EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Kidney transplantation, Latent tuberculosis infection, Liver transplantation, Mycobacterium tuberculosis

In solid-organ transplant (SOT) recipients, the incidence of Mycobacterium tuberculosis disease has been reported to range from 0.2% to 13.7%, which is 20 to 74 times higher than in the general population. Mortality associated with M. tuberculosis can be as high as 31% in the SOT population^1,2 as a result of immunosuppressive drugs, which inhibit T-cell (CD4-positive T cell) proliferation. Although there is an explicit time delay between M. tuberculosis infection and T-cell response, it has been proved that T cells play a key role in protection against the infection.^3-5

Active tuberculosis (TB) in transplant recipients can arise from latent TB (LTBI) in the candidate recipient or donor, can occur from a de novo posttransplant infection, and can occur in a patient with TB after transplant.^6,7 Latent TB is defined by the World Health Organization as “a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB.”⁸ The lifetime average rate of LTBI conversion to active TB disease is approximately 5% to 10%, which can be as high as 22% to 25% in SOT recipients, especially in those who do not receive treatment.^7-10

Pretransplant screening of recipients and, if possible, donors for TB infection is an important component of the transplant process.^2,7 Current methods for screening LTBI are tuberculin skin test (TST) and interferon-gamma release assay (IGRA), which are based on measuring immune responses to M. tuberculosis antigens.¹¹ However, there is no strong evidence in the superiority of IGRAs over TST for LTBI diagnosis, as IGRA positivity is more related to the radiological evidence of previous TB.¹²

The recommended cutoff points of positive TST in SOT recipients vary between guidelines (considering induration size of either ?5 mm or ?10 mm) on the basis of local TB endemicity.² Although the incidence of TB in Iran has decreased in recent years as a result of better control measures, the danger of infections still exists because of proximity to high-TB burden countries like Pakistan and Afghanistan.¹³ In this study, we analyzed rates of active TB disease conversion in kidney and liver transplant recipients who had pretransplant TST induration results of ?5 mm and the association of outcomes in these patients with medication adherence. Patients with TST induration results of 5 to 9 mm versus ?10 mm were also compared.

Materials and Methods

Study design and population
This cross-sectional study included kidney and liver transplant recipients who had pretransplant TST indurations of ?5 mm and who were seen from March 2009 to March 2019 at the Shiraz Nemazi Hospital Transplant Center, Shiraz University of Medical Sciences (Shiraz, Iran).

Data collection
Demographic data and laboratory results of kidney and liver transplant recipients were retrospectively obtained from medical records at the Transplantation Office and the Health Center (Shiraz University of Medical Sciences). Data collected included sex, age, transplant time, cause of end-stage renal disease or liver cirrhosis, comorbid diseases, pretransplant TST and chest radiograph results, duration of LTBI treatment, and any history of conversion to active TB disease. We also collected information on posttransplant immunosuppressant drugs, transplant rejection, posttransplant admission duration, and any history of drug use.

Inclusion and exclusion criteria
Inclusion criteria were as follows: all kidney or liver transplant recipients who had pretransplant TST indurations of ?5 mm. Exclusion criteria were as follows: pretransplant active TB disease, well-founded suspicion of active TB disease, patients who refused to attend follow-ups, patients with incomplete medical record data, and patients who died. All patients received deceased donor transplant procedures.

Screening and treatment of latent tuberculosis
Tuberculin skin test was performed by intradermal injection of 0.1 mL purified protein derivative (PPD); check-ups for induration results were viewed after 48 to 72 hours (Mantoux method). All patients with TST indurations of ?5 mm were considered to have a positive test. Patients were categorized into the following 2 groups on the basis of their TST induration size: 5 to 9 mm and ?10 mm. Active TB disease was ruled out in all patients with the use of an acid-fast bacteria culture for any patient who had clinical and/or radiological data in favor of the disease.

For treatment of LTBI, isoniazid and pyridoxine were prescribed for 9 months. Patients were followed up for any symptom of active TB disease (including fever, weight loss, night sweats); if any appeared, the diagnosis was confirmed by laboratory tests and radiographs. A complete treatment for LTBI prophylaxis was defined as taking isoniazid 300 mg/day supplemented with pyridoxine regularly for 9 months.⁶

Ethical considerations
The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee of Shiraz University of Medical Sciences. Patients provided consent for use of their anonymized data before registration in the medical record database.

Statistical analyses
The results of continuous variables are presented as means ± SD and those related to the quantitative or categorical data are presented as frequency and percentage. Chi-square tests were used to assess the relationship of qualitative data, and independent t tests were used to evaluate the correlation of a quantitative data. We used Statistical Package for Social Sciences version 23 (SPSS Inc) for statistical analysis. P < .05 was considered significant.

Over the 10-year study period, there were 6289 SOT recipients seen at our center, of which 3334 patients had liver transplant, 2817 had kidney transplant, and 138 had kidney and pancreas transplant. Of these 6289 SOT recipients, 334 (5.3%) had TST indurations of ?5 mm (5.3%) and were included in our study. Among these 334 kidney or liver transplant recipients with pretransplant diagnosis of LTBI, only 34 (10.1%) developed active TB.

Table 1 shows characteristics of patients included in our study. Mean age was 46.0 ± 13.8 years, and 226 recipients (67.6%) were men. The mean age of women was significantly lower compared with the mean age of men (42.2 ± 13.5 vs 47.8 ± 13.5 years; P < .001). Of total recipients included in the study, 76.3% had kidney transplant; the most common causes of end-stage renal disease were hypertension (71.8%) and diabetic nephropathy (28.6%). In the liver transplant recipients, the most common causes of cirrhosis were viral hepatitis (50.6%) and cryptogenic cirrhosis (17.7%).

The mean duration time of transplant of studied patients was 4.7 ± 3.3 years (most of the patients have been included in our study 2 years after transplant). Patients had a mean of 3.8 ± 1.5 posttransplant admissions (range, 0-8). Of 334 recipients included in the study, 58 (17.3%) had a transplant rejection episode. The primary maintenance immunosuppressants used included steroids (94.6%), calcineurin inhibitors (93.1%), and mycophenolate mofetil (91.6%).

Patients who developed active TB (n = 34) had a mean age of 49.8 ± 11.2 years. Of these patients, 24 (70.5%) were men and 10 (29.4%) had allograft rejection. In addition, 22 patients with active TB (64.7%) were kidney transplant recipients and 12 were liver transplant recipients (Table 2). That is, of 2955 kidney transplant recipients, 0.75% developed active TB.

Of 303 patients (90.7% of total studied population) who received complete treatment regimens for LTBI, only 26 patients (8.6%) developed active TB disease. However, in 16 patients (4.8% of total studied population) who did not adhere to their medication, 7 (43.7%) developed active TB. Thus, the rate of LTBI conversion to active TB was significantly higher in patients who had poor adherence to their anti-TB regimens (P < .001).

Our results also showed that the rate of active TB development was significantly higher in patients who had pretransplant TST induration results of ?10 mm versus those with TST induration of 5 to 9 mm (15.8% vs 3.4%; P < .001) (Table 3).

In this study, we evaluated the rate of active TB disease conversion in 334 SOT recipients who had been diagnosed and treated for pretransplant LTBI. We also classified patients into 2 groups according to their pretransplant TST induration size (5-9 vs ?10 mm) in order to compare the incidence rate of active TB disease between the 2 groups; this comparison could help us to consider a reasonable threshold for positive TST in SOT candidates in Iran.

In patients with chronic renal failure, TB tests are recommended, with induration of at least 10 mm being considered as a positive reaction.¹⁴ Although some guidelines from different countries recommend a positive TST threshold of ?5 mm,^15-18 other countries that have high TB burden recommend a threshold of >10 mm for a positive test.^5,19 Thus, cutoff points considered for TST positivity in SOT recipients vary across guidelines as result of different epidemiological burdens of TB among countries.^10,15 Positivity of TST results has been shown to range from 12% to 26%, 10% to 62%, and 17%, respectively, in countries with low, intermediate, and high TB burden.²⁰ Iran is a high-risk country due to its proximity to Pakistan and Afghanistan, which have high TB burden.¹³ Studies conducted by Moradi and colleagues²¹ and Tabrizi and colleagues²² in Iran showed a high incidence of TB among immigrants who came from Afghanistan, Pakistan, Bangladesh, and India.

Although the currently used cutoff point for TST in SOT recipients in Iran is ?5 mm,²³ our results showed a significant higher LTBI progression to active disease among patients who exhibited induration size of ?10 mm (15.8%) compared with those with TST results of 5 to 9 mm (3.4%). Although the main LTBI treatment options, including isoniazid and rifamycins, are associated with serious side effects like hepatotoxicity1 and the cutoff point of 5 mm for TST positivity may cause an increased number of patients with LTBI diagnosis (and consequently more patients would be at risk of medication side effects²⁴), our recommendation is to modify the cutoff point to ?10 mm in Iran.

We found that the rate of active disease conversion was higher among patients who failed to adhere to their treatment regimens compared with those who took their medications regularly (43.7% vs 8.6%). The beneficial effect of isoniazid therapy for LTBI has been evaluated and confirmed in a retrospective 9-year cohort study in which the results showed that the rate of active TB conversion among 155 patients who did not receive isoniazid was higher (2%) than the 0% active TB conversion among 177 patients who received isoniazid therapy.²⁵ In our study, the rate of active TB disease conversion in SOT recipients was 10.1%, which confirmed the results of a prospective study conducted by Torre-Cisneros and colleagues.²⁶ In that study, 19% of all SOT recipients who did not have pretransplant PPD tests showed positive results (induration of ?5 mm), with 6.2% developing active TB. In a retrospective 10-year study on liver transplant patients from Benito and colleagues,²⁷ the results were surprisingly different, with pretransplant TST results positive in 24% of patients and 0% developing TB disease; however, among 76% of patients with negative TST, 1.8% experienced active TB conversion. Furthermore, the results from Benito and colleagues also showed that the rate of active disease conversion was greater among patients who received isoniazid. This could have happened because of the impact of previous TB infection as a major risk factor for progression of posttransplant active disease, as confirmed in a retrospective 10-year study from South Korea,²⁸ which showed that positive pretransplant TSTs and radiographic features of untreated TB were significantly associated with posttransplant TB disease. In a retrospective 13-year study on kidney and liver transplant recipients, 2.3% of patients developed posttransplant TB of whom 22.2% had pretransplant positive TSTs; 1 patient had positive IGRA and 10 patients had radiographic features of untreated TB. Therefore, LTBI was reported as a major risk factor for development of active TB.²⁹

Limitations
The limitations of our study were the use of TST as the main diagnostic test; these results can be false positive (exposure to non-TB bacteria or BCG vaccination) and can be false negative (cutaneous anergy due to impairment of cell-mediated immunity).30 In addition, the time elapsed between transplant and active TB disease conversion was not mentioned in the patients’ records. We also did not identify anergic patients.

Diagnosis and treatment of LTBI before SOT can reduce active TB conversion and its associated morbidity and mortality. Although TST is the current diagnostic test to identify LTBI in Iran, the consideration of a reasonable cutoff point for its positivity is essential. Although further evaluations must be done to draw a definite conclusion, our recommendation is to modify the cutoff point considered for TST positivity for SOT candidates in Iran to ?10 mm.

Volume: 20 Issue: 8 August 2022

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