4. Summary of the evidence

Systematic reviews were conducted to address the following questions (see Annex 3 for questions in PICO format)

1. What is the optimal composition of the diet for patients receiving treatment for active TB?

2. Should macronutrient supplements be recommended to improve TB treatment and health outcomes for well-nourished or undernourished patients (children, adolescents, adults and pregnant and lactating women) being treated for active TB?

3. Should micronutrient (alone, combined or as a multiple micronutrient) supplements be recommended as a component of normal care in well-nourished or undernourished patients (children, adolescents, adults and pregnant and lactating women) being treated for active TB for improving TB treatment and nutrition outcomes?

4. Are there population-level nutritional interventions that could reduce the progression from latent to active TB in household contacts of patients with active TB?

Optimal composition of the diet for patients receiving treatment for active TB

This question was considered a background question and the findings from the review of the literature on the subject were integrated in the background section of this guideline. The only aspect of the diet composition considered for inclusion in the questions in a PICO format and systematic review of the literature was that of energy requirements.

When assessing energy requirements in patients with TB and other pulmonary diseases (63), only two observational studies were included in the review on energy requirements in people on TB treatment, with a total of 40 persons with TB. The studies found that basal metabolic rate was 14% higher in the patients compared with the controls (see GRADE Table 1, Annex 1). One study measured energy expenditure in six TB subjects with 10% weight loss at diagnosis, compared with six healthy controls; the second study’s objective was to investigate whether the leptin concentration in 32 TB patients is higher during active TB disease versus recovery and how it related to energy metabolism. In this study, there was no comparison group. Both studies were of very low quality. The evidence is limited to judge whether, or by how much, the daily energy requirements are increased in people with active TB.

Macronutrient and micronutrient supplementation for patients with active TB

One Cochrane systematic review assessed the effects of oral nutritional supplements (food, protein/energy supplements or micronutrients) on TB treatment outcomes and recovery in people on antituberculous drug therapy for active TB (27). Twenty-three trials, with a total of 6842 participants, were included in the review on these two subjects (see GRADE Tables 2 and 3, Annex 1).

In relation to macronutrient supplementation, five trials assessed the provision of free food, or high-energy supplements, although none were shown to result in a total daily kilocalorie intake above the current daily recommended intake for the non-infected population. The available trials were too small to reliably prove or exclude clinically important benefits on mortality, TB cure or completion of TB treatment. One small trial from India did find a statistically significant benefit on completion of TB treatment, and clearance of the bacteria from the sputum, but these findings have not been confirmed in larger trials elsewhere (very low quality evidence).

The provision of free food or high-energy nutritional products may produce a modest increase in weight gain during treatment for active TB (moderate quality evidence). Two small studies on people coinfected with TB and HIV provide some evidence that physical function and quality of life may also be improved but the trials were too small to have much confidence in the result (low quality evidence). These effects were not seen in the one trial that included only HIV-positive patients.

In relation to micronutrient supplementation, five trials assessed multimicronutrient supplementation in doses up to 10 times the dietary reference intake, and 12 trials assessed single or dual micronutrient supplementation.

There is insufficient evidence to judge whether multi-micronutrients have a beneficial effect on mortality in HIV-negative patients with TB (very low quality evidence), but the available studies show that multi-micronutrients probably have little or no effect on mortality in HIV-positive patients with TB (moderate quality evidence).

No studies have assessed the effects of multi-micronutrients on TB cure, or completion of TB treatment. Multiple micronutrient supplements may have little or no effect on the proportion of TB patients remaining sputum positive during the first 8 weeks (low quality evidence), and probably have no effect on weight gain during treatment (moderate quality evidence). No studies have assessed quality of life. Plasma levels of vitamin A appear to increase following initiation of TB treatment, regardless of supplementation. In contrast, plasma levels of zinc, vitamin D and E, and selenium may be improved by supplementation during the early stages of TB treatment, but a consistent beneficial effect on outcomes of TB treatment or nutritional recovery has not been demonstrated. There is insufficient evidence to know whether routinely providing free food or energy supplements results in better TB treatment outcomes or improved quality of life. Although blood levels of some vitamins may be low in patients starting treatment for active TB, there is currently no reliable evidence that routinely supplementing at or above recommended daily amounts has clinical benefits.

Population-level nutritional interventions to reduce the progression from latent to active TB

A literature review was conducted to investigate whether household contacts with poor nutritional status were at higher risk of contracting or developing active TB disease. No intervention study was included. Six studies on the risk for children in contact with people with active TB were identified. Two of the studies found that malnutrition and younger age individually increased the risk of household contacts developing active TB. One study was cross-sectional and it was difficult to determine the direction of influence between active TB and failure to thrive. Two studies were not designed to measure differences in variables by household contact and the last study found that vitamin D deficiency was associated with increased risk of development of active disease in close contacts (62).

Although undernutrition is a risk factor for progression from TB infection to active TB disease, it is not known whether or with how much macro- or micronutrient supplementation reduces the risk of progression. Among young children who have had recent contact with a case of active TB, it is not known whether nutritional supplementation in combination with treatment of latent TB infection reduces the risk of progression to active TB more than treatment for latent TB infection alone.

The overall evidence base on effects of nutritional supplements for TB prevention and care remains very weak. It is not known whether nutritional supplementation, as an addition to standard care, improves health outcomes among people with TB, or prevents progression from TB infection to active disease. Owing to a lack of evidence that people with TB should receive nutritional care and support that is different from that which should be provided to others, the recommendations in this guideline are fully consistent with WHO’s general recommendations on nutritional care and support (2–4).

Implications for future research

Discussion with Nutrition Guidance Advisory Group members and stakeholders highlighted the limited evidence available in themes related to the areas listed next.

1. Nutrient requirements

a. Energy requirements in TB patients compared with persons without TB, considering TB treatment, coexistent HIV, phase of treatment and multidrugresistant tuberculosis (MDR-TB)

b. Requirements/utilization of proteins, as well as fat requirements

c. Risk of micronutrient deficiencies in people with active TB in relation to people without TB

d. Proportional causes of malnutrition in people with TB

e. The natural course of weight change during the intensive phase of TB treatment in drug-sensitive TB and MDR-TB, in people with different levels of malnutrition, and in settings with varying levels of food security

2. Supplementation

a. The effect of macronutrient intake/food supplementation in addition to treatment alone, on TB treatment outcomes

b. The effect of macronutrient supplementation or routine supplementation with micronutrients at 1× recommended nutrient intake in pregnant women with active TB, on neonatal complications

c. Benefits of macro- or micronutrient supplementation on growth and development in the 5–19-year age groups with active TB, compared to those without TB

d. Definition of nutritional parameters/TB-specific outcomes to be measured in nutritional supplementation trials

3. Programmes

a. The effect of implementation of the new WHO nutrition and TB recommendations on nutritional recovery/TB treatment outcomes in TB patients

b. The relative importance of food assistance (compared with other enablers) as an enabler to adherence

4. Assessment and counselling

a. Aspects of nutritional counselling that enhance the effectiveness and uptake of advice on nutritional outcomes

b. The best measure of nutritional status in pregnant women, with and without TB, considering both maternal and infant outcomes

c. The optimal BMI for healthy maternal and infant outcomes in pregnant women with TB

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