EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Tuberculosis risk in solid-organ transplant recipients is more than the general population, although tuberculosis incidence has been reported to decrease 5% in the last decade in Turkey. In Turkey, solid-organ transplants started in 1975; however, routine pretransplant tuberculosis risk screening programs are still not established. Therefore, we conducted a meta-analysis of tuberculosis prevalence, clinical forms, and prognosis of tuberculosis in solid-organ transplant recipients.

Materials and Methods: We searched PubMed, Web of Knowledge, Google Scholar, EBSCOhost, and Scopus databases in English and Turkish Medical Index of Turkish Academic Network and Information Center, Turkish Citation Index, Turkish Medline, Central Thesis of ULAKBIM databases in Turkish (from inception until December 2018) for national and international reference lists of all relevant papers. We used standard methodological procedures (Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009).

Results: We found 199 published studies in English and 26 in Turkish. After exclusion of noneligible studies, there were 10 retrospective research articles and 16 case reports. There were 148 (3.2%) tuberculosis cases with 4553 solid-organ transplant recipients (4031 renal, 522 liver). Of the tuberculosis cases, 50 (33.8%) were pulmonary, 21 (14.2%) were pulmonary and extrapulmonary, 13 (8.8%) were miliary, 27 (18.2%) were disseminated, and 37 (25.0%) were extrapulmonary tuberculosis cases involving a maximum of 2 organs. There were 19 cases (12.8%) of graft lost. Of the patients with tuberculosis, 34 (19.9%) died resulting from either tuberculosis or other reasons.

Conclusions: In this meta-analysis, most of the centers did not perform pretransplant risk evaluations; every center had different clinical procedures and follow-ups. Tuberculosis prevalence in solid-organ transplant recipients differs according to study population.

Case reports were mostly about extrapulmonary tuberculosis. All such patients should be followed-up by a standard regimen during pretransplant and posttransplant periods. Prospective studies should be considered.

Key words : Extrapulmonary, Pulmonary, Tuberculosis, Transplantation, Turkey

Turkey started tuberculosis (TB) control 100 years ago, and an annual decrease in incidence of TB of approximately 5% has been reported.¹ However, despite this decline, active TB risk in solid-organ transplant (SOT) recipients was found to be 74-fold more than in the general population.² Solid-organ transplants have been successfully performed in Turkey since 1975. Single-center studies have reported a TB incidence rate of 1.2% to 6.7% in SOT recipients.1 Diagnosis of TB is not challenging in the presence of pulmonary symptoms; however, extrapulmonary TB and presentation with nonspecific symptoms may lead to misdiagnosis. Therefore, it is recommended to evaluate SOT recipients for pulmonary and extrapulmonary TB risk during the pretransplant period.^1,3 However, routine pre- and posttransplant national TB risk scoring systems do not exist, and procedures differ among different centers. Thus, we conducted a meta-analysis that included studies of TB in SOT recipients in Turkey and determined the prevalence, clinical forms, and prognosis of TB in these patients.

Materials and Methods

We searched PubMed, the Web of Knowledge, Google Scholar, EBSCOhost research databases, and Scopus databases in English and Turkish Medical Index of Turkish Academic Network and Information Center (ULAKBIM), Turkish Citation Index, Turkish Medline, and the Central Thesis of ULAKBIM databases in Turkish (from inception until December 2018) for national and international reference lists of all relevant papers published between November 1975 and December 2018.

Selection criteria
We only included original articles and case reports with the following keywords: solid-organ transplant (renal, hepatic, heart, lung, pancreas, small intestine) and/or Mycobacterium tuberculosis, TB, and extrapulmonary TB (genitourinary, musculoskeletal, miliary, lymph node TB, etc.). We used standard methodological procedures defined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) published in 2009. Two review authors who are experts in the field each independently assessed study eligibility and risk of bias and extracted data. Repeated studies, poster presentations, unrelated articles, and reviews were excluded (Figure 1). Data were analyzed with SPSS software (version 16.0; SSPS Inc.). We used mean and standard deviation or median and minimum-maximum values in accordance with the distribution of the data.

Most studies were found in the PubMed database. The number of studies was 225, of which 199 were in English and 26 in Turkish. No prospective randomized controlled trials were found. Of the English studies, 155 (77.8%) were found in multiple databases. After exclusion of noneligible studies (reviews, short reports, and poster presentations), there were 44 studies in English language, among which 12 (27.2%) were retrospective research articles and 17 (38.6%) were case reports.^4-28 One research article investigated TB prevalence among pulmonary complications, and 2 other research articles evaluated TB prevalence only in SOT recipients who underwent fiberoptic bronchoscopy.^4,5,29 Other research articles in English reported TB prevalence rates of SOT recipients in different centers (Table 1).

According to the same criteria, with regard to Turkish studies, we found 1 retrospective research article (3.8%) and 2 case reports (7.7%); overall, 3 studies (11.5%) were selected from the 26 Turkish articles.^30-32 No thesis studies relevant to our investigation were found in Council of Higher Education National Thesis Center searches. A summary of the 10 research articles investigating TB prevalence in SOT recipients is presented in Table 1, and a summary of case reports is presented in Table 2. Three English case reports, which are not included in Table 2, were about transplants performed to mitigate hepatotoxicity of TB drugs.^33-35

Prevalence
With regard to original articles, there were 148 TB cases (141 renal transplants, 7 liver transplants) involving 4553 SOT recipients (4031 renal, 522 liver) (Table 1). Therefore, TB prevalence in SOT recipients was 3.25% (148/4553) for the study population with a rate of 3.49% (141/4031) for renal transplant and a rate of 1.34% (7/522) for liver transplant. Tuberculosis development was reported within the first year of transplant in 53/128 patients (41.4%). Among the 16 case reports included in the meta-analysis, 23 TB cases (20 renal transplants, 2 liver transplants, 1 heart transplant) were observed (Table 2). Six of these patients (26.1%) were also diagnosed within the first year after transplant. The organ involvements of TB patients in all the study populations are presented in Tables 1 to 3.

Symptoms and diagnosis
Only 5 research articles investigated symptoms; fever was observed in 31 of 88 TB patients (35.2%) within 2397 SOT recipients^.6-8,13,14 Other symptoms were constitutional symptoms like fatigue, weight loss, nausea, and night sweats. Studies from Koseoglu and colleagues and Apaydin and colleagues reported 6 clinically diagnosed patients (3.5%).^8,9 Radiological findings were evaluated in 6 research articles (n = 2955) and reported in 55 of 92 TB patients (59.8%).^{4,6,8,10,11,14} The aforementioned radiological findings were infiltration, cavity, ground-glass opacity, pleural effusion, micronodular/reticulonodular pattern, consolidation, and fibrotic lesions. Radiological findings were used to demonstrate involved organs with extrapulmonary TB. For example, for central nervous system intracranial mass, for intestinal TB millimetric superficial infiltrations in the colon, and for vertebral TB osteolysis and/or mass, etc., tissue involvement was demonstrated. Among all reported TB cases in research articles and case reports (148 + 23 = 171), 165 patients (96.5%) were diagnosed with the use of microbiological and/or histopathological methods.

Treatment and prognosis
Patients were treated with a standard anti-TB treatment regimen (isoniazid, rifampicin, ethambutol, pyrazinamide). After early deaths were excluded, TB treatment duration ranged from 4 to 19 months (Table 2). Two research articles reported isoniazid resistance, and 1 case report described isoniazid- and rifampicin-resistant TB disease.^8,10,22Table 4 presents adverse events during treatment in the research articles. Five case reports addressed drug monitorization and 2 cases were reported to have hepatotoxicity.^{19,21,23,26,28} Only 6 of the case reports mentioned adverse events.^{17,18,20,25,31,32} There were 19 reports (12.8%) of graft loss. Within all patients with TB, 34 patients (19.9%) died as a result of TB or other reasons (Tables 1 and 2).

In Turkey, TB incidence was 14.6/100 000 in 2017 and has decreased approximately 5% in the past 10 years.1 However, TB prevalence in SOT recipients has been reported as 3.2%. This rate highlights the increased prevalence of TB in SOT recipients versus the normal population, emphasizing the need for a TB risk evaluation in these patients. In this meta-analysis, higher TB prevalence in renal transplant recipients (3.49%) versus liver transplant recipients (1.34%) might be explained by the fact that renal transplants were the first SOTs practiced in Turkey; also, more renal transplants (versus other types) were performed in Turkish centers and 90% of the study population were renal transplant recipients. We found only 2 research articles and 2 case reports that described TB prevalence in liver transplant recipients.^10,14,16,24 The prevalence of TB was shown to be related to the transplanted organ (most frequent in lung transplants), the incidence rate in the country, presence of chronic diseases (diabetes mellitus, chronic liver disease, etc.), immunity of the recipients, and graft rejection.¹

An additional explanation for the higher TB rate in renal transplant recipients versus liver transplant recipients may be that TB prevalence in SOT recipients differs according to the study population. For example, in a study that evaluated 136 renal transplants in the first year posttransplant, 15 patients (11%) were found to have pulmonary complications, of which 12 (80%) had pneumonia, and 2 of these cases (33.3%) were due to TB.29 On the other hand, TB prevalence was 6.1% to 6.7% in SOT recipients who underwent fiberoptic bronchoscopy.^4,5 As shown in Table 1, TB prevalence ranged from 0.87% to 5.8% in different centers. These findings demonstrate the importance of the composition of the study population when evaluating the prevalence of TB.

In this meta-analysis, TB developed within the first year posttransplant in 41.4% of the study patients^1-3; however, this period has been reported to range from 1 to 255 months, indicating that TB may occur any time in the posttransplant period (Tables 1 and 2). Therefore, pretransplant risk evaluations should be performed, and TB should be considered in the differential diagnosis of long-lasting fever and/or constitutional symptoms. In a study by Yildiz and colleagues, the results of a pretransplant risk evaluation of 23 renal transplant recipients led to the recommendation for 300 mg/day isoniazid for 12 months, and none of the patients developed TB or hepatotoxicity.⁶ Sayiner and colleagues combined the data of Istanbul University with that of Ege University in their study and reported similar results.⁷ Ozgen-Alpaydin and colleagues mentioned a pretransplant screening with tuberculin skin test in 25.9% of the SOT recipients in their center.¹⁴

Disseminated and/or extrapulmonary involvement has been reported more frequently in SOT recipients.^1-3 We found that disseminated and/or extrapulmonary TB was reported in 66.2% of the research articles. Among the case reports, only 1 was about pulmonary involvement; others defined disseminated, pulmonary, and/or extrapulmonary involvement. Cutaneous TB, otitis media, cecal perforation, isolated hepatic abscess, abdominopelvic involvement, and gastrointestinal involvement were the other distinct clinical presentations, thus indicating difficulties in the diagnosis. Especially in the case of long-lasting unknown origin of fever, different clinical presentations of TB should be investigated. We noted that long-lasting fever was shown in 35.2% of our study patients, with constitutional symptoms accompanying this type of fever. Radiological findings in these patients also differed according to the involved organ, supporting the diagnosis. The definite diagnosis could be achieved by investigating acid-fast bacillus by microbiological (conventional and molecular methods) or histopathological methods of the specimens (sputum, tissue, aspiration, bronchial lavage, etc.). We found that 96.5% of patients were diagnosed by microbiological or histopathological methods. The remaining 3.5% of patients were diagnosed clinically.^8,9 Thus, we showed the importance of laboratory procedures for diagnosis.

The treatment of TB and follow-up procedures in SOT recipients are the same as in the general population. The recommended duration of TB treatment is 6 months.¹ However, in this meta-analysis, after early deaths were excluded, we found that treatment duration (mostly including regimens with rifampicin) ranged between 4 and 19 months (Table 2). Treatment duration differs according to the involved organ, transplant type, treatment response, and/or treatment complications. Hepatotoxicity is the most commonly reported adverse event (Tables 2 and 4). Treatment pause and/or interaction with rifampicin, calcineurin inhibitors, and/or dissemination during the treatment period are factors that may influence the treatment duration. The ideal treatment duration is controversial.³ In SOT recipients, different treatment options for different types of donor organs and reduction of drug-drug interactions will facilitate individualized therapies and determine the treatment duration.

Limitations
One of the limitations of this meta-analysis is the different procedural approaches in the diagnosis and treatment of TB in different centers. Another limitation is the difference in focus among the different studies. Although the research articles mostly had determined TB prevalence, these articles do not reflect the overall profile for Turkey since all of the studies were conducted at a single center.

We found that, in our analysis of research articles, 3.2% of SOT recipients were diagnosed with TB. Most centers included in our analysis did not perform a pretransplant risk evaluation. In addition, every center had different clinical and follow-up procedures. Case reports were mostly about extrapulmonary TB. All of these studies emphasized the importance of a pretransplant TB risk evaluation, as well as diagnosis, a standard treatment, and a follow-up regimen.

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