1.2. Ruling out active tuberculosis disease

Giving TB preventive treatment to someone who has active TB can delay resolution of disease and favour the emergence of drug resistance. Excluding active TB disease before initiating preventive treatment is one of the critical steps in the LTBI care pathway. This section proposes approaches to rule out active TB and diagnose LTBI in people at risk of infection following key decision points, namely HIV status, symptoms, household contact, other risk factors, age, LTBI test results and abnormality on chest radiography (Fig. 1). The evidence and the recommendations underpinning these steps are also briefly discussed.

People living with HIV

11. Adults and adolescents living with HIV should be screened for TB according to a clinical algorithm. Those who do not report any of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered preventive treatment, regardless of their ART status. (Strong recommendation, moderate certainty in the estimates of effect)

12. Adults and adolescents living with HIV who are screened for TB according to a clinical algorithm and who report any of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases and offered preventive treatment if active TB is excluded. (Strong recommendation, moderate certainty in the estimates of effect)

13. Chest radiography may be offered to people living with HIV on ART and preventive treatment be given to those with no abnormal radiographic findings. (Conditional recommendation, low certainty in the estimates of effect)

14. Infants and children living with HIV who have poor weight gain⁷ , fever or current cough or who have a history of contact with a person with TB should be evaluated for TB and other diseases that cause such symptoms. If TB disease is excluded after an appropriate clinical evaluation or according to national guidelines, these children should be offered TB preventive treatment, regardless of their age. (Strong recommendation, low certainty in the estimates of effect)

Justification and evidence

The first two recommendations featured already in the 2015 guidelines and were updated in 2018 (13),(16). The third recommendation on chest radiography was first released in 2018, updating a position made in the 2011 guidelines (11). In 2011, WHO conducted a systematic review and a meta analysis of individual patient data and recommended a symptom-screening rule of a combination of current cough, weight loss, night sweats and fever to exclude active TB in adults and adolescents (45). The review showed that the rule had a sensitivity of 79%, a specificity of 50% and a negative predictive value of 97.7% at a TB prevalence of 5%. Most People with HIV in studies included in the systematic review were not receiving ART.

During the 2018 update of the guidelines, a systematic review was undertaken to compare the performance of the four-symptom screen in People with HIV who were and were not receiving ART (see PICOs 2 and 3 in Annex 2 and Table 2 of (46)). Data from 17 studies were included in this analysis. The pooled sensitivity of the four-symptom screen for People with HIV on ART was 51.0% (95% CI 28.4; 73.2), and the specificity was 70.7% (95% CI 47.7; 86.4); in People with HIV who were not receiving ART the pooled sensitivity was 89.3% (95% CI 82.6; 93.6), and the specificity was 27.2% (95% CI 17.3; 40.0). Two studies provided data on addition of abnormal chest radiographic findings to the screening rule for People with HIV on ART (47),(48). The pooled sensitivity was higher (84.6%, 95% CI 69.7; 92.9), but the specificity was lower (29.8%, 95% CI 26.3; 33.6) when compared with the symptom screen alone.

In all studies, the median prevalence of TB among People with HIV on ART was 1.5% (interquartile range, 0.6– 3.5%). At a 1% prevalence of TB, the negative predictive value of the symptom screening rule was 99.3%; addition of abnormal chest radiographic findings increased the negative predictive value by 0.2%. No studies of the addition of chest radiography to the symptom rule for pregnant women were found in the review.

In infants and children, a systematic review conducted for the 2011 guidelines identified limited evidence on the best approach to screening (11). Based on these few studies and expert opinion, the previous GDG recommended a screening rule consisting of poor weight gain, fever, current cough and a history of contact with a person with TB. Another systematic review to assess the performance of this screening rule was attempted for the 2018 update. The only publication found was a conference abstract of a study of 176 hospitalized children with HIV aged ≤ 12 years in Kenya (49). The study had a sensitivity of 100% (95% CI, 76.8; 100.0) and a specificity of 4.3% (95% CI, 1.8; 8.7).

The GDG agreed that in adults and adolescents living with HIV the four-symptom screen – current cough, fever, weight loss or night sweats – is very useful for ruling out active TB, regardless of ART use. Confirmation of LTBI using IGRA or TST would be desirable before starting TB preventive treatment. It noted the potential benefits of adding an abnormal chest radiographic finding to the rule, while recognizing that the improvement in performance was marginal. Moreover, increased use of chest radiography would add more false-positive results to the screening rule, which would require more investigations for TB and other illnesses. Therefore, the GDG reiterated that chest radiography may be added as an additional investigation only if it does not pose a barrier to the provision of preventive treatment for People with HIV. It should not be a requirement for initiating preventive treatment. Although no study was found of the additive role of chest radiography in testing pregnant women, the GDG noted that pregnant women living with HIV could also benefit, as long as good practices are observed to prevent harmful radiation exposure to the foetus (50).

Infants and children living with HIV should be screened for TB as part of standard, routine clinical care, regardless of whether they are receiving TB preventive treatment or ART. The GDG noted that less data were available on the performance of a standardized screening rule for children living with HIV when compared with the screen rule for adults and adolescents. The single study showed that the symptom screening rule currently used in children living with HIV performs well, but no study has been reported on the harm or challenges of the rule, such as resource requirements for implementation. Symptom-based screening is generally acceptable to caregivers and people and is feasible even in resource-limited settings. Therefore, the GDG decided to make a strong recommendation for use of the symptom screen in children living with HIV. In those who have one or more symptoms, active TB should be ruled out. The GDG also noted that clinicians should broaden the differential diagnosis to include other diseases that may cause current cough, fever and poor weight gain in children with HIV. If the evaluation shows no signs of active TB and the clinician has decided not to treat for TB disease, children with HIV should be offered TB preventive treatment, regardless of their age. However, infants < 12 months of age should be given TB preventive treatment only if they have a history of household contact with a person with TB and active TB has been excluded according to national guidelines. Guidance on further testing for TB in People with HIV who have suggestive clinical features is available elsewhere (39).

Household contacts of a person with pulmonary TB

Infants and children < 5 years of age⁸
Justification and evidence

In 2012, a systematic review was carried out to assess the sensitivity and specificity of different combinations of one or more symptoms and/or chest radiography to screen for bacteriologically confirmed active pulmonary TB in HIV-negative persons and persons with unknown HIV status (51)⁹. While updating this review ahead of the 2018 guidelines only one study was identified for young children (mean age, 19.2 months) in which various symptoms were evaluated, such as failure to thrive and prolonged cough (52). This study did not discuss the value of symptoms for excluding TB. Symptom-based screening has been reported to be a safe and feasible contact management  strategy in children, even in resource-limited settings (53),(54). A modelling study using high TB burden setting parameters also suggested that providing preventive treatment without LTBI testing is cost-effective for child contacts under 5 years of age (55). See also Section 1.1 for more background on the recommendation for LTBI testing and treatment in this risk group.

Household contacts aged ≥ 5 years and other risk groups

15. The absence of any symptoms of TB and the absence of abnormal chest radiographic findings may be used to rule out active TB disease among HIV-negative household contacts aged ≥ 5 years and other risk groups before preventive treatment. (Conditional recommendation, very low certainty in the estimates of effect)

Justification and evidence

This is a conditional recommendation based on very low-quality evidence, newly released in the 2018 guidelines (16). It is based on the systematic review used to determine the sensitivity and specificity of screening based on symptoms and/or chest radiography for ruling out active TB in HIV-negative people and people of unknown HIV status for the 2015 guidelines (see PICO 3 in Annex 2) (51). To illustrate how the various screening and diagnostic algorithms are expected to rule out active TB, a simple model was constructed to compare the following six screening criteria: (i) any TB symptom, (ii) any cough, (iii) cough for 2–3 weeks, (iv) chest radiographic abnormality suggestive of TB, (v) any chest radiographic abnormality and (vi) a combination of any chest radiographic abnormality or any TB symptom. The model suggested that the combination of any chest radiographic abnormality and the presence of any symptoms suggestive of TB (i.e. any cough of any duration, haemoptysis, fever, night sweats, weight loss, chest pain, shortness of breath and fatigue) would offer the highest sensitivity (100%) and negative predictive value (100%) for ruling out TB. Ahead of the 2018 guidelines update this review was updated focusing on household contacts aged ≥ 5 years of pulmonary TB patients in high TB burden countries (56). Seven studies evaluating the accuracy of ‘any CXR abnormality’ had a pooled sensitivity of 94.1% (95%CI 85.8–97.7) and pooled specificity 86.8% (95%CI 79.7–91.7). In a hypothetical population of 10,000 HIV-negative individuals and at a TB prevalence of 2%, use of any TB symptoms alone would wrongly classify 54 TB patients as not having active TB and they would be offered TB preventive treatment. In contrast, use of any abnormal chest radiography finding would result in 12 TB patients being offered preventive treatment. Use of the combination of any TB symptoms plus any chest radiography abnormal findings would result in no patients with active TB being incorrectly offered preventive treatment. At a TB prevalence of 2%, use of any TB symptoms alone would require TB investigations of 16 extra non-TB patients for every TB case identified, whereas use of any abnormal chest radiography finding would require TB investigations of 7 extra non-TB patients for every TB case identified. Use of the combination of any TB symptoms plus any chest radiography abnormal finding would increase the number of individuals requiring TB investigations to 15 extra non-TB patients for every TB case identified.

In conclusion, a screening algorithm using any symptom of TB and any abnormal chest radiographic findings is likely to offer high sensitivity. This implies that the absence of any TB symptoms and chest radiographic abnormality can be used to exclude active pulmonary TB before initiating TB preventive treatment among household contacts.

The GDG noted the shortage of new data and agreed to continue using the existing symptom-based algorithms for infants and children who are household contacts of a person with TB. The GDG reiterated that national guidelines should specify what investigations are necessary to rule out active TB. It noted that screening of child contacts could include LTBI testing and chest radiography, although the absence of those investigations should not pose a barrier for either diagnosis of active TB disease or provision of preventive treatment. In the absence of these tests, clinical assessment alone is sufficient to decide on initiation of TB preventive treatment particularly for household contacts < 5 years of a bacteriologically confirmed pulmonary TB.

The GDG concluded that symptom screening with or without the addition of chest radiography should be acceptable for individuals and programme managers. Chest radiography could increase the confidence of healthcare providers that active TB has been ruled out and lower concerns that TB preventive treatment is being administered inappropriately.

Implementation considerations

Fig. 1 is an algorithm for LTBI testing and treatment with separate entry points for People with HIV, household contacts or other persons at risk for LTBI.

The four-symptom screening method is recommended for all People with HIV at every visit to a health facility or contact with a health worker to ensure early detection of active TB. Other clinical features may also be helpful (e.g. poor weight gain in pregnant women). Other diseases that cause any of the four symptoms should be investigated in accordance with national guidelines and sound clinical practice. Individuals found not to have active TB should then be assessed for preventive treatment.

Where radiography or expert interpretation is not available, the absence of any TB symptoms alone may be considered sufficient before TB preventive treatment. This would offer the highest sensitivity among symptom-based screening rules, and its negative predictive value is high in most settings. The addition of abnormal chest radiographic findings to the symptom screening rule would increase logistical and infrastructural requirements, cost to individuals and health services, and need for qualified staff. The optimal frequency of chest radiography in regular TB screening of People with HIV is uncertain. Carrying out a chest radiograph in addition to symptom screening at every visit represents a significant burden on the individual and the health system. Local authorities should define its application and frequency based on their local epidemiology, health infrastructure and resources. Radiologists or other trained healthcare workers must be available to interpret chest radiography.

The GDG noted that chest radiography should not be a prerequisite or a barrier for initiating TB preventive treatment in People with HIV because of the need for additional resources, in view of the marginal gain in negative predictive value. Conversely, in People with HIV with low CD4 counts, active TB may occur despite a normal chest radiography. People with HIV who have any of the four symptoms or abnormal chest radiographic findings may have active TB and should be investigated for TB and other diseases. Xpert® MTB/RIF should be used as the initial diagnostic test.

Preventive treatment should not be withheld in an asymptomatic individual at risk of infection should LTBI testing and/or chest radiography be unavailable. It is conceivable that some people may have two risks (e.g. People with HIV who are also contacts of TB patients), in which case the triage shown in the figure would need to be adapted.

It is critical to ensure proper follow-up and evaluation for TB and other diseases in household contacts with abnormal chest radiographic findings or TB symptoms. The investigations should be performed in accordance with national guidelines and sound clinical practice. Contacts found not to have active TB need to be assessed for preventive treatment. Although LTBI testing is not a requirement for initiating TB preventive treatment, it may be done as a part of eligibility screening where feasible (see Section 1.3). A previous history of TB or TB preventive treatment should not be a contraindication for preventive treatment in case of exposure, following the exclusion of reactivated disease. These individuals, including those with fibrotic radiological lesions, may be at increased risk of progression (57),(58). Choice of TB preventive treatment also depends on presence of contraindication (e.g. active hepatitis; symptoms of peripheral neuropathy when isoniazid is considered) or likelihood of drug-drug interactions (see Section 1.4).

Algorithm for LTBI testing and TB preventive treatment

1. If <10 years, any one of current cough or fever or history of contact with TB or reported weight loss or confirmed weight loss >5% since last visit or growth curve flattening or weight for age <-2 Z-scores. Asymptomatic infants <1 year with HIV are only treated for LTBI if they are household contacts of TB. TST or IGRA may identify People with HIV who will benefit most from preventive treatment. Chest radiography (CXR) may be used in People with HIV on ART, before starting LTBI treatment

2. Any one of cough or fever or night sweats or haemoptysis or weight loss or chest pain or shortness of breath or fatigue. In children <5 years, they should also be free of anorexia, failure to thrive, not eating well, decreased activity or playfulness to be considered asymptomatic

3. Including silicosis, dialysis, anti-TNF agent treatment, preparation for transplantation or other risks in national guidelines.

4. Including acute or chronic hepatitis; peripheral neuropathy (if isoniazid is used); regular and heavy alcohol consumption. Pregnancy or a previous history of TB are not contraindications.

5. Regimen chosen based on considerations of age, strain (drug susceptible or otherwise), risk of toxicity, availability and preferences.

6. CXR may have been carried out earlier on as part of intensified case finding.

⁷ Poor weight gain is here defined as reported weight loss, very low weight-for-age (< –3 Z-scores), underweight (weight-for-age < –2 Z-scores), confirmed weight loss (> 5%) since the last visit or growth curve flattening

⁸ For LTBI testing and TB preventive treatment in <5 years see recommendations in Section 1.1 and the algorithm in Fig. 1.

⁹ Bacteriological confirmation may be by smear microscopy, culture or a WHO-approved molecular test such as Xpert® MTB/RIF (see Definitions).

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