OBJECTIVES:

Xpert Mycobacterium tuberculosis and rifampicin (MTB/RIF) Ultra assay has increasingly been used in adult tuberculosis diagnosis, but data relating to its diagnostic accuracy in children are lacking. Because a qualified sputum specimen is difficult to obtain in children, this study evaluated the diagnostic value of Ultra in childhood tuberculosis using bronchoalveolar lavage fluid.

METHODS:

The accuracy of Ultra was calculated by using bacteriologic results and clinical evidence as reference standards. Concordance between Ultra and Xpert MTB/RIF assays was assessed by using к coefficients.

RESULTS:

In total, 93 children with pulmonary tuberculosis and 128 children with respiratory tract infections were enrolled. The sensitivity of Ultra, in all pulmonary tuberculosis cases and in bacteriologically confirmed tuberculosis cases, was 70% and 91%, respectively. Ultra could detect Mycobacterium tuberculosis in 58% of cases with negative culture or acid-fast–staining results. The specificity of Ultra was 98%. There was no significant difference in sensitivity between samples with a volume ≤1 and >1 mL (66% vs 73%; P = .50; odds ratio [OR] = 0.71). Among 164 children for which Ultra and Xpert were simultaneously performed, the sensitivity was 80% and 67%, respectively, indicating good agreement (к = 0.84). An additional 6 children were identified as Ultra-positive but Xpert-negative. The positive rate decreased from 93% to 63% after 1 month (P = .01; OR = 0.12) and to 71% after 2 months (P = .03; OR = 0.18) of antituberculosis treatment.

CONCLUSIONS:

Ultra using bronchoalveolar lavage fluid has good sensitivity compared with bacteriologic tests and adds clinical value by assisting the rapid and accurate diagnosis of pulmonary tuberculosis in children.

What’s Known on This Subject:

Early diagnosis of childhood tuberculosis can reduce child mortality, but it is often hindered by a lack of bacteriologic evidence. We evaluated the diagnostic value of Xpert MTB/RIF Ultra in childhood tuberculosis using bronchoalveolar lavage fluid (BALF).

What This Study Adds:

Xpert MTB/RIF Ultra using BALF offers higher sensitivity than bacteriologic tests. In children with tuberculosis, Xpert MTB/RIF Ultra using BALF provides early and accurate etiologic results. A comparison between Xpert MTB/RIF and Xpert MTB/RIF Ultra was performed in this study.

Children carry nearly 10% of the global tuberculosis disease burden and account for 15% of the total deaths.1  The World Health Organization (WHO) estimated that there were 99 000 new pediatric tuberculosis cases in China in 2017, but only 10% of them were notified and reported.1  Precise data on the percentage of pediatric tuberculosis cases confirmed microbiologically are not reported by many countries.1  The large number of missing cases suggests poorer access to diagnosis and treatment in childhood tuberculosis than in adult tuberculosis. Timely and accurate diagnosis will be crucial to achieve the global aim of minimizing childhood tuberculosis.

However, management of childhood tuberculosis is hampered by difficulties in attaining an etiologic diagnosis because of the challenge of obtaining samples and low bacterial loads. In general, the diagnosis of pediatric tuberculosis in the clinic mainly depends on contact history, clinical symptoms, and chest radiography results.2  On the basis of their higher sensitivity, molecular tests have increasingly been used to confirm the presence of Mycobacterium tuberculosis in patients with active tuberculosis3  as a promising alternative to traditional diagnostic methods.

The Xpert Mycobacterium tuberculosis and rifampicin (MTB/RIF) assay is an automated molecular test based on seminested real-time polymerase chain reaction and molecular beacon technology targeting the rifampicin-resistance–determining region of the rpoB gene.4  Rifampicin resistance is viewed as an indicator of multidrug-resistant tuberculosis because most patients with rifampicin resistance also have isoniazid resistance. The WHO officially endorsed this assay as a primary diagnostic test for children suspected of having multidrug-resistant tuberculosis or HIV-associated tuberculosis and as a conditional test for children suspected of having tuberculosis.4,5  Nowadays, the Xpert MTB/RIF Ultra assay has been developed as a next-generation assay to overcome these limitations. To improve sensitivity for the detection of MTB, another 2 multicopy amplification targets (IS6110 and IS1081) and a larger DNA reaction chamber are used in Ultra. Furthermore, melting temperature–based analysis replaces real-time polymerase chain reaction to improve the accuracy of rifampicin resistance detection.6 

Although Ultra has gradually been introduced for diagnosing tuberculosis in adults,7,8  data are still lacking regarding its diagnostic accuracy in children. A multicenter comparative study in children demonstrated the higher sensitivity of Ultra over Xpert using sputum samples but slightly reduced specificity compared with Xpert in detecting pulmonary tuberculosis.9  Most current research uses sputum specimens or gastric aspirates to diagnose pulmonary tuberculosis in children.10,11  However, qualified sputum specimens are difficult to obtain in children, especially those of younger age.

Bronchoalveolar lavage is an effective tool to control severe infection. Fiber-optic bronchoscopy is also an important intervention in children who present with dyspnea, obstructive pneumonia, pulmonary atelectasis, or localized emphysema. It is sometimes difficult to confirm whether pulmonary atelectasis is due to extrinsic compression on a bronchus from regional lymphadenopathy or from caseous necrosis in an airway by using standard pulmonary imaging. In children who present with these signs or symptoms in addition to pulmonary tuberculosis, fiber-optic bronchoscopy can be used to confirm the reasons for pulmonary atelectasis and improve ventilation.7  As such, bronchoalveolar lavage fluid (BALF) appears to be a good alternative sample for children who have difficulty producing sputum. The sensitivity of MTB culture from BALF is significantly higher than that from sputum samples (39.2% vs 35.3%) in adult patients with tuberculosis.12  Positive rates obtained from smears and MTB culture by using gastric aspirates or BALF are similar and are higher than those obtained by using sputum samples from children with suspected complicated intrathoracic tuberculosis.13 

BALF shows a superior diagnostic yield in patients with smear-negative or sputum-scarce pulmonary tuberculosis. However, there are little data about its diagnostic value in pulmonary tuberculosis in children. For this study, we enrolled children with indications for fiber-optic bronchoscopy and had the following aims: (1) evaluate the diagnostic value of Ultra in childhood tuberculosis by using BALF, (2) compare the accuracy of Ultra with that of Xpert, and (3) confirm the value of Ultra in monitoring treatment effectiveness. The results presented provide data for informed management of childhood tuberculosis.

This retrospective study was performed at the Beijing Children’s Hospital affiliated with Capital Medical University. Children were defined as those <15 years old according to the WHO definition5  and were enrolled in the study if (1) they had suspected symptoms of tuberculosis; (2) they had the indications to undergo fiber-optic bronchoscopy, including those who presented with dyspnea, obstructive pneumonia, or localized emphysema, and those needing further microbiologic confirmation because of atypical imaging changes, no contact history with an index patient with confirmed tuberculosis, or negative microbiologic results by using sputum or gastric aspirates; and (3) informed consent to fiber-optic bronchoscopy had been given. BALF specimens were collected from February 2014 to April 2019 and were stored at −80°C for further analysis.

The children enrolled were categorized into 3 groups14 : (1) bacteriologically confirmed tuberculosis (positive for acid-fast staining or culture of MTB), (2) clinically diagnosed tuberculosis (at least 1 symptom and sign, radiographic evidence consistent with tuberculosis, and at least 1 of the following: positive tuberculin skin test or interferon-γ release assay results, clinical and radiologic improvement seen after antituberculosis chemotherapy, or documented exposure to tuberculosis), and (3) patients without tuberculosis with respiratory tract infections (RTIs) (symptomatic but not fitting the above definitions and confirmed etiologic evidence of infection with virus, mycoplasma, or bacteria).

This study was approved by the Medical Ethics Committee of Beijing Children’s Hospital. Written informed consent was obtained from the guardians of the patients.

All children enrolled were tested with Ultra and simultaneously with Xpert if the volume of the BALF sample was sufficient. If children with endobronchial tuberculosis presented with severe dyspnea due to caseous necrosis during treatment, fiber-optic bronchoscopy was performed to remove the caseous necrosis in the airway once or twice during follow-up.

Preprocessing of samples for Ultra and Xpert (Cepheid, Sunnyvale, CA) was performed in accordance with the manufacturer’s instructions, as described earlier.15  A 1:1 volume of sample reagent was added to each BALF sample. If the volume was <1 mL, sample reagent was added to give a total volume of 2 mL and mixed for 15 to 20 seconds before adding to the sample chamber of the cartridge. Results were automatically read within 2 hours. Test specimen results included invalid, not detected (negative), detected (positive with semiquantitation), and rifampicin-resistant (detected, not detected, or indeterminate) samples. Results of analysis were reported as semiquantitative readouts on the basis of the minimal cycle threshold . The semiquantitative scale for Xpert was set as very low, low, medium, or high. The semiquantitative scale for Ultra was set as trace, very low, low, medium, or high.

Demographic information and clinical data were collected by 2 independent interviewers. Data included age, sex, Bacillus Calmette–Guérin scar, history of contact with a patient with tuberculosis, antituberculosis treatment, and medical comorbidities, such as HIV infection.

The sensitivity, specificity, positive predictive value, and negative predictive value were calculated by using bacteriologic results and clinical evidence as reference standards. Concordance between Ultra and Xpert was assessed by using the percentage agreement and к coefficients, and concordance of the semiquantitative scale of the 2 tests was presented by using Spearman’s rank correlation coefficients. McNemar’s test was used to evaluate differences in sensitivity and specificity between Ultra and Xpert. P < .05 was considered statistically significant. SPSS 23.0 software (IBM SPSS Statistics, IBM Corporation) was used for statistical analysis.

Between February 2014 and April 2019, 580 children were enrolled for tuberculosis evaluation at our hospital, of whom 221 children with suspected pulmonary tuberculosis were enrolled in this study (Fig 1). Ninety-three of these children were diagnosed as having pulmonary tuberculosis, including 34 (37%) with bacteriologically confirmed tuberculosis (28 children confirmed by MTB culture and 6 by acid-fast staining) and 59 (63%) classified as clinically diagnosed tuberculosis. Among the children with pulmonary tuberculosis, 71 (76%) were <5 years of age, and 84 (90%) were <10 years of age. Of the children, 128 were diagnosed with RTIs (Table 1).

In total, 261 BALF specimens from 221 children were collected. For all 221 children, 1 BALF sample was collected within 1 week of admission, and for 29 of the children, 1 or 2 more samples were collected during follow-up.

Diagnostic accuracy was calculated when considering the first BALF specimen (Table 2). The sensitivity of Ultra was 70% (65 of 93), twice as high as that of bacteriologic tests (37%; 34 of 93), including both culture and acid-fast staining. The specificity of Ultra was high (98%; 125 of 128).

Among 34 children with bacteriologically confirmed tuberculosis, the high sensitivity of Ultra was demonstrated at 91% (31 of 34). Among 59 children with clinically diagnosed tuberculosis, the sensitivity of the test was 58% (34 of 59).

The volume of the BALF obtained in each case varied from 0.5 to 2.5 mL. This permitted comparison of the sensitivity of the assays regarding this variable. The sensitivity of Ultra in 41 of the 93 first BALF samples that had a volume ≤1 mL was 66% (27 of 41), whereas its sensitivity in the 52 samples that had a volume >1 mL was 73% (38 of 52). There was no significant difference between these 2 groups (P = .50; odds ratio [OR] = 0.71; 95% confidence interval [CI] 0.29–1.73).

In total, 164 children (46 tuberculosis case patients and 118 case patients with RTIs) were enrolled to be tested simultaneously with Ultra and Xpert. The sensitivity of Ultra was higher than that of Xpert (80% vs 67%), and Ultra permitted the detection of 6 out of 15 children with negative Xpert results. The specificity of the 2 tests was 97% (115 of 118) and 99% (117 of 118), respectively (P = .61; OR = 0.33; 95% CI 0.03–3.20; Table 3).

The agreement between Ultra and Xpert was further analyzed for 46 children with pulmonary tuberculosis. Concordant results were obtained for 40 children (31 with positive and 9 with negative results). Discordant results were found in 6 children with Ultra-positive and Xpert-negative results. Among children with RTIs, 3 had Ultra-positive and Xpert-negative results with a trace load and 1 child had Ultra-negative and Xpert-positive results with a very low load. The agreement between the 2 tests was moderate for the pulmonary tuberculosis group (κ value 0.67) and higher for the entire group of 164 children (κ value 0.84).

Concordance of the semiquantitative scale for Ultra and Xpert was also analyzed in 46 children with pulmonary tuberculosis (Fig 2). Good agreement was observed, with a Spearman’s rank correlation coefficient of 0.81 (P < .001).

Two or 3 BALF samples were collected for 29 of the 93 children with pulmonary tuberculosis during antituberculosis treatment. The positive rate for the first sample was 93% (27 of 29). Sixteen samples were collected 1 month after the first sample, and the positive rate was 63% (10 o f16). Twenty-four samples were collected 2 months later, and the positive rate was 71% (17 of 24). The positive rate decreased after antituberculosis treatment, with P = .01 (OR = 0.12; 95% CI 0.02–0.72) when compared with 1 month later and P = .03 (OR = 0.18; 95% CI 0.03–0.97) when compared with 2 months later.

All 29 children showed improvement in symptoms. During 1- or 2-month follow-up appointments, 79% (23 of 29) of the children presented with alleviated tracheal and bronchobronchial lesions, which were detected by fiber-optic bronchoscopy. Ultra results for 10 (43%) of these 23 children (positive on the basis of the first sample) converted to negative results during follow-up. For the other 8 children with persistent positive Ultra results, the semiquantitative scale of MTB in the BALF samples decreased. There were no differences in radiographic or fiber-optic bronchoscopy findings between those children whose follow-up molecular test results remained positive versus those who had test result conversions to negative.

One child was detected as being rifampicin resistant in both the first sample and the second sample collected 1 month later by using both Ultra and Xpert. One child detected as rifampicin sensitive in the first sample converted to rifampicin resistant in the second sample 2 months later when using Ultra while remaining rifampicin sensitive in the second sample when using Xpert. No MTB was isolated from these 2 patients.

Data from meta-analysis reported that the positive rate of detection from sputum smears in children is low, ranging from 0.5% in children aged 0 to 4 years to 14% in children aged 5 to 14 years.16  Xpert and Ultra are rapid tests for the diagnosis of tuberculosis and rifampicin resistance and are suitable for point-of-care testing, the latter having higher sensitivity. To date, most studies on Ultra detection have been conducted in adults, with data lacking for children.

The first aim in our study was to evaluate the accuracy of Ultra for diagnosing pulmonary tuberculosis from BALF in children. Various biological samples have previously been evaluated with Ultra, including sputum, gastric aspirates, BALF, cerebrospinal fluid, and feces.17  Three studies have evaluated Ultra in pediatric tuberculosis diagnosis to date, 2 of which used sputum samples alone9,18  and 1 of which used sputum, gastric aspirates, and BALF.17  BALF samples were collected from children with the indications required for fiber-optic bronchoscopy.19  For example, fiber-optic bronchoscopy was performed if the chest radiograph results suggested the presence of obstructive pneumonia, pulmonary atelectasis, or localized emphysema or if clinical manifestations (chronic persistent cough, hemoptysis, or dyspnea) existed but the etiology was unclear.

Ultra was shown to have higher sensitivity than acid-fast staining or MTB culture. Importantly, 58% of children with negative etiologic results were detected by Ultra, which suggested that Ultra has higher diagnostic effectiveness in children. A high sensitivity of 64.3% was previously reported in children with pulmonary tuberculosis in an HIV-prevalent setting by using sputum,9  and 67.5% was reported in microbiologically confirmed childhood tuberculosis.18  The positive rate was not affected by a limited sample volume. This improved sensitivity of Ultra might lead to not only a larger proportion of confirmed childhood tuberculosis cases, but also rapid and accurate diagnosis. In addition, both Ultra and Xpert had a shorter turnaround time than conventional culture. These tests may prove valuable in cases in which only a small volume of sample can be collected.

Our second aim was to compare Xpert with Ultra when the 2 tests were run using the same samples. The sensitivity of Ultra was higher than that of Xpert. These results were consistent with previous studies.9,15,20  A multicenter study in children reported sensitivities of 64.3% and 53.6% for Ultra and Xpert, respectively.9  In adults with smear-negative sputum results, the sensitivities of Ultra and Xpert were reported to be 63% and 46%, respectively.15  The high specificity of the 2 tests was also observed in our study, with good concordance observed between the tests. In children with RTIs, 3 with Ultra-positive and 1 with Xpert-positive results presented a very low load of MTB, and on repeating the tests, the results remained positive. All 4 children were diagnosed with Mycoplasma pneumoniae based on detection of M pneumoniae and positive responses to azithromycin treatment. It is possible that the positive result may have been caused by nonspecific amplification. One study reported no cross-reactivity of Ultra to 30 different isolates of nontuberculous mycobacteria or 18 different bacteria.21  However, there are no data showing the impact of a background of M pneumoniae on the specificity of the assay.

A third aim in our study was to assess the value of Ultra in monitoring treatment effectiveness. The positive detection rate of Ultra decreased with the duration of antituberculosis treatment in our study, which suggested that the treatment was effective. However, even after >2 months of treatment, the positive rate was still 71%. Several studies assessed the ability of Xpert to monitor responses to tuberculosis treatment.2224  Most of these studies concluded that Xpert cannot be used as an indicator of therapeutic efficacy because DNA fragments from lysed or damaged bacteria could still be detected. To date, little is known about Ultra in this regard. As for the low etiologic results in this study and the high percentage of first-time occurrence of tuberculosis in children, future studies will be needed to determine the usefulness of Ultra in monitoring treatment effectiveness.

Identification of the most efficient and cost-effective strategies for the implementation of current and novel diagnostic tests for tuberculosis in children is an ongoing research focus. Because specimen processing, DNA amplification, and detection are performed under closed conditions in the Ultra test, it is possible to perform MTB detection outside of a laboratory equipped for advanced biosafety. This increases the applicability of the assay and decreases delays in the diagnosis of tuberculosis. However, the current cost of Ultra is a prohibitive factor in its implementation as a point-of-care test, especially given that higher tuberculosis burdens are commonly found in settings where resources for health care are already under great strain. The necessary equipment is also not readily available for primary medical institutions. To be financially viable in low-income countries, a large increase in tuberculosis funding and/or a further reduction in the price of the Ultra test would be needed.

As an innovative operation, fiber-optic bronchoscopy requires experienced physicians and well-equipped operating rooms. Only children with indications should undergo fiber-optic bronchoscopy. The difficulties in acquiring samples therefore limit the use of BALF in diagnosing tuberculosis in children.

It was highlighted by the WHO that existing tests included in the diagnostic algorithms of active tuberculosis can be tailored to be highly specific to each country’s settings and resources.4  Our data provide insight into the added value of Ultra in the diagnosis of pulmonary tuberculosis in children in China, a country with a high burden of tuberculosis.

The Ultra assay using BALF offers good diagnostic value compared with acid-fast staining or MTB culture. Slightly higher sensitivity was detected for Ultra than for Xpert. Ultra added clinical value in assisting the rapid and accurate diagnosis of pulmonary tuberculosis in children when fiber-optic bronchoscopy is recommended according to a chest radiograph. Further studies are required to assess its value in early diagnosis and the monitoring of treatment effectiveness.

We thank Dr Joy Fleming (Chinese Academy of Sciences Institute of Biophysics in Beijing) for help with English-language editing of the article.

Dr Sun and Mr Shen conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Mr Qi and Dr Guo collected data and performed the tests; Ms Liu, Ms Guo, and Drs Wu, Yin, Xu, and Jiao enrolled the subjects and collected the samples; Drs Jiao, Shen, and Xiao analyzed the data; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by the National Science and Technology Major Project of China (grants 2018ZX10103001-003 and 2018ZX10101004-002-005). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-2944.

BALF

bronchoalveolar lavagefluid

CI

confidence interval

MTB

Mycobacterium tuberculosis

MTB/RIF

Mycobacterium tuberculosis and/or rifampicin

OR

oddsratio

RTI

respiratory tract infection

WHO

World Health Organization

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.