Preventing tuberculosis in paediatric kidney transplant recipients: is there a role for BCG immunisation pre-transplantation in low tuberculosis incidence countries?

Assessment for tuberculosis (TB) infection and disease has three components:

Bacillus Calmette-Guérin (BCG) is a live-attenuated vaccine which remains viable for several years after administration. BCG has a risk of local side effects, and more importantly of disseminated BCG disease when immunosuppression for transplantation is commenced. Practice in low incidence countries in Europe varies between universal, risk-based and no BCG immunisation. Risk-based immunisation is usually based on the risk of TB exposure, for example if there is travel to or parental origin from countries with high TB incidence. In some countries, BCG is also recommended based on increased host susceptibility, irrespective of the exposure risk.

Practices relating to screening for TB and administration of BCG to children with chronic kidney disease (CKD) vary between countries. As an example, in paediatric kidney transplant centres in the UK, practice has previously been to:

Treatment of TB infection or disease, or of disseminated BCG should involve paediatric infectious diseases and nephrology teams, with input from a specialist pharmacist. The most commonly used drugs used for treating TB infection and disseminated BCG (rifampicin and isoniazid) do not require dose adjustment in CKD or after transplantation, but may do during dialysis. Both drugs also have the potential for interaction with other medications used in CKD or for immune suppression, and may have additive toxicities. Use of more complex regimens for TB disease, including for drug-resistant disease, should all be assessed for potential need for dose adjustments and for interactions and toxicities.

The reported prevalence of Stage III, IV and V (GFR < 60) CKD with estimated glomerular filtration rate less than 60 ml/min/1.73 m² in children and young people aged less than 20 years in Europe is 55 to 60 per million of age-related population (incidence 11–12 per million of age-related population); the global estimate is a prevalence of 65 per million of age-related population and incidence of 9 per million of age-related population [1]. These figures, especially the global estimates, are likely to be significant underestimates as there are only limited or no data available from some low-income regions. CKD is frequently asymptomatic and reporting practices vary greatly between countries, with more detailed information available in higher income settings. A recent survey and review of national paediatric kidney replacement therapy registries highlighted variation in practice and significant gaps in coverage [2].

The incidence of CKD in children less than 16 years old in the UK was 9 per million of age-related population in 2016. A higher prevalence was noted in children from ethnic minorities, especially South Asian children in whom the prevalence was almost double the whole population estimate [3]. This observed difference is thought to be in part attributable to ethnic differences in rates of inherited kidney disease [4].

TB infection can be divided into that causing disease (TB disease or active TB) and that not causing disease (latent TB infection (LTBI)), although there is increasing evidence that these are not discrete entities, but rather different states along a continuum [5]. Estimating the burden of TB disease in children is challenging, in part due to under-recognition, difficulties in establishing a diagnosis and incomplete reporting in countries with some of the highest burden of disease [6]. Nevertheless, it is estimated that in 2017, 1 million children globally developed TB disease, while the number of TB-related deaths was approximately 150,000. The majority of these cases occurred in the African, South-East Asian and Western Pacific regions [7]. The reported rate of TB disease in children less than 15 years old in England born outside the UK was 7.3 per 100,000 in 2017, while the rate for children born in the UK was 1.4 per 100,000. When combining reports from adults and children, rates were highest for individuals of non-white ethnicity born outside the UK [8].

The global prevalence of LTBI is much greater than that of TB disease. Approximately 6% of children under 15 years of age were estimated to be infected with TB in 2016, equating to around 90 million children worldwide [9].

Most data on TB in CKD, kidney replacement therapy and kidney transplantation come from studies in adults, with only a few case series reported in children. The reasons for higher observed rates of TB disease in kidney patients are likely to be multifactorial, relating to immune impairment secondary to CKD itself, underlying causative disease, co-morbidity, immunosuppressive therapy and socio-economic factors and common risks for kidney disease and exposure to TB [10].

A review completed for the 2011 version of the UK NICE TB guidelines estimated the relative risk of TB disease in adults was 10 to 25 for CKD or haemodialysis patients and 37 for kidney transplant recipients, although it should be taken into account that this was based on data from more than 20 years ago when the incidence of TB in the UK was significantly higher. A more recent report in adults from the UK found that the cumulative incidence of TB disease was 1267 per 100,000 population in haemodialysis patients (95% confidence interval (CI): 630–1904; 85 times higher than the background UK TB rate), 398 per 100,000 in patients on peritoneal dialysis (95% CI: 80–1160; 26 times higher than the background UK rate); and 522 per 100,000 in kidney transplant recipients (CI: 137–909; 35 times higher than the background UK rate) [11].

Overall, the risk of TB disease in adult solid organ transplant patients is estimated to be 20 to 74 times higher than in the general population [12]. This is largely attributable to immunosuppression. Extrapulmonary and disseminated TB are more common in this patient group. Symptoms of disease are more likely to be non-specific and TB-related mortality is much higher than in the general population [13].

Data on TB in paediatric CKD and kidney transplant recipients are scarce. Risk varies depending on background TB incidence in the general population. Rates of TB disease following kidney transplantation in children have been reported to be between 8 and 9.7% in highly TB endemic areas [13]. In a South African case series, 7 of 72 (9.7%) children undergoing kidney transplantation developed TB disease [14]. In contrast, in a Spanish retrospective study covering a 26-year period, only 3 of 345 (0.9%) children undergoing kidney transplantation were subsequently diagnosed with TB disease, although this rate was still much higher than that observed in the general population of a similar age [15].

TB disease in children is more commonly due to progression after primary infection rather than reactivation of latent infection; immunosuppression after organ transplantation increases both the likelihood of progression after infection, and the risk of reactivation of LTBI. Children also have higher rates of disseminated and extrapulmonary TB disease than adults, as well as higher TB-related mortality [16].

The TST demonstrates a type IV hypersensitivity reaction to intradermally injected purified protein derivative, a heterogenous mixture of approximately 200 mycobacterial peptide antigens. The TST has several limitations, including the need for the patient to return for the reading (i.e. requiring two visits), and a degree of subjectivity with substantial inter-operator variability when reading the test result. Importantly, there is strong evidence to suggest that the TST has reduced sensitivity in individuals with primary or secondary immunodeficiency, including patients receiving immunosuppressive medication. The TST is also not specific for TB infection, and positive results can be caused by BCG immunisation or infection with non-tuberculous mycobacteria (NTM) [17].

Currently, there are two commonly available commercial IGRAs, the QuantiFERON-TB (QFT) Gold Plus and the T-SPOT.TB assay. Both tests are functional assays that rely on measuring interferon-gamma produced in response to stimulation with only two relatively M. tuberculosis–specific peptides (ESAT-6 and CFP-10). IGRAs are more specific than the TST, as those peptides are absent in BCG; prior BCG immunisation does therefore not impact on test results. However, a few NTM species do express those peptides, including M. marinum, M. kansasii and M. szulgai, and therefore false-positive results can occur in patients infected with NTM [18, 19]. IGRAs have relatively poor reproducibility when serial testing is performed [20], and considerable variability associated with delays in incubation and variations in environmental temperatures has been reported [21, 22]. There are substantial data showing that IGRAs perform less well, and are more likely to give indeterminate results, in young children than in adults [23‐25].

It is important to consider the reliability of IGRAs in the presence of CKD when interpreting test results. There is strong evidence that the performance of IGRAs is impaired in the context of immunodeficiency (e.g. HIV-infected patients with low CD4⁺ T cell counts) [25‐27]. Data on the performance of IGRAs in patients with CKD are conflicting [28‐31]. A recent study reported a high degree of discordance between QFT and T-SPOT. TB and TST results in kidney dialysis patients who had been exposed to a healthcare worker with infectious TB, indicating that all three immune-based TB tests may have suboptimal performance in this patient population [32].

In accordance with guidance from the European Centre for Disease Prevention and Control (ECDC) and the Tuberculosis Network European Trials Group (TBNET) [13, 33], the authors of this review recommend that both TST and IGRA are performed in parallel, in individuals with impaired immune function, including children with CKD, when investigating for TB infection, as chronic uraemia impairs innate as well as adaptive T cell–mediated immune responses [34]. If either test produces a positive result, the presence of TB infection should be assumed and LTBI treatment should be initiated once TB disease has been excluded. It should be noted that BCG is contraindicated in children with a history of TB infection. Further guidance on the management of TB infection in the pre-transplantation setting can be found in the TBNET consensus statement [13]. Children with significant CKD in a low TB incidence country and significant confirmed TB contact should be considered for LTBI treatment even if TST and IGRA results are negative in view of the likely lower sensitivity of these tests in the context of severe kidney impairment and/or immunosuppression. The significance of possible TB exposure should be assessed in conjunction with a paediatric TB specialist.

In the post-transplantation setting, once immunosuppressive medication has been initiated, both TST and IGRAs should be regarded as unreliable for the same reasons as discussed above. With regards to IGRAs, clinical studies have produced conflicting results, with some authors stipulating that their performance is sustained, and others concluding that their performance is impaired [13, 30, 35]. Some studies have been limited by the absence of a true gold standard test for LTBI, which complicates their interpretation. More recent data from in vitro models show that a range of immunosuppressive agents, including corticosteroids, anti-TNF-alpha agents and calcineurin inhibitors have detrimental effects on the performance of IGRAs [36‐38]. Therefore, negative TST and IGRA results post-transplantation must be interpreted with great caution. A positive test result remains useful, but currently it is impossible to determine whether a negative result indicates absence of LTBI or alternatively a false-negative test result due to the underlying medical condition and/or immunosuppressive therapy.