCULOSIS - McGill Universitydigitool.library.mcgill.ca/thesisfile110718.pdf · NUTRITION AND TUBERCULOSIS Anurag Bhargava Department of Epidemiology, Biostatistics
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
NUTRITION AND TUBERCULOSIS
Anurag Bhargava
Department of Epidemiology, Biostatistics & Occupational Health
McGill University, Montreal, Canada
May 2012
A thesis submitted to McGill University in partial fulfillment of the requirements
reactions (transient radiologic densities that appeared and resolved completely). Tuberculin
skin testing was done in 136 child contacts using Moro’s tuberculin ointment. However X-rays
were used to diagnose TB infection, perhaps due to completeness of data, and issues of
sensitivity and interpretation of the Moro’s test. 178
TB disease – presence of clinical symptoms with sputum smear and gastric lavage examinations
positive or radiologic abnormalities documented on serial X-rays. This was classified as
childhood tuberculosis (pulmonary and extrapulmonary) or adult-type (cavitary) pulmonary TB.
Data analysis
We compared outcomes in 2 groups of child contacts, based on their place of birth (as was
done in the original study). The village-born cohort included all children born within the
settlement. The admitted cohort included children born outside Papworth, who were later
admitted with their families. Both groups of children lived in the same house as their parent
62
with active TB at Papworth. We analyzed outcomes in the two cohorts during different time
periods defined as follows:
The pre-Papworth period, applied only to the admitted group, and extended from the year of
TB diagnosis in the source case to the year of admission to Papworth.
The Papworth period began with the year of birth (village-born) or the year of admission to
Papworth (admitted), and extended to the year the child left, or to the end of the study period
(1943).
The post-Papworth period was the same for both cohorts, and extended from the year of
leaving to the year of re-evaluation at Papworth; this could be analyzed only for those later re-
evaluated. However, all those discharged were evaluated and were known to be free of disease
at the time of discharge.
For each period, we calculated the total person-years of exposure of each child within three age
groups: 0-5 years, 6-12 years, and 13 years and older.
The prevalence of TB infection and the annual risk of infection in the village born and admitted
cohorts were compared in a series of analyses: The village- born children were exposed to TB
since birth; hence the duration of exposure to TB at the time of assessment for TB infection was
equal to their age. For the admitted cohort, their exposure was estimated in three ways:
Analysis 1: The duration of household exposure to TB at the time of assessment was considered
as the age at assessment minus their age when TB was first diagnosed in their parent. Analysis
2: The age at assessment was considered as the duration of exposure - which incorporated both
household and community exposure to TB. Analysis 3: The analysis was restricted to the subset
63
of children in the admitted cohort who were exposed to TB since birth, in whom the duration of
exposure was equal to their age at the time of assessment for TB infection. This analysis was
considered the most comparable to that in the village born children.
The annual risk of infection per year of exposure (ARI) was calculated using the formula: ARI =
1-(1-P)1/A,179, 180 where P is the mean prevalence of infection, and A is the weighted mean
duration of exposure.
TB incidence rates were estimated in the two cohorts of children, the three age groups, and in
the three time periods. Incidence rate ratios (IRR) were calculated to compare disease
incidence in the two cohorts, and between time periods. Confidence intervals (CIs) for
incidence rates were calculated using the Poisson distribution. 95% CIs were calculated, unless
explicitly stated. Confounding was assessed using a priori criteria and stratified analysis. All data
was analyzed using STATA 11.1.
5.3 Results
The 315 child contacts consisted of 84 children in the village born cohort, and 231 children in
the admitted cohort. Figure 5.1 provides an overview of all families and children, while figure
5.2 describes the number of child contacts in the pre-Papworth, Papworth, and post-Papworth
periods. In 135 families, the fathers alone were the source cases, while in 15 families; the
fathers plus additional family members had active TB. Source cases spent a median of 1 year
(IQR 1-2 years) in the sanatorium before admission to the settlement. The median age of the
source cases was 33 years (inter-quartile range [IQR] 28-38). Among the source cases, sixty-four
percent had sputum smear-positive TB of which 44% died after their admission to the
64
settlement (Table 5. 1). Proportions of children in contact with sputum smear-positive cases
were similar amongst the two cohorts (Table 5.2). The children’s stay in the settlement totaled
2980 person-years and was similar in both cohorts (median stay 9 years, p=0.09); a high
proportion (272; 87.2 %) resided in the settlement for more than three years.
Children in both cohorts underwent detailed clinical evaluation on admission and at regular
intervals, or on suspicion of TB disease. The number of evaluations was similar in the two
cohorts, such as the number of X-rays per child. Table 5.3 describes the prevalence of TB
infection based on radiologic abnormalities and estimated annual risk of infection in the two
cohorts on the basis of analysis 1-3. The age- specific prevalence of infection in the two cohorts
including the subset of admitted children exposed to TB since birth was similar. The estimated
ARI was high in both cohorts with no significant difference (Table 5.3).
Table 5.4 describes the incidence and TB disease characteristics in children before they were
admitted to Papworth. The median age of disease onset was 11 years (range 2-25 years).
Calculated incidence rates were 578/100,000 person-years (95% Confidence interval (CI): 70 to
2088) in the 6-12 age group, 1217/100,000 person-years (95% CI: 395 to 2839) in the 0-5 years
age group, and 5263/100,000 person-years (95% CI: 1931 to 11456) in children who were 13
years and older. Six deaths occurred in children whose active TB began prior to admission to
Papworth. Of these three deaths occurred before admission to Papworth (one of which was
due to disseminated TB in an infant), and three deaths occurred after admission.
65
TB incidence, disease characteristics, and mortality data for the Papworth period is described in
Table 5.5. Most of the cases, and all the TB-related deaths, occurred in the admitted cohort. In
the village-born cohort only a single case of active TB developed, which was cervical
lymphadenitis in a 10-year old girl (Table 5.5). No cases of TB disease were diagnosed in the age
group of 5 and under, and no serious forms of extrapulmonary disease occurred in the village
born cohort. The median age at TB diagnosis in the admitted cohort was 15 years (range 12-19
years). The incidence rate of the admitted cohort during the Papworth period was significantly
lower than in the pre-Papworth period. The reduction in incidence rate in those aged 13 years
and older was also significant. There was no significant difference in the overall incidence rates
of the village-born and admitted cohorts, while living in Papworth. There were a number of
neonatal deaths in the village-born group, and deaths unrelated to TB in both cohorts.
Excluding neonatal deaths, there was no significant difference in the all-cause mortality rate in
the two cohorts.
Of the admitted cohort, 105 were discharged from Papworth, of whom 34 (32%) were re-
evaluated, compared to 3 of the 21 (14%) of the village born group who were discharged from
the settlement. As seen in Table 5.6, of those who left Papworth five persons were diagnosed
to have active TB at a median age of 23 years (range 13-26 years). All five cases, occurred in the
admitted cohort, although only three village born children were re-evaluated. Person time was
contributed only by those who returned for re-evaluation after discharge. If we assume that all
diseased children reported back to Papworth, while those who did not return remained healthy
then the incidence rate in the post-Papworth period would have been lower (Table 5.6).
66
Table 5.7 provides a summary of disease characteristics and TB incidence calculated for the
different time periods. A total of 24 cases of active TB were seen. Most TB cases (20/24; 83.3%)
were contacts of sputum smear-positive disease cases and the majority (17/24; 70.8%)
developed pulmonary manifestations. Cases were most common during the pre-Papworth
period, followed by the Papworth and the post-Papworth periods.
5.4 Discussion
The Papworth experiment documented the impact of social interventions on TB infection and
disease in child TB contacts followed closely over an extended time period. The prevalence of
TB infection and estimated annual risk of infection (ARI) was high, but was similar in the two
cohorts of children. There was however a marked difference in incidence of disease in two high
risk age groups, 181 associated with the period of residence at Papworth. Among young children
(≤ 5 years), none of the village born cohort developed TB in the Papworth period, compared to
5 children in the same age group who developed TB prior to admission to Papworth (IR 1217
/105 person-years at risk). In the admitted cohort aged ≥13 years, the incidence rate of disease
was sixteen fold higher prior to admission to Papworth, than while living in Papworth. Overall
only one of 84(1.2%) village-born children developed TB, while nearly 10% of children born
outside the settlement developed TB; the majority of these disease episodes started before
admission to Papworth. There were 12 deaths related to TB, all in the admitted cohort.
The monograph on the Papworth survey offered the following explanations for the reduced
incidence of TB in children at Papworth: adequate food supply, decreased stress, and reduced
intensity of TB exposure through implementation of hygienic precautions and provision of
67
improved housing.36 Interestingly, the results indicate that conditions at Papworth did not
reduce the risk of TB infection, although some infection control measures may have reduced
the intensity of exposure. Rather the Papworth experiment was associated with a substantially
reduced risk of disease and related deaths. Recent systematic reviews have underscored the
role of under-nutrition as a risk factor for progression of TB infection to TB disease.6, 19 In 22
high TB burden countries, 5.2-62.6% (weighted average of 26.9%) of TB cases were attributable
to under-nutrition,24 while in a cohort of childhood contacts of TB it was found to be strongly
associated (hazard ratio of 37.5) with TB disease risk.26
Ensuring adequate nutrition was given high priority at Papworth. One of the children, who
entered the village settlement in 1929, observed in 2011 “There was always enough to eat.”
(Peter Pattle, personal communication). Since weights were not reported we can only speculate
that adequate nutrition likely played a significant role in the prevention of TB disease at
Papworth. The significant independent effect of nutrition on TB incidence, under similar
conditions of housing and stress, was illustrated in ecologic studies from the pre-
chemotherapy era.110, 111 In prisoner of war camps in Germany, TB incidence in British soldiers
receiving a 1000 calorie/day Red Cross supplement in addition to the camp diet of 1600
calories /day was 1.2%, whereas the incidence of TB in Russian prisoners who subsisted on the
camp diet alone was 19%.(Risk ratio of 0.06. 95% CI: 0.03, 0.14).110 The even greater protection
from TB seen in the village born cohort could perhaps reflect early life influences on immune
and thymic function, consequent to birth under conditions of better nutrition.88, 182
A comparison of the results at Papworth with other reports from the same period shows
comparable rates of TB infection. Annual risk of infection in children aged 0-10 years, estimated
68
from a 1930 study tuberculin skin test survey, was 0∙16 (95% CI: 0∙12,0∙22) in TB contacts and
0∙04 (95% CI: 0∙03,0∙05) in children not living with an adult TB patient.183 Interestingly the
incidence of TB disease in the admitted cohort prior to admission to Papworth period was
comparable to rates reported elsewhere in that era, but rates in children while living in
Papworth were significantly lower. The incidence rate of TB in family contacts reported from 4
studies in the US in the same era showed incidence rates in the range of 1030-1330 per
100,000 person-years.184 A notable feature in the Papworth period was the complete absence
of severe disease manifestations in young children, although their numbers were limited. Young
children living in contact with TB patients in the pre-chemotherapy and pre-BCG era were
particularly susceptible to developing tubercular meningitis, which was a major cause of TB-
related mortality in this age group.183, 185
This study has important limitations. It mostly involved child contacts of men with moderately
advanced pulmonary TB; contacts of women with TB or bedridden patients with advanced TB
were under-represented. The definition of TB infection was based on the absence of symptoms
and the presence of radiologic signs suggestive of infection rather than results of tuberculin skin
tests. This could have resulted in an underestimation of TB infection prevalence, or
misclassification. However, the main finding relates to reduced risk of TB disease progression,
for which case detection methods were very similar to what is in use today. There would have
been no blinding to the child’s birth status -village born or otherwise, but there is no indication
that this may have biased the results. The intensity of exposure to TB may have differed in the
two cohorts, since village-born children were exposed to source cases after sanatorium
“treatment”, and occurred in conditions which may have reduced the intensity of exposure.
69
However the estimated risk of infection was very similar in the two groups, suggesting that
exposure was very similar. Many children were lost to follow up after they left the settlement,
and so estimates of disease risk in the Post-Papworth period are much less certain.
Strengths of this re-analysis include the documented experience of more than 300 childhood
contacts with close to 4000 person years at risk. The two cohorts had comparable
characteristics, TB exposure (at least during their stay in Papworth), and were assessed for
study outcomes in a similar manner. The diagnosis of TB disease was based on chest
radiography and clinical signs similar to those used today, although cultures were not
performed. TB incidence estimates for the Papworth period were reliable due to the
completeness of data and close medical supervision. There appeared to be no confounding by
sputum status of the source case. Differences in the child’s age at exposure, or assessment
were handled by restricted and age-stratified analyses. The results of the analyses suggest that
unmeasured community exposure to TB in the admitted cohort is unlikely to have influenced
the outcomes of TB infection and disease in this study, especially in the case of young children.
This study is of particular relevance to the present problem of child contacts living with patients
with multi-drug resistant (MDR)-TB in high burden settings. Their current predicament is
reminiscent of that of TB patients and their child contacts in the pre-chemotherapy era.
Patients often lack access to effective chemotherapy and remain infectious over long periods.
Children are at high risk,186 of developing a potentially fatal disease without the benefit of
protection by chemoprophylaxis. The World Health Organization(WHO) does not currently
recommend chemoprophylaxis with second line drugs, suggesting careful clinical follow-up of
child contact with initiation of MDR-TB treatment should they develop signs consistent with TB
70
disease.187 Ensuring adequate nutrition seems a feasible and necessary intervention in such
child contacts in settings where childhood under-nutrition is highly prevalent. For example the
prevalence of severe under-nutrition was 31.0 % and 26.7% in child contacts in South African
and India, respectively.188 189
5.5 Conclusions
The Papworth experiment suggests that even in the absence of BCG vaccination or
chemoprophylaxis, social interventions were associated with reduced incidence of TB disease,
despite high rates of infection in highly vulnerable child contacts. Trials evaluating the efficacy
and feasibility of such interventions (including adequate nutrition) in child contacts of patients
with drug resistant TB should be conducted as a priority.
71
Acknowledgements
We wish to acknowledge the generous help of Mr. Peter Pattle of Papworth-Everard, U.K. in
clarifying many aspects of the Papworth village settlement.
72
CHAPTER 6: DISCUSSION AND CONCLUSIONS
The Papworth experiment in the pre-antibiotic era in England, and the study of the prevalence,
distribution and impact of undernutrition on selected outcomes in TB patients in present day
rural India, present a picture of the interactions of Tuberculosis with nutrition in two different
population groups ( children, adults) in three dimensions. These dimensions are the effects of
social interventions including adequate nutrition on development of active TB in a highly
exposed and infected cohort; the association of active TB and nutritional status of adult
patients in a setting with a background prevalence of under-nutrition, and the association of
nutritional status with mortality despite receiving effective therapy for TB.
6.1. Synopsis of Studies
6.1.1. Synopsis of findings of the Papworth experiment: The Papworth experiment involved
young children who are at high risk of progressing to serious forms of active TB when infected.
It was conducted during 1918 to 19-43 when Tuberculosis was still a significant problem in
England, with a mortality rate of 135.8 /100,000 in 1918 when the experiment began.190 The
cohort comprised 315 children living in contact with a parent (the father and sometimes also
the mother) with active TB, at the Papworth village settlement. 84 were born in the settlement
(village born) and 231 were admitted at varying ages after birth (admitted cohort). The annual
risk of infection was high and similar for children in both cohorts, with a 20% -24% probability
of getting infected per year of exposure to parental TB. However the rates of disease in the 2
cohorts were very different. In the pre-Papworth period, 13 (of 231) children in the admitted
cohort developed active TB over a median period of 3 years. During the stay at Papworth, 5 of
the remaining 218 children developed disease over a median period of 9 years, compared to
only 1 out of 84 village born children over a median period of 9 years. In the post-Papworth
period, which could be documented only in a minority of children, 5 children belonging to the
admitted cohort developed TB, compared to none of the village born children Overall half of
the children who developed TB disease died – all deaths occurred only in the admitted cohort.
The overall incidence in the admitted cohort declined six-fold (IRR 0.16 CI 0.04-0.47) after
admission to Papworth, with an even greater reduction in incidence rates in the children above
73
the age of 12 years (IRR 0.06 CI 0.01-0.27). Among the children born in Papworth, there was
zero incidence of TB in the highest risk period – i.e. while they were under 5 years old.
6.1.2. Synopsis of findings of the Jan Swasthya Sahyog (JSS) study: The study of nutritional
status of adult patients with pulmonary TB and its impact on TB outcomes was conducted in a
rural Chhattisgarh in central India, where under-nutrition affects nearly half of women, and
more than one-third of men in the general population. The JSS cohort comprised 1695 patients
with active TB, the majority of whom had smear positive pulmonary tuberculosis .Moderate to
severe undernutrition (BMI<17.0) was present in more than two-thirds of men and more than
three-quarters of women at diagnosis. BMIs of < 13 kg/m2 in men and BMI of < 12 kg/m2 which
are considered incompatible with life,191 were encountered in more than a hundred patients.
Case fatality during treatment was 7.3% and 80% of deaths during treatment occurred in
patients with moderate to severe undernutrition. Death during treatment was associated with
HIV status, age, weight, and BMI but not with AFB sputum smear status, treatment history, and
gender. After controlling for age, sex, smear status, HIV status, and treatment history, body
weight (and pre-treatment BMI were significantly associated with death. Based on these point
estimates, and in comparison to reference values for BMI (BMI of 18.5 kg/m2 both sexes),
women with the median values of BMI (BMI of 15.0 in women) had a 2.5 fold higher risk of
death, and men with median BMI (BMI of 16.0in men) had a 1.9 times increased risk of death. If
the relationship between under-nutrition and TB death is considered causal then nearly 50% of
deaths during treatment in both sexes in the entire cohort could have been prevented, if their
pre-treatment weights had been in the ideal range. The severe under-nutrition at diagnosis
with tuberculosis could have been a result of TB alone or of pre-existing under-nutrition
worsened by TB. Three features suggest the presence and influence of pre-existing under-
nutrition in this cohort. Firstly the short stature in both sexes, provided indication of chronic
under-nutrition in childhood and adolescence. The heights were 10 cm lower than the Indian
reference heights and below the 3rd percentile of the reference heights for 18 year olds in the
Center for Disease Control(CDC) growth charts.150 Secondly the nutritional status was
significantly associated with gender, but not associated with disease related characteristics like
AFB sputum smear status, treatment history or co-morbidities like HIV infection. In India at the
74
population level, under-nutrition is higher in prevalence in women.10 The third suggestive
feature was the low weights at end of successful treatment. Successful therapy was associated
with improvements of around 10% in body weights but they were still more than 20-30% lower
than the reference weights for adults, and moderate-severe undernutrition (BMI<17.0)was still
seen in one-third of men and half of women. One would have expected pre-morbid weights, if
they had been normal, to return to that level after successful treatment.
6.2. Limitations and strengths of the studies:
6.2.1. The Papworth study: The limitations included the nature of the source cases - men with
moderately advanced pulmonary TB that did not require hospitalization, while women and
bedridden patients with advanced disease were under-represented. The prevalence of infection
may have been under-estimated, and disease occasionally mis-classified as infection, by the
measurement by X-ray rather than tuberculin skin testing. The lack of adequate follow-up for
disease in the children who left Papworth was a limitation. Another limitation of the study was
the absence of baseline and follow up data on nutritional status. These were recorded in the
clinic records but were not available in the monograph.
The Papworth study has numerous strengths, with the experience of a large number of child
contacts documented meticulously over nearly 4000 person years at risk. The two groups of
children had comparable characteristics, periods of exposure to Papworth, and assessment, and
had similar levels of exposure to and infection with TB. The diagnosis of active TB was based on
criteria which are comparable to current criteria, and the estimates for disease incidence for
the Papworth period were reliable due to the completeness of data and close medical
supervision. There appeared to be no confounding by sputum status of index case and the age
at exposure to infection.
6.2.2. The JSS study: The limitations of this study included, missing information on heights - in
about 10%, and no information with regard to loss of lean body mass vs. body fat or
micronutrient malnutrition. Disease severity had to be inferred from the smear status and
grade of smear positivity in the absence of radiographic information.HIV testing was offered but
was not accepted by all subjects. The outcomes in the patients who defaulted could not be
75
ascertained. Information on smoking, and alcohol use was not available .The strengths of this
study are that it represents a large sample of rural patients studied over 6 years. The
composition of patients reflects status of patients diagnosed at both primary and secondary
care level, and the nutritional status was similar in patients who accessed the healthcare
services as a primary or secondary care facility. The median heights of patients in this study
were nearly identical to that obtained in a large survey of nutritional status conducted in rural
India.160 This suggests that the exposure to inadequate nutrition in childhood was similar across
rural India and these findings could be generalizable to other populations in rural India.
6.3. Implications of the studies:
6.3.1. At the level of individual patients:
6.3.1. A. Implications of the Papworth study: Prevention of TB – generally and especially in
contacts of patients with MDR-TB.
In the Papworth experiment, the social interventions resulted in almost complete prevention of
disease development in children born in the settlement, and substantial reduction in TB disease
incidence in the admitted cohort members. The annual risk of infection (ARI) in the Papworth
children was similar to the ARI reported in child contacts at the time. The incidence rates of
disease at Papworth of 235/100,000 person-years (in admitted cohort) and 132/100,000
person-years (in village born) were however much lower than the incidence rates of 1030-
1390/100,000 person-years reported in 5 contact studies conducted in that era.192 This
difference was significant at a time when cohabitation with parents with TB was considered
dangerous and led to practices such as raising children in foster homes ( Grancher system in
France) or separate residential facilities(preventoriums in the US).193
In the monograph on the Papworth families, the protection against clinical disease in the
children was attributed to adequate nutrition as a result of adequate income and dietetic
advice, decreased intensity of exposure due to proper housing, better ventilation, segregation
of patients, and scrupulous attention to cough etiquette.36 A reduced risk of active TB can result
from either a reduced risk of exposure, or reduced risk of infection following exposure, or a
76
reduced risk of progression of infection to active TB. Since there was high prevalence of
tuberculosis infection, the reduction in risk of active TB in the Papworth children must have
been mediated by reduced progression of infection to disease. The state of cell mediated
immunity (CMI) in a person is an important determinant of the progression from LTBI to active
TB. Among the various interventions at Papworth, the maintenance of adequate nutrition was
the most likely to have directly influenced the CMI. Recent epidemiologic research has
revealed that while nutrition in children in the post-natal period is important for development
of immunity, nutrition in the fetal period may exert a crucial influence on thymic
development, early programming of cell mediated immunity and thereby on susceptibility to
tuberculosis.182 A recent study in Swedish twins born between 1926 and1958 showed a 11%
decrease in risk of TB in twins with a 500 g greater birth weight.182
In current practice, treatment with Isoniazid is highly effective for prevention of TB disease in
subjects with LTBI due to drug sensitive organisms and increased risk of developing active TB
(children under five years, persons with HIV infection).The results of the Papworth experiment
have possible relevance for prevention of TB disease in child contacts of MDR-TB patients. In
such children isoniazid is unlikely to be effective, and no other drugs are currently
recommended for use by WHO.194 In low-middle income countries, such child contacts are
often undernourished which increases their risk of developing active TB.188, 195 The evidence
from the Papworth study suggests that restoration and/or maintenance of nutrition of their
child contacts may help prevent active MDR-TB in child contacts .Prevention of MDR-TB disease
can be highly beneficial, as treatment for MDR-TB in children is expensive, prolonged, toxic and
marked by significant morbidity and mortality.196
6.3.1. B. Implications of the JSS study: Nutritional support for patients with TB and severe
under-nutrition.
In the JSS study, half of men and two-thirds of women had a BMI < 16.0 kg/m2 at diagnosis. The
weights and BMI of patients in this cohort were significantly lower than those recorded in other
case series.32, 33, 122, 125, 134, 197 The anthropometric measures for example were lower than those
77
in urban HIV positive TB patients from south India,29 and other cohorts of predominantly HIV
positive patients in sub-Saharan Africa.32, 33, 124
Under-nutrition is association with increased mortality in patients with tuberculosis in both HIV
positive and HIV negative patients with tuberculosis.25 The death rate in this study was twice
that reported elsewhere in patients undergoing treatment.45 The strength of the association of
under-nutrition with mortality was broadly consistent with other studies.BMI of less than 17
was associated with a mortality rate ratio of 1.7(95% CI 1.18, 2.62),71 while in a cohort from
south India where body weight was used as a predictor, weight < 35 kg was associated with 4
fold risk of death [ aOR 3.9(CI 1.9, 7.8)].30In a study in MDR-TB patients, low BMI associated
with severe disease was an important predictor of the time to treatment failure and TB death (
Hazard ratio 3.23 (95% CI 0.90, 11.53).155AFB sputum smear status was not associated with TB
deaths in a study from south India, similar to the finding in this study.72
Apart from the risk of mortality being underweight at baseline has been shown to be an
independent risk factor for relapse in HIV negative patients(Hazard ratio 3.0, 1.8 -4.9).166The
loss of lean body mass in cachexia due to tuberculosis has an adverse effect on physical
function and performance status.
Nutritional interventions in patients with TB can be considered in two differing contexts- The
first is nutritional management of patients with severe under-nutrition aimed at restoration of
normal nutritional status. The second is nutritional supplementation (by macronutrients or
micronutrients) of patients, irrespective of their nutritional status, with the aim of improving
tuberculosis related outcomes, and quality of life,
Severe under-nutrition (BMI< 16.0) is considered an indication for intensive nutritional
interventions.161 The available literature pertains mainly to children but the physiological
principles and principles of management in adults are considered similar and have been
detailed in a WHO manual. 161 According to these recommendations patients with severe
under-nutrition, including those with a co-existing illness, should be managed in a hospital. The
protein requirements are up to 2 g/kg/day, the energy requirements are considered about 40 -
50 cal /kg, which may be given initially as a formula feed, and later as traditional foods.
78
Micronutrients should be supplemented to the daily recommended allowance, and a mineral
mix is also recommended as a supplement. The WHO recommends a supplemented diet till the
BMI comes over18.5 kg/m2.161 A recent consensus statement has endorsed these guidelines
and suggested similar guidelines for severely undernourished patients with HIV disease.198
While these are generic guidelines, in the context of patients with TB,WHO’s currently
recommends nutritional support only for patients with MDR-TB nutritional support to prevent
the vicious cycle of under-nutrition and disease.48 More than half of the patients in our study
would have been eligible for nutritional management according to the standards mentioned
above. However there were constraints in the management of patients at the hospital level,
and patients were hospitalized only when indicated for the primary illness (TB).
The effect of free food and energy supplements, and micronutrients alone on TB treatment
outcomes, physical function and quality of life, on patients with/without under-nutrition have
been recently reviewed.135 This Cochrane review reported that the research in this field had
been insufficient to reach any conclusion.135 High energy supplements were reported to result
in modest weight gain, but results on mortality, physical function and quality of life were
inconclusive. Micronutrient supplementation at or above the physiologic doses did not result in
any clinical benefits. No studies on nutritional support to prevent TB have been undertaken.
There is need for operational and clinical research to clarify the nutritional management of
severely underweight TB patients in different settings (hospital vs. non-hospital based), use of
culturally acceptable locally available foodstuffs, and the cost-benefit analysis of such
interventions. As suggested in the Cochrane review, future randomized controlled trials of
nutritional supplements should be conducted in food insecure settings , in patients with
different levels of under-nutrition, with an adequate sample size, with a clearer patho-
physiologic rationale for the interventions (micronutrients are unlikely to result in weight gain)
and should evaluate a range of clinically and patient important outcomes like mortality,
physical function, risk of relapse and quality of life.135
79
6.3.2. Implications of the studies at Population level: Action on risk factors and social
determinants as a complementary strategy in TB control and the case of India.
The Papworth experiment was not a study at a population level, though it could be considered
a microcosm of TB control. It showed that reduction in TB incidence in a cohort was possible
despite high prevalence of infection as a result of social interventions (including adequate
nutrition and improved living conditions) and their effect on the progression of LTBI to active
TB.
Can the findings of the Papworth study be applied to prevent the progression of LTBI at the
population level in low-middle income countries which have significant burden of persons with
LTBI? How would a package of interventions similar to the Papworth experiment compare to
medical measures for prevention like treatment of LTBI with Isoniazid? Would adequate
nutrition alone be adequate to produce the effect that was seen at Papworth, and what should
be the composition of a basic nutrition package in light of current knowledge? Should such
interventions be targeted only to vulnerable groups (e.g. food insecure) or the larger
population? Should they be applied for a particular time period, or be available as entitlements
as a matter of social policy?
The Papworth experiment was a hypothesis generating study which offered a complementary
perspective to TB control. This mode of TB control did not involve treatment of active disease,
but involved measures to reduce susceptibility to disease by focusing on maintenance of health
and better living conditions. A number of recent analyses of the global epidemiology of TB have
also pointed out the need for action on risk factors and social determinants as a complement to
the current medical model of TB control.23, 55The following sections use India as a point of
reference, as it has the largest global burden of incidence of drug susceptible and multi-drug
resistant tuberculosis, and has not witnessed a decline in TB incidence. The efficacy and
limitations of the medical model of TB control is discussed followed by a discussion on the need
to address under-nutrition amongst the various risk factors at the population level in India.
6.3.2. A. Medical model of TB control evolved since Papworth: Its efficacy and limitations,
especially in low income countries. The existing medical measures of TB control consist of
80
treatment of active TB with highly effective antibiotics, use of BCG vaccination and use of
isoniazid treatment of persons with LTBI.199 Treatment with antibiotics has major benefits in
reducing mortality and morbidity for patients with TB. The prognosis for patients with active
pulmonary TB has improved dramatically where patients with drug-susceptible TB can expect
a more than 95% chance of cure Such treatment also has public health benefits by making
patients with TB non-infectious within a few weeks – thereby stopping transmission of
M.tuberculosis. BCG vaccination protects children from serious forms of tuberculosis in
childhood. Treatment of persons with LTBI is highly effective in preventing active TB.
However these medical measures have some limitations especially in the context of low income
and high TB burden countries like India. Medical measures do not prevent the occurrence of
new TB infections in the community. Treatment of active cases decreases the period of
transmission of M.tuberculosis, but a significant amount of transmission to contacts occurs in
cases before they have been diagnosed and treated .This period can be significant with the
patient and health system related delays that are common in low-middle income countries. The
median delay in diagnosis due to patient and health system delay in a study from south India
was 60 days.200 Reliance on smear microscopy for diagnosis means that patients have more
advanced disease by the time they are diagnosed. Efficacy of Treatment in many low-middle
income countries like India is lowered by increasing drug resistance, which further reduces their
ability to decrease transmission in the community.
The most important limitation of medical measures presently available in low-middle income
countries is that they cannot prevent re-activation to active TB in the vast pool of persons with
LTBI.A large trial in south India found that BCG vaccination had zero efficacy in prevention of
the adult infectious forms of TB.201 BCG vaccination therefore plays no role in controlling TB at
the population level in India. The other alternative- of treatment of LTBI with Isoniazid would be
a formidable exercise in countries like India (where an estimated 400 million persons have
LTBI). Also this form of treatment would not be effective in those with LTBI due to drug
resistant organisms. There are also concerns about duration of protection from TB conferred by
this therapy in settings where re-infection with M.tuberculosis is possible. Currently no low-
middle income country implements LTBI treatment on a population level for control of TB, and
81
the Stop TB department of the WHO does not deem this as a feasible option for prevention of
TB in high TB burden countries.202
The efficacy of medical measures for TB control can be complemented or counteracted by
changes in socioeconomic status and living conditions. High income countries had experienced
significant decline in TB as a result of improved living conditions. In these countries the
introduction of the medical model of TB control produced excellent results at the patient level
as well as an epidemiologic impact on the disease burden; for example a decline of TB incidence
of 14% per year was seen in the Netherlands.112 In low-middle income countries with no
preceding or concomitant improvement in the TB burden by improved nutrition and living
conditions, and with less than optimal TB care, the impact on TB incidence has been minimal (
<1% per year).4 Exceptions to this rule are countries like Cuba where TB treatment programs
functioned in concert with improvements in other public health programmes, and food
security. With this dual approach TB incidence declined at more than 5% per year from
65/100,000 in 1965 to 4.7/100,000 in 1991– lower than the TB incidence in many high income
countries.203 An economic crisis in 1991-1994 saw caloric consumption per capita fall by 18% to
2513 calories per day, with a steeper fall in products of animal origin. Coupled with setbacks to
the TB program during this period, TB incidence increased to 14.7/100,000 in 1994.204, 205
6.3.2. B. A TB prevention strategy in India directed at risk factors like under-nutrition. A
prevention strategy for control of TB in India would either have to involve medical measures
like treatment of LTBI with Isoniazid at a mass scale, or action on the risk factors which
determine incidence at the population level like under-nutrition. A current focus on under-
nutrition is also required because of the decline in already low levels of per capita calorie
consumption in India.89 The comparative efficacy, operational feasibility and cost-effectiveness
of INH vs. nutritional interventions could be evaluated in pragmatic trials done under field
conditions by the RNTCP in India or at sites elsewhere where families are receiving food
assistance during TB care e.g. by the World Food Programme.206 A trial of nutritional
intervention in lieu of LTBI treatment by Isoniazid would be ethically problematic, and a trial
could compare Isoniazid alone with Isoniazid supplemented with nutrition.
82
In sub-Saharan Africa, the HIV/AIDS epidemic is chiefly responsible for TB incidence at the
population level, whereas in India the immunodeficiency associated with under-nutrition or
‘nutritionally acquired immuno-deficiency syndrome’ (N-AIDS)92 is a major driver of the TB
epidemic. One conservative(see footnote†) estimate of population attributable fraction(PAF)of
TB for under-nutrition was 32%, while similar PAF for other risk factors in India were diabetes
mellitus ( 7%), smoking(11%), alcohol (7%), HIV (5%).24 In rural India, like rural Chhattisgarh
where the prevalence of adult nutrition is higher than the national average, the population
fraction of TB attributable to under-nutrition would be up to 50% for women and 43% in men. If
one accepts the considerable evidence for a causal role of under-nutrition in TB ,19 up to 50%
of cases with pulmonary TB in rural Chhattisgarh could have been prevented by eliminating
under-nutrition. The benefits of addressing under-nutrition in India could have the following
advantages.
Firstly it could be an effective tool for TB control. The recent systematic review of the cohort
studies of TB incidence and nutritional status estimated a 13.8% decrease in TB incidence for
every unit increase in BMI,19 though the validity of these estimates at the population level
would need to be proven. Improving population nutritional status if proven cost-effective,
might have a significant impact on TB incidence in low-middle income countries like India.
Secondly this approach could help prevent multi-drug resistant tuberculosis. While prevention
of exposure to MDR-TB may not be possible, and treatment of MDR-TB is difficult and
expensive, it may be possible to prevent LTBI with multi-drug resistant organisms from
progressing to active TB by improving the nutritional status of the infected person.
Thirdly improving population nutritional status could impact on incidence of TB across
categories of age and gender as under-nutrition is prevalent in all age groups and both sexes in
India. The impact of such an intervention would be greater in women, who suffer higher levels
of under-nutrition in India, and in whom TB currently causes more deaths than all causes of
maternal mortality combined.207 In the JSS study the median post-TB treatment weight of
†The calculation of the PAF for under-nutrition was based on prevalence and relative risk of only severe under-
nutrition, while even mild and moderate under-nutrition can impair defenses against TB
83
women was only 38 kg, while the deaths in women occurred at a highly premature age (median
32.5 years).
Finally improving population nutritional status could have spin-offs on population health
beyond TB control. The incidence of a host of other infectious diseases whose prevalence and
severity is affected by under-nutrition could improve e.g. 50% of the estimated 2.1 million
deaths occurring in under-fives are a result of under-nutrition potentiating the effects of
common infections.20 Malnutrition was the risk factor responsible for greatest loss of disability
adjusted life years lost in India (22.4%) according to the global burden of disease study,208 and
improvements in nutrition could have thus enormous economic and public health benefits.
A national food security bill has been proposed which seeks to provide a legal entitlement to
food grains at subsidized prices to 75% of the rural and about 50% of India’s urban
population.209 This represents an opportunity to improve the nutritional status of India’s
population, especially the poor, and this proposed entitlement should be carefully scrutinized
by nutritionists. Inputs could be provided to the Government so that this entitlement addresses
the basic needs for energy and proteins, and plays its part in the prevention of diseases.
6.4. Conclusions:
There has been a resurgence of interest in the biological and social determinants of TB
incidence. This is due to the failure of the treatment based strategy for TB control to result in
the anticipated decline in TB incidence in high burden countries. Under-nutrition causes
impairment of cell mediated immunity which is crucial to prevention of progression of
M.tuberculosis infection to active disease. There is consistent evidence from cohort studies
which favours a causal association between under-nutrition and TB incidence and TB related
mortality, and under-nutrition is the risk factor with the highest population attributable fraction
for TB in high burden countries.24
The retrospective cohort study of adult patients with pulmonary tuberculosis in rural India
showed that rural Indian patients had a higher prevalence and more severe forms of under-
nutrition. Under-nutrition was significantly associated with deaths during treatment. Nutritional
84
management is indicated for patients with severe under-nutrition but the impact of nutritional
interventions on tuberculosis related outcomes like mortality needs to be assessed as a priority
in future research.
The effect of adequate nutrition and other social interventions on TB incidence was assessed in
a reanalysis of the Papworth experiment (1918-43). This study showed that even in the absence
of effective treatment for patients with active TB, adequate nutrition and other social
interventions could have a powerful biological effect on TB incidence possibly by preventing
progression of LTBI to active TB.
The current medical model of TB control in low-middle income countries based on antibiotic
treatment of infectious cases is of individual benefit to patients with TB but has not lead to
prevention of TB at the population level. The Papworth study results suggest that a strategy
directed at reducing susceptibility to TB by social interventions (including adequate nutrition)
could reduce TB incidence and complement the current DOTS strategy for TB control. In the
particular case of India, under-nutrition is the major biological risk factor and social
determinant for TB incidence. A focus on addressing under-nutrition at the population level
could have a significant effect on TB incidence including incidence of MDR-TB, in adults and
children, in India.
The Papworth and JSS studies have identified the need for future clinical and operational
research in two keys areas. The first would be feasibility, efficacy, and cost-effectiveness of
nutritional improvements as an instrument of TB control in populations with a high burden of
under-nutrition. The second is the need for research on appropriate nutritional interventions
for patients with tuberculosis and severe under-nutrition, and to evaluate the impact of
nutritional supplements on a range of clinically important and patient important outcomes in
undernourished patients with TB.
85
REFERENCES 1. Global Tuberculosis Control: WHO report 2011. Geneva: World Health Organisation; 2012. 2. Steinbrook R. Tuberculosis and HIV in India. New Engl J Med. 2007; 356(12): 1198-9. 3. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle. 1991; 72(1): 1-6. 4. Global Tuberculosis Control. Geneva: World Health Organisation.; 2009. Report No.: WHO/HTM/TB/2009.411. 5. Dye C, Lonnroth K, Jaramillo E, Williams BG, Raviglione M. Trends in tuberculosis incidence and their determinants in 134 countries. Bull World Health Organ. 2009; 87: 683-91. 6. Cegielski JP, McMurray DN. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis. 2004; 8(3): 286-98. 7. Raviglione M, Krech R. Tuberculosis: still a social disease [Editorial]. Int J Tuberc Lung Dis. 2011; 15(Supplement 2): S6-S8. 8. Repositioning nutrition as central to development : A strategy for large scale action. Washington D.C.: World Bank 2006. 9. The State of Food Insecurity in the world. Rome: Food and Agriculture Organisation of the United Nations,; 2011. 10. International Institute for PopulationSciences (IIPS) Macro International. National Family Health Survey (NFHS-3), 2005-06: India:Volume 1. Mumbai:IIPS; 2007. 11. Newsholme A. Prevention of tuberculosis London Methuen & Co.; 1908. 12. Major Greenwood. Epidemics and crowd diseases. London Williams and Northgate; 1935. 13. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and infection. Americal Jounal of Medical Sciences. 1959: 367-403. 14. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and infection. Monogr Ser World Health Organ. 1968; 57: 3-329. 15. Department of Health and Human Services. The Surgeon General's report on Nutrition and Health. Washington, DC: US Government printing office; 1988. 16. Palmer CE, Jablon S, Edwards PQ. Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build. Am Rev Tuberc. 1957; 76(4): 517-39. 17. Edwards LB, Livesay VT, Acquaviva FA, Palmer CE. Height, weight, tuberculous infection, and tuberculous disease. Arch Environ Health. 1971; 22(1): 106-12. 18. Tverdal A. Body mass index and incidence of tuberculosis. Eur J Respir Dis. 1986; 69(5): 355-62. 19. Lonnroth K, Williams BG, Cegielski P, Dye C. A consistent log-linear relationship between tuberculosis incidence and body mass index. Int J Epidemiol. 2010; 39(1): 149-55. 20. Pelletier DL, Frongillo EA, Schroeder DG, Habicht JP. The effects of malnutrition on child mortality in developing countries. Bull World Health Organ ; :. 1995; 73(4): 443-8. 21. Hargreaves JR, Boccia D, Evans CA, Adato M, Petticrew M, Porter JDH. The Social Determinants of Tuberculosis: From Evidence to Action. Am J Public Health. 2011; 101(4): 654-62. 22. Rasanathan K, Sivasankara Kurup A, Jaramillo E, nnroth K. The social determinants of health: key to global tuberculosis control. Int J Tuberc Lung Dis. 2011; 15(Supplement 2): S30-S6. 23. Lönnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: The role of risk factors and social determinants. Soc Sci Med. 2009; 68(12): 2240-6. 24. Lönnroth K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, et al. Tuberculosis control and elimination 2010–50: cure, care, and social development. Lancet. 2010; 375: 1814-29. 25. Waitt CJ, Squire SB. A systematic review of risk factors for death in adults during and after tuberculosis treatment [Review article]. Int J Tuberc Lung Dis. 2011; 15(7): 871-85. 26. O. Morán-Mendoza, S. A. Marion, K. Elwood, D. Patrick, FitzGerald JM. Risk factors for developing tuberculosis: a 12-year follow-up of contacts of tuberculosis cases. Int J Tuberc Lung Dis. 2010; 14(9): 1112-9.
86
27. Cegielski JP, Arab L, Cornoni-Huntley J. Nutritional Risk Factors for Tuberculosis Among Adults in the United States, 1971-1992,. Am J Epidemiol; 2012 Jul 11.[Epub ahead of print]. 28. Connell DW, Berry M, Cooke G, Kon OM. Update on tuberculosis: TB in the early 21st century. European Respiratory Review. 2011; 20(120): 71-84. 29. Swaminathan S, Padmapriyadarsini C, Sukumar B, Iliayas S, Kumar SR, Triveni C, et al. Nutritional status of persons with HIV infection, persons with HIV infection and tuberculosis, and HIV-negative individuals from southern India. Clin Infect Dis. 2008; 46(6): 946-9. 30. Santha T, Garg R, Frieden T, Chandrasekaran V, Subramani R, Gopi P. Risk factors associated with default, failure and death among tuberculosis patients
treated in a DOTS programme in Tiruvallur District, South India, 2000. . Int J Tuberc Lung Dis. 2002; 6: 780-8. 31. Kennedy N, Ramsay A, Uiso L, Gutmann J, Ngowi FI, Gillespie SH. Nutritional status and weight gain in patients with pulmonary tuberculosis in Tanzania. Trans R Soc Trop Med Hyg. 1996; 90(2): 162-6. 32. Zachariah R, Spielmann MP, Harries AD, Salaniponi FML. Moderate to severe malnutrition in patients with tuberculosis is a risk factor associated with early death. Trans R Soc Trop Med Hyg. 2002; 96(3): 291-4. 33. Villamor E, Saathoff E, Mugusi F, Bosch RJ, Urassa W, Fawzi WW. Wasting and body composition of adults with pulmonary tuberculosis in relation to HIV-1 coinfection, socioeconomic status, and severity of tuberculosis. Eur J Clin Nutr. 2005; 60(2): 163-71. 34. Onwubalili JK. Malnutrition among tuberculosis patients in Harrow, England. Eur J Clin Nutr. 1988; 42(4): 363-6. 35. Brieger EM. Children in a tuberculosis colony. Arch Dis Child. 1943; 18: 178-85. 36. Brieger EM. The Papworth Families. A 25 years survey. London: Heinemann 1944. 37. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Starke JJ, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004; 8(4): 392-402. 38. The Case for a Rehabilitation Board. Lancet. 1940; 235(6073): 131-2. 39. Bryder L. Papworth village settlement- A unique experiment in the treatment and care of the Tuberculous? Med Hist. 1984; 28: 172-90. 40. Trail RR. Environment and education at Papworth. Health education journal. 1952; 10: 158-64. 41. Reider HL, editor. Epidemiologic basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Disease; 1999. 42. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982; 125(3 Pt 2): 8-15. 43. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC, Surveillance ftWG, et al. Global Burden of Tuberculosis. JAMA. 1999; 282(7): 677-86. 44. Smith I. Mycobacterium tuberculosis Pathogenesis and Molecular Determinants of Virulence. Clinical Microbiology Reviews. 2003; 16(3): 463-96. 45. Straetemans M, Glaziou P, Bierrenbach AL, Sismanidis C, van der Werf MJ. Assessing Tuberculosis Case Fatality Ratio: A Meta-Analysis. PLoS One. 2011; 6(6): e20755. 46. National Tuberculosis Institute. Tuberculosis in a rural population of South India: a five year epidemiological study. Bull World Health Organ. 1974; 51: 473-88. 47. Thim S, Sath S, Sina M, Tsai EY, Delgado JC, Shapiro AE, et al. A community-based tuberculosis program in Cambodia. JAMA. 2004; 292(5): 566-8. 48. WHO. Guidelines for the programmatic management of
drug-resistant tuberculosis,
Emergency update 2008. Geneva: World Health Organisation; 2008.
87
49. World Health Organisation. What is DOTS? A guide to understanding the WHO-recommended TB control strategy known as DOTS: World Health Organisation; 1999. 50. Lawn SD, Zumla AI. Tuberculosis. Lancet. 378(9785): 57-72. 51. Tackling poverty in TB control. Lancet. 2005; 366: 2063. 52. Reider HL. Annual risk of infection with Mycobacterium tuberculosis. European Respiratory Journal. 2005; 25(1): 181-5. 53. Styblo K. Overview and Epidemiologic Assessment of the Current Global Tuberculosis Situation with an Emphasis on Control in Developing Countries. Rev Infect Dis. 1989; 11(SUPPLEMENT 2): S339-46. 54. Guelar A, Gatell JM, Verdejo J, Podzamczer D, Lozano L, Aznar E, et al. A prospective study of the risk of tuberculosis among HIV-infected patients. AIDS. 1993; 7(10): 1345-9. 55. Lönnroth K, Raviglione M. Global Epidemiology of Tuberculosis: Prospects for Control. Semin Respir Crit Care Med. 2008; 29(05): 481,91. 56. Leung CC, Lam TH, Chan WM, Yew WW, Ho KS, Leung G, et al. Lower Risk of Tuberculosis in Obesity. Arch Intern Med. 2007; 167(12): 1297-304. 57. Hanrahan CF, Golub JE, Mohapi L, Tshabangu N, Modisenyane T, Chaisson RE, et al. Body mass index and risk of tuberculosis and death. AIDS. 2010; 24(10): 1501-8. 58. Chocano-Bedoya P, Ronnenberg AG. Vitamin D and tuberculosis. Nutr Rev. 2009; 67(5): 289-93. 59. Jeon CY, Murray MB. Diabetes Mellitus Increases the Risk of Active Tuberculosis: A Systematic Review of 13 Observational Studies. PLoS Med. 2008; 5(7): e152. 60. Stevenson C, Forouhi N, Roglic G, Williams B, Lauer J, Dye C, et al. Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence. BMC Public Health. 2007; 7(1): 234. 61. Lin H-H, Ezzati M, Murray M. Tobacco Smoke, Indoor Air Pollution and Tuberculosis: A Systematic Review and Meta-Analysis. PLoS Med. 2007; 4(1): e20. 62. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJD. Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review. PLoS One. 2011; 6(4): e17601. 63. Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011; 378(9785): 57-72. 64. Kotler D, Tierney A, Wang J, Pierson R. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr. 1989; 50(3): 444-7. 65. Waaler HT. Height. Weight and Mortality The Norwegian Experience. Acta Medica Scandinavica. 1984; 215(S679): 1-56. 66. Pednekar MS, Hakama M, Hebert JR, Gupta PC. Association of body mass index with all-cause and cause-specific mortality: findings from a prospective cohort study in Mumbai (Bombay), India. Int J Epidemiol. 2008; 37(3): 524-35. 67. Prospective studies collaboration. Body mass index and cause specific mortality in 900,000 adults: colllaborative analyses of 57 prospective studies. Lancet. 2009; 373: 1083-96. 68. Garcia-Garcia Mde L, Ponce-De-Leon A, Garcia-Sancho MC, Ferreyra-Reyes L, Palacios-Martinez M, Fuentes J, et al. Tuberculosis-related deaths within a well-functioning DOTS control program. Emerg Infect Dis. 2002; 8(11): 1327-33. 69. Kim HJ, Lee CH, Shin S, Lee JH, Kim YW, Chung HS, et al. The impact of nutritional deficit on mortality of in-patients with pulmonary tuberculosis. Int J Tuberc Lung Dis. 2010; 14(1): 79-85. 70. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Mwinga AG, Tembo G, et al. The impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in Zambia. Trans R Soc Trop Med Hyg. 1995; 89(1): 78-82. 71. Gustafson P, Gomes V, Vieira C, Samb B, Nauclér A, Aaby P, et al. Clinical Predictors for Death in HIV-positive and HIV-negative Tuberculosis Patients in Guinea-Bissau. Infection. 2007; 35(2): 69-80.
88
72. Kolappan C, Subramani R, Kumaraswami V, Santha T, Narayanan PR. Excess mortality and risk factors for mortality among a cohort of TB patients from rural south India. Int J Tuberc Lung Dis. 2008; 12(1): 81-6. 73. Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR. Risk of tuberculosis from exposure to tobacco smoke: a systematic review and meta-analysis. Arch Intern Med. 2007; 167(4): 335-42. 74. Kaulagekar A, Radkar A. Social status makes a difference: Tuberculosis scenario during the National Family Health Survey-2. Indian Journal of Tuberc. 2007; 54: 17-23. 75. Lankester A. Tuberculosis in India: Its prevalence, causation and prevention: Butterworth and co.; 1920. 76. Ukil AC. A note on the epidemiology and pathology of tuberculosis in India. Tubercle. 1931; 12(6): 244-50. 77. Davis M. Late Victorian Holocausts: El nino famines and the making of the third world. London, New York: Verso books; 2001. 78. Famine in India 2012 [cited 2012 April 9]; Available from: http://en.wikipedia.org/wiki/Famine_in_India 79. Chadha VK. Tuberculosis epidemiology in India : a review. Int J Tuberc Lung Dis. 2005; 9(10): 1072-82. 80. Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res. 2004; 120: 248-76. 81. Tuberculosis Research Centre. Trends in the prevalence and incidence of tuberculosis in south India Int J Tuberc Lung Dis. 2001; 5(2): 142-57. 82. Brinkman HJ, de Pee S, Sanogo I, Subran L, Bloem MW. High food prices and the global financial crisis have reduced access to nutritious food and worsened nutritional status and health. J Nutr. 2010; 140(1): 153S-61S. 83. Shetty P. Malnutrition and undernutrition. Medicine. 2006; 34(12): 524-9. 84. The State of the World's Children. Geneva: United Nations Children's Fund,; 1998. 85. CDC Growth charts. 2012 [cited 2012 April 7]; Available from: http://www.cdc.gov/growthcharts/percentile_data_files.htm 86. UNICEF. Under-nutrition a challenge for India 2011 [cited 07.08.2011]; Available from: http://www.unicef.org/india/nutrition_1556.htm 87. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007; 261(5): 412-7. 88. Moore SE, Cole TJ, Collinson AC, Poskitt EM, McGregor IA, Prentice AM. Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa. Int J Epidemiol. 1999; 28(6): 1088-95. 89. Deaton A, Dreze J. Food and nutrition in India : Facts and Interpretations. Economic and Political Weekly. 2009; 44(7): 42-65. 90. Fogel RW. The Escape from Hunger and Premature Death, 1700-2100: Cambridge University Press; 2004. 91. Dubey A. Poverty and under-nutrition among scheduled tribes in India: a disaggregated analysis Indira Gandhi Institute of Development Research; 2009. 92. Beisel WR. Nutrition and Immune Function: Overview. J Nutr. 1996; 126(10 Suppl): 2611S-5S. 93. Schaible UE, Kaufmann SH. Malnutrition and infection: complex mechanisms and global impacts. PLoS Med. 2007; 4(5): e115. 94. McMurray D, Loomis S, Casazza L, Rey H, Miranda R. Development of impaired cell-mediated immunity in mild and moderate malnutrition. Am J Clin Nutr. 1981; 34(1): 68-77. 95. McMurray DN. Disease model: pulmonary tuberculosis. Trends Mol Med. 2001; 7(3): 135-7. 96. McMurray DN, Bartow RA, Mintzer CL, Hernandez-Frontera E. Micronutrient status and immune function in tuberculosis. Ann N Y Acad Sci. 1990; 587: 59-69.
97. Hernandez-Frontera E, McMurray DN. Dietary vitamin D affects cell-mediated hypersensitivity but not resistance to
experimental pulmonary tuberculosis in guinea pigs. . Infect Immun 1993; 61: 2116–21. 98. McMurray DN, Carlomagno MA, Mintzer CL, Tetzlaff CL. Mycobacterium bovis BCG vaccine fails to protect protein-deficient guinea pigs against respiratory challenge with virulent Mycobacterium tuberculosis. Infect Immun. 1985; 50(2): 555-9. 99. McMurray DN, Mintzer CL, Tetzlaff CL, Carlomagno MA. The influence of dietary protein on the protective effect of BCG in guinea pigs. Tubercle. 1986; 67(1): 31-9. 100. Chan J, Tian Y, Tanaka KE, Tsang MS, Yu K, Salgame P, et al. Effects of protein calorie malnutrition on tuberculosis in mice. Proc Natl Acad Sci U S A. 1996; 93: 14857-61. 101. Reed LJ, Love AG. Biometric studies on U.S.Army Officers-Somatological norms in disease. Human Biology. 1933; 5(1): 61-93. 102. Love AG. Somatological norms in tuberculosis and heart disease. Human Biology. 1929; 1(2): 166-97. 103. Keys A. Overweight, Obesity, Coronary Heart Disease and Mortality. Nutr Rev. 1980; 38(9): 297-307. 104. Long E, Jablon S. Tuberculosis in theArmy ofthe UnitedStates in World War II: An Epidemiological Study With an Evaluation of X-ray Screening,. Washington, DC: Veterans Administration; 1955. 105. Berry WTC, Nash FA. Studies in the aetiology of pulmonary tuberculosis. Tubercle. 1955; 36(6): 164-74. 106. Comstock GW, Palmer CE. Long term results of BCG vaccination in the southern United States. Am Rev Respir Dis. 1966; 93: 171-83. 107. Thorn PA, Brookes VS, Waterhouse JAH. Peptic ulcer, partial gastrectomy, and pulmonary tuberculosis. BMJ. 1956; (1): 603-8. 108. Hemila H, Kaprio J, Pietinen P, Albanes D, Heinonen OP. Vitamin C and other compounds in vitamin C rich food in relation to risk of tuberculosis in male smokers. Am J Epidemiol. 1999; 150(6): 632-41. 109. Cegielski JP, L K, Cornoni-HuntleyJ. Relative and population attributable risks of tuberculosis due to under and over-nutrition. 110. Leyton GB. Effects of Slow starvation. Lancet. 1946; 248(6412): 73-9. 111. Cochrane AL. Tuberculosis among prisoners of war in Germany. BMJ. 1945: 656-8. 112. Dye C. Epidemiology. In: Davies PDO, Barnes PF, Gordon SB, editors. Clinical Tuberculosis Fourth ed: Hodder Arnold; 2008. 113. McKeown T, Record RG. Reasons for the Decline of Mortality in England and Wales during the Nineteenth Century. Population Studies. 1962; 16(2): 94-122. 114. Steckel RH. Strategic Ideas in the Rise of the New Anthropometric History and Their Implications for Interdisciplinary Research. J Econ Hist. 1998; 58(3): 803-21. 115. Grange JM, Gandy M, Farmer P, Zumla A. Historical declines in tuberculosis: nature, nurture and the biosocial model. Int J Tuberc Lung Dis. 2001; 5(3): 208-12. 116. Szreter S. Rethinking McKeown: Relationship between Public health and social change. Am J Public Health. 2002; 92(5): 722-5. 117. Faber K. Tuberculosis and Nutrition. Acta Tuberc Scandinavica. 1938; 12: 287. 118. Marche J, Gounelle H. The Relation of Protein Scarcity and Modification of Blood Protein to Tuberculosis among Undernourished Subjects. Milbank Mem Fund Q. 1950; 28(2): 114-26. 119. Zachariah R, Spielmann MP, Harries AD, Salaniponi FM. Moderate to severe malnutrition in patients with tuberculosis is a risk factor associated with early death. Trans R Soc Trop Med Hyg. 2002; 96(3): 291-4.
90
120. Schwenk A, Macallan DC. Tuberculosis, malnutrition and wasting. Curr Opin Clin Nutr Metab Care. 2000; 3(4): 285-91. 121. Macallan DC. Malnutrition in tuberculosis. Diagnostic Microbiology and Infectious Disease. 1999; 34(2): 153-7. 122. Kennedy N, Ramsay A, Uiso L, Gutmann J, Ngowi FI, Gillespie SH. Nutritional status and weight gain in patients with pulmonary tuberculosis in Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1996; 90(2): 162-6. 123. Harries AD, Nkhoma WA, Thompson PJ, Nyangulu DS, Wirima JJ. Nutritional status in Malawian patients with pulmonary tuberculosis and response to chemotherapy. Eur J Clin Nutr. 1988; 42(5): 445-50. 124. Van Lettow M, Kumwenda JJ, Harries AD, Whalen CC, Taha TE, Kumwenda N, et al. Malnutrition and the severity of lung disease in adults with pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis. 2004; 8(2): 211-7. 125. Karyadi E, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, et al. Poor micronutrient status of active pulmonary tuberculosis patients in Indonesia. J Nutr. 2000; 130(12): 2953-8. 126. Morley JE, Thomas DR, Wilson M-MG. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006; 83(4): 735-43. 127. Tan BHL, Fearon KCH. Cachexia: prevalence and impact in medicine. Current Opinion in Clinical Nutrition & Metabolic Care. 2008; 11(4): 400-7. 128. Harries AD, Thomas J, Chugh KS. Malnutrition in African patients with pulmonary tuberculosis. Hum Nutr Clin Nutr. 1985; 39(5): 361-3. 129. Van Lettow M, Fawzi WW, Semba PH, Semba RD. Triple Trouble: The Role of Malnutrition in Tuberculosis and Human Immunodeficiency Virus Co-infection. Nutr Rev. 2003; 61(3): 81-90. 130. Thomas DR. Distinguishing starvation from cachexia. Clinics in Geriatric Medicine. 2002; 18(4): 883-91. 131. Tuberculosis Research Centre .A concurrent comparison of home and sanatorium treatment of tuberculosis in south India. Bull World Health Organ. 1959; 21: 51-144. 132. Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting. Am J Clin Nutr. 2004; 80(2): 460-5. 133. Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr. 2002; 75(4): 720-7. 134. Pakasi TA, Karyadi E, Suratih NMD, Salean M, Darmawidjaja N, Bor H, et al. Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia. Nutr J. 2010; 9: 41. 135. Sinclair D, Abba K, Grobler L, Sudarsanam TD. Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Syst Rev. 2011; 11: CD006086. 136. TB India 2009. RNTCP Status Report; 2009. 137. Kolappan C, Gopi PG. Tobacco smoking and pulmonary tuberculosis. Thorax. 2002; 57(964-966). 138. Hassmiller K. The Impact of Smoking on Population Level Tuberculosis Outcomes. TSRU progress report The Hague: KNCV; 2007. 139. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax. 1996; 51(2): 132-6. 140. Subramanian SV, Smith GD, Subramanyam M. Indigenous Health and Socioeconomic Status in India. PLoS Med. 2006; 3(10): e421. 141. Sarkar S, Mishra S, Dayal H, Nathan D. Development and Deprivation of Scheduled Tribes. Economic and Political Weekly. 2006; 41(46): 4824-7.
91
142. Alkire S, Maria E S. India Country Briefing: Oxford Poverty & Human Development
Initiative (OPHI) Multidimensional Poverty Index Country Briefing Series; 2010. 143. Health profile: Chhattisgarh. National Rural Health Mission State Profiles 2012 [cited 2012 February 27]; Available from: http://mohfw.nic.in/NRHM/State%20Files/chhattisgarh.htm 144. TB India 2011: Revised Tuberculosis Control Programme Annual Status Report: Central TB division, Ministry of Health and Family Welfare, Government of India.; 2011. 145. Managing the Revised National Tuberculosis Control Programme in your area. A training course: Modules 1-4. New Delhi: Central TB division Ministry of Health and Family Welfare.; 2005. 146. World Health Organisation. Treatment of Tuberculosis : Guidelines for National Programmes: World Health Organisation; 2003. 147. WHO Expert consultation.Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004; 363(9403): 157-63. 148. WHO.Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series 854. Geneva: World Health Organisation; 1995. 149. Nutrient Requirements and Recommended Dietary Allowances for Indians. Hyderabad: National Institute of Nutrition. Indian Council of Medical Research; 2010. 150. CDC. STATAGE. Stature-for-age charts, 2 to 20 years, LMS parameters and selected smoothed stature percentiles in centimeters, by sex and age. . National Center for Health Statistics,; 2000. 151. Venkaiah K, Damayanti K, Nayak MU, Vijayaraghavan K. Diet and nutritional status of rural adolescents in India. Eur J Clin Nutr. 2002; 56: 1119-25. 152. Szklo M, Nieto FJ, editors. Epidemiology : Beyond the basics: Jones and Bartlett Publishers; 2007. 153. Tuberculosis Chemotherapy Centre. A concurrent comparision of home and sanatorium treatment of pulmonary tuberculosis in south India. Bull World Health Organ. 1959; 21: 51-144. 154. Vasantha M, Gopi PG, Subramani R. Weight gain in patients with tuberculosis treated under directly observed treatment short-course (DOTS). Indian J Tuberc. 2009; 56(1): 5-9. 155. Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcántara F, et al. Community-Based Therapy for Multidrug-Resistant Tuberculosis in Lima, Peru. New Engl J Med. 2003; 348(2): 119-28. 156. Walpola HC, Siskind V, Patel AM, Konstantinos A, Derhy P. Tuberculosis-related deaths in Queensland, Australia, 1989-1998: characteristics and risk factors. Int J Tuberc Lung Dis. 2003; 7(8): 742-50. 157. Rao VK, Iademarco EP, Fraser VJ, Kollef MH. The Impact of Comorbidity on Mortality Following In-hospital Diagnosis of Tuberculosis. Chest. 1998; 114(5): 1244-52. 158. Matos ED, Moreira Lemos AC. Association between serum albumin levels and in-hospital deaths due to tuberculosis. Int J Tuberc Lung Dis. 2006; 10(12): 1360-6. 159. National AIDS Control Organisation. Annual Report 2010-11. New Delhi: Department of AIDS Control, Ministry of Health and Family Welfare. 160. National Nutrition Monitoring Bureau. Diet and Nutritional status of Rural Population.Technical Report No 21. Hyderabad: National Institute of Nutrition, ICMR,; 2002. 161. WHO. Management of severe malnutrition: A manual for physicians and other senior health workers. Geneva: World Health Organisation; 1999. 162. WHO. Treatment of tuberculosis: guidelines. 4th edition. ed. Geneva: World Health Organisation; 2010. 163. Hopewell P, Pai M, Maher D, Uplekar M, Raviglione M. International Standards for Tuberculosis Care. Lancet Infect Dis. 2006; 6(11): 710-25. 164. World care council. The Patients' Charter for Tuberculosis Care. 2006. 165. Scoping meeting for the development of guidelines on nutritional/food support to prevent TB and improve health status among TB patients. Geneva: World Health Organisation,; 2009.
166. Consortium TTT. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV negative patients: a randomised clinical trial. Lancet. 2002; 360(9332): 528-34. 167. RNTCP Modules 1-4. New Delhi: Central TB division; 2011. 168. Long ER. Certain Theoretical and Practical Tuberculosis Problems. Yale J Biol Med. 1943; 15(3): 403-10. 169. Dubos RJ. Health and Disease. JAMA. 1960; 174(5): 505-7. 170. McDougall JB. Tuberculosis : A global study in social pathology. Baltimore: Williams & Wilkins Company; 1949. 171. Papathakis P, Piwoz E. Nutrition and Tuberculosis: A Review of the Literature and Considerations for TB Control Programs: United States Agency for International Development, Africa's Health 2010 Project (2008. 172. Lienhardt C. From Exposure to Disease: The Role of Environmental Factors in Susceptibility to and Development of Tuberculosis. Epidemiology Reviews. 2001; 23(2): 288-301. 173. Warmelink I, ten Hacken NH, van der Werf TS, van Altena R. Weight loss during tuberculosis treatment is an important risk factor for drug-induced hepatotoxicity. Br J Nutr. 2011; 105(3): 400-8. 174. Khan A, Sterling TR, Reves R, Vernon A, Horsburgh CR. Lack of weight gain and relapse risk in a large tuberculosis treatment trial. Am J Respir Crit Care Med. 2006; 174(3): 344-8. 175. Sir Pendrill Varrier-Jones. Papers of a Pioneer: Hutchinson & Co.; 1943. 176. Rasanathan K, Sivasankara Kurup A, Jaramillo E, Lonnroth K. The social determinants of health: key to global tuberculosis control. . Int J Tuberc Lung Dis. 2011; 15(Supplement 2): S 30-6. 177. Varrier-Jones PC. A tuberculosis colony in the making. British Journal of Tuberculosis. 1919; 13(1): 14-21. 178. Ustvedt H. Technique of tuberculin testing: A comparative study. . Bull World Health Organ. 1950; 2(26): 335-40. 179. Cauthen GM, Pio A, ten Dam HG. Annual risk of tuberculous infection( WHO/TB/88.154). Geneva: World Health Organization, ; 1988. 180. Rieder H. Annual risk of infection with Mycobacterium tuberculosis. Eur Respir J. 2005; 25(1): 181-5. 181. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974; 99(2): 131-8. 182. Villamor E, Iliadou A, Cnattingius S. Evidence for an Effect of Fetal Growth on the Risk of Tuberculosis. J Infect Dis. 2010; 201(3): 409-13. 183. Schlesinger B, Hart PD. Human contagion and tuberculous infection in childhood. Arch Dis Child. 1930; 5(27): 191-206. 184. Downes J. Salient Points of Attack against Tuberculosis. Milbank Mem Fund Q. 1940; 18(1): 44-60. 185. Joint Tuberculosis Council Research Committee. Report of the Lancashire Group of Tuberculosis Officers on the fate of young children in tuberculosis households.: G. Tinling & Co.; 1929. 186. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of Young Children in Contact With Adult Multidrug-Resistant Pulmonary Tuberculosis: A 30-Month Follow-up. Pediatrics. 2002; 109(5): 765-71. 187. World Health Organization Stop TB Partnership Childhood TB Subgroup. Chapter 4: childhood contact screening and management. Int J Tuberc Lung Dis. 2007; 11(1): 12-5. 188. Beyers N, Gie RP, Schaaf HS, Zyl SV, Talent JM, Nel ED, et al. A prospective evaluation of children under the age of 5 years living in the same household as adults with recently diagnosed pulmonary tuberculosis. Int J Tuberc Lung Dis. 1997; 1(1): 38-43.
93
189. Singh M, Mynak ML, Kumar L, Mathew JL, Jindal SK. Prevalence and risk factors for transmission of infection among children in household contact with adults having pulmonary tuberculosis. Arch Dis Child. 2005; 90(6): 624-8. 190. TB mortality data since 1913. [cited 2012 April 12]; Available from: http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Tuberculosis/TBUKSurveillanceData/TuberculosisMortality/TBMortality01trend/ 191. Henry CJK. The biology of human starvation: some new insights. Nutrition Bulletin. 2001; 26(3): 205-11. 192. Downes J. Salient Points of Attack against Tuberculosis. Milbank Mem Fund Q. 1940; 18(1): 44-60. 193. Connolly C. The TB preventorium. American Journal of Nursing. 2000; 100(10): 62-5. 194. Chapter 4: childhood contact screening and management. Int J Tuberc Lung Dis. 2007; 11(1): 12-5. 195. Singh M. Prevalence and risk factors for transmission of infection among children in household contact with adults having pulmonary tuberculosis. Archives of Disease in Childhood. 2005; 90(6): 624-8. 196. Seddon JA, Godfrey-Faussett P, Hesseling AC, Gie RP, Beyers N, Schaaf HS. Management of children exposed to multidrug-resistant Mycobacterium tuberculosis. Lancet Infect Dis. (0). 197. van Lettow M, Harries AD, Kumwenda JJ, Zijlstra EE, Clark TD, Taha TE, et al. Micronutrient malnutrition and wasting in adults with pulmonary tuberculosis with and without HIV co-infection in Malawi. BMC Infect Dis. 2004; 4(1): 61. 198. Raiten DJ, Mulligan K, Papathakis P, Wanke C. Executive summary—Nutritional Care of HIV-Infected Adolescents and Adults, including Pregnant and Lactating Women: What Do We Know, What Can We Do, and Where Do We Go from Here? Am J Clin Nutr. 2011; 94(6): 1667S-76S. 199. Canetti G. The eradication of tuberculosis: Theoretical problems and practical solutions. Tubercle. 1962; 43(3): 301-21. 200. Rajeswari R, Chandrasekaran V, Suhadev M, Sivasubramaniam S, Sudha G, Renu G. Factors associated with patient and health system delays in the diagnosis of tuberculosis in South India. Int J Tuberc Lung Dis. 2002; 6(9): 789-95. 201. Tuberculosis Prevention Trial. Trial of BCG vaccines in South India for tuberculosis prevention. Indian J Med Res. 1980; 72 Suppl: 1-74. 202. Lonnroth K. Risk factors and social determinants of TB. 15th conference of The Union North America region 2011; Vancouver, British Columbia, Canada; 2011. 203. Marrero A, Caminero JA, Rodríguez R, Billo NE. Towards elimination of tuberculosis in a low income country: the experience of Cuba, 1962–97. Thorax. 2000; 55(1): 39-45. 204. Gonzalez E, Armas L, Llanes MJ. Progress towards tuberculosis elimination in Cuba. Int J Tuberc Lung Dis. 2007; 11(4): 405-11. 205. Ross JE. Food security in Cuba. In: Font MA, editor. Cuba Today: Continuity and Change Since the ‘Período Especial,’. New York Bildner Center for Western Hemisphere Studies,; 2004. p. 115-25. 206. Getting started: WFP Food Assistance in the context of Tuberculosis Care and Treatment: World Food Programme; 2007. 207. Connolly M, Nunn P. Women and tuberculosis. World Health Stat Q. 1996; 49(2): 115-9. 208. Murray CJL, Lopez AD. Global mortality, disability and contribution of risk factors: the Global Burden of Disease study Lancet. 1997; 349: 1436-42. 209. National Food Security Bill. National Advisory Council. 2011.
Figure 2.1: Vicious cycle of under-nutrition and TB disease (in both drug-susceptible and drug-
resistant disease)
UNDER-NUTRITION
POOR CELL MEDIATED IMMUNITY
POOR CONTAINMENT OF M.TUBERCULOSIS
INCREASED SEVERITY OF
DISEASE
ANOREXIA
CYTOKINE DRIVEN CACHEXIA
95
Figure 2.2: UNICEF framework for causes for under-nutrition (figure adapted from R.E. Black
et al: Maternal and child undernutrition: global and regional exposures and health
consequences. Lancet 2008; 371:243-60)
Short-term consequences:
Mortality, morbidity, disability
Long-term consequences:
Adult size, intellectual ability, economic
productivity, reproductive performance,
metabolic and cardiovascular disease
Inadequate dietary intake Disease
Household food
insecurity
Inadequate care Unhealthy household
environment and lack of
health services
Income poverty: employment,
self-employment, dwelling,
assets, remittances, pensions,
transfers, etc
Lack of capital: financial, human,
physical, social and natural
Social, economic, and political
context
Underlying causes
Immediate causes
Basic causes
Adult and child under nutrition
96
Figure 2.3: Annual tuberculosis mortality rates England and Wales, 1850-1960. BCG, Bacillus
Calmette Guerin.
[Figure from Lienhardt C. From Exposure to Disease: The Role of Environmental Factors in Susceptibility to and Development of Tuberculosis. Epidemiology Reviews 2001; 23(2): 288-301.]
97
Figure 3.1: Box plot showing distribution of pre-treatment and post-treatment weights in
adult patients with pulmonary Tuberculosis at JSS (2004-9).
Distribution of body mass index in pulmonary TB patients
BMI pre-treatment BMI post-treatment
99
Figure 5.1: Overview of the families and children who were the subject of the Papworth
survey (1918-1943).
100
Figure 5.2: Summary of children in the village-born and admitted cohorts before admission to
Papworth, while living in Papworth, and after discharge.
PRE-PAPWORTH Period:
231 child contacts were born outside the settlement of which 3 died of TB in this period. The
rest were admitted to the settlement with their families.
c
PAPWORTH Period :
312 child contacts of TB patients lived at Papworth between1918-43
228 were admittedto the settlement after their birth outside
(admitted cohort).
84 child contacts were born in the settlement (village-born cohort).
Village- born cohort: 84 child contacts
Of these, 63 children were in the settlement till
end of study period or development of TB (n=1).
All others were followed in settlement beyond the
major risk period for TB development (mean 4.0
years)
Admitted cohort: 228 child contacts Of these, 123 children were in the settlement till end of study period or development of TB(n=5).
All others were followed in settlement beyond the major risk period for TB development (mean 6.7
years)
POST PAPWORTH Period in village- born cohort
21 children were of families which left the
settlement.
3 children were re-evaluated at the settlement
POST-PAPWORTH Period in admitted cohort
105 children were of families which left the
settlement.
34 children were re-evaluated at the settlement.
101
Table 3.1: The international classification of adult underweight, overweight and obesity
according to BMI (based on references.*)
Classification BMI kg /m2
Underweight <18.5
Severe thinness <16.0
Moderate thinness 16.0-16.99
Mild thinness 17.0-18.49
Normal range 18.5-24.99
Overweight >25.0
Pre-obese 25.0-29.99
Obese >30.0
Obese Class I 30.0-34.99
Obese Class II 30.0-34.99
Obese Class III 30.0-34.99
*References:
1. WHO.Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series 854. Geneva: World Health Organisation; 1995. 2.WHO. Obesity: preventing and managing the global epidemic. Report of a WHO consultation.WHO Technical Report Series 894. Geneva: World Health Organisation, ; 2000. 3.WHO Expert consultation.Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. The Lancet. 2004; 363(9403): 157-63.
102
Table 3.2. Demographic and clinical characteristics of adult patients with pulmonary tuberculosis at JSS (2004-2009). Characteristic N=1695
DEMOGRAPHIC AND GEOGRAPHIC
Median age in years, (IQR) 38(29,50)
Age groups, no. (%)
18-25 years 306(18)
26-35 years 475(28)
36-45 years 388(23)
46-55 years 267(16)
≥56 years 259(15)
Gender, (%)
Men 1152 (68)
Women 543 (32)
Residence, (%)
Rural 1601(94)
Urban 94 (6)
Location of residence, (%)
Group 1:related to outreach clinics 193 (11)
Group 2: within radius of 20 km of hospital 161 (9)
Group 3:beyond 20 km radius from hospital 1341 (80)
DISEASE RELATED
Sputum smear, (%)
Smear positive 1119 (66)
Smear negative 576 (34)
Sputum grade, (%)
1+ 357 (32)
2+ 302 (27)
3+ 460(41)
Treatment history, (%)
New cases 1395 (82)
Retreatment cases 300 (18)
No. of retreatment patients with MDR-TB 20
CO-MORBIDITIES
No. of patients with HIV infection 2004-2009 91
No. of patients with Pulm. TB- HIV co-infection 39
No. of patients with Diabetes mellitus 77
No. of patients with anemia (Hb*.<12 g/dl) 515
severe anemia (Hb*.<8 g/dl) 143
FAMILY HISTORY OF TB
No. of patients with family history of TB, (%) 389(23)
No. of patients with family history of TB related death, 207
*Hb.: Hemoglobin
103
Table 3.3: Demographic and clinical characteristics of adult patients with pulmonary
tuberculosis who were treated at JSS (2004-2009), stratified by outcomes.
Characteristic Treatment
success*
N=756
TB
death§
N=60
Default¶
during TB treatment
N=354
P values
(Treatment
success vs.
TB death)
P values
(Treatment
success vs.
default)
DEMOGRAPHIC & GEOGRAPHIC
Median age in years, (IQR) 35(27,45) 40(35,53) 40(29,52) P<0.0001††
P<0.0001†
Gender, (%)
Men 479(63) 46 (77) 251 (71) P=0.04‡ P=0.01‡
Women 277(37) 14 (23) 103 (29)
Residence, (%)
Rural 722 (96) 54 (90) 327 (92) P=0.06‡ P=0.03‡
Urban 34 (4) 6 (10) 27 (8)
Location of residence, (%)
village program/outreach clinics 140(18) 11(18) 34 (10) P<0.0001‡ P<0.0001‡
Previously treated case 0.65 (0.48,0.87) 0.70 (0.50,0.97)
Location of residence
group 1: 1 1
group 2: 0.65 (0.40,1.07) 0.54 (0.30,0.98)
group 3: 0.52 (0.36, 0.75) 0.43 (0.27, 0.68)
Family history of TB
No history of TB 1
Positive History of TB in family 1.22 (0.92, 1.63) 1.13 (0.84,1.53)
§ Adjusted for age, sex, pre-treatment weight, height, sputum status, HIV status, treatment category, location of residence and family history of TB. ‡ Logistic regression on BMI was done after omitting weight, height from the model *OR scaled to represent increase of age of 10 years. **OR scaled to represent increase of weight of 5 kg. NA: Not applicable as variable is not in final model
108
Table 3.8: Comparative weights and body mass index in patients with pulmonary TB from other high TB burden countries (reference numbers in superscripts). Country ,Year Setting,
(86,806) *PTB denotes pulmonary TB. † EPTB denotes extra-pulmonary TB. ‡ Causes of death: pneumonia (1), road accident(1). §Causes of death: Diphtheria(1),Laryngismus(1),Diabetes(1), Road accident(1). || PYAR denotes person-years at risk- person-time in years that a child was at risk for TB during the Papworth period. This was measured from year of admission to the year of the end of study (1943) in those who remained in the settlement. In children who left the settlement, this was measured from the year of admission to the year of leaving the settlement. In children who developed the disease, it was measured from year of admission to the year of diagnosis.95% CIs denotes 95% confidence intervals. ** denotes one-sided 97.5% confidence intervals.
114
Table 5.6: Mortality and morbidity in admitted and village born cohorts after discharge from
Papworth
Admitted cohort Village-born
Cohort
Total
No. of children evaluated at least once, after discharge