Clinical Characteristics and Outcomes of Tuberculosis Infection in Adult Patients with MDS

Background and aim Despite the high incidence of tuberculosis infection (TBI) in patients with hematological diseases, there were few researches on TBI in MDS patients. We retrospectively analyzed the characteristics of MDS patients with TBI in our center to improve the clinical diagnosis and treatment of these patients. Methods Primary MDS patients diagnosed between 2014 and 2019 at the First Aliated Hospital of Zhejiang University were retrospectively reviewed, TBI was diagnosed by positive culture(s) or acid fast bacilli on modied Ziehl-Neelsen staining on clinical samples as well as compatible symptoms and signs. Results Thirty-four of 1347 MDS patients were diagnosed with TBI, nine patients had blast (cid:0) 5%, twelve patients were MDS with excess blast-1(MDS-EB1), and the rest 13 patients were MDS with excess blast-2 (MDS-EB2). Ten patients had lower risk (low and intermediate) and 24 patients had higher risk (high and very high) according to revised international scoring system (IPSS-R). Moreover, fteen patients were classied into synchronous group (dened as TBI occurring within 3 months of MDS diagnosis), and the rest 19 patients were non-synchronous group (dened as TBI developed after MDS more than 3 months). Patients in synchronous group have higher rate of persistent fever (11/15 vs. 7/19, p=0.03), higher risk classication ( 14/15 vs. 8/19, P=0.002 ), and higher tendency to transform to acute myeloid leukemia (AML) (8/15 vs. 4/19, P=0.04 than those in non-synchronous group. The median time to AML was signicantly shorter in synchronous group (7.68 months vs. 23.83 months, P<0.01). patients

(MDS-EB2). Ten patients had lower risk (low and intermediate) and 24 patients had higher risk (high and very high) according to revised international scoring system (IPSS-R). Moreover, fteen patients were classi ed into synchronous group (de ned as TBI occurring within 3 months of MDS diagnosis), and the rest 19 patients were non-synchronous group (de ned as TBI developed after MDS more than 3 months).
Conclusion TBI is not uncommon among patients with MDS, patients with synchronous TBI and MDS progress faster and have shorter OS, which may be associated with genetic susceptibility and lack of active therapy.

Background
Myelodysplastic syndromes (MDS) is a group of clonal hematological stem cell disorders, manifested as persistent cytopenia, accompanied by innate humoral and cellular immune-paresis [1,2]. As a result, these patients are prone to various new infections and reactivation of latent infections including TB [3][4][5]. With the increasing incidence of cancer and the advance in treatment, opportunistic TBI has indeed increased signi cantly in cancer patients recently [6,7], especially in hematological malignancies [8][9][10][11]. A largescale clinical retrospective study in Taiwan found that the rate of TBI in patients with hematological malignancies ranking second [12], with an incidence rate of 3.7%. In another research by Ganzel C et al found that among patients with hematological tumors, MDS and lymphoma patients have the greatest risk of TBI [13], the hazard ratio was highest (2.74, P = 0.012 and 2.70, p < 0.001). These researches encourage a heightened awareness for TBI among patients with a background of MDS. However, only sporadic reports of TBI in MDS patients have appeared until now [14][15][16].
Here, we retrospectively analyzed 34 patients with MDS and TBI and try to investigate the characteristics and outcomes thus providing experience for the clinical diagnosis and treatment of TBI in MDS patients.

Patients
This retrospective study included all primary MDS patients with TBI between January 2014 and December 2019. All medical records of the identi ed cases were retrieved and systemic analysis of characteristics pertaining to MDS, treatment, organs involved with TBI was conducted. This study was approved by the Ethics Committee of the First A liated Hospital, College of Medicine, Zhejiang University.
De nition and diagnosis of TBI TBI was considered if it ful lled one of the following criteria: 1, Modi ed Ziehl-Neelsen staining on clinical samples (sputum, body uids, ne needle aspirate or antemortem/postmortem biopsy) as well as epithelioid granuloma and caseous necrosis, or culture was positive, 2, clinical symptoms and typical radiologic characteristics such as cavitation, lymphadenopathy and effusion were presented, 3, response to ATT and no evidence of alternative bacterial or fungal etiology based on cultures or serologic tests. Interferon-γ release assay was also used to further identify TB infection. Response to ATT was de ned as resolution of fever and resolution of lesions by radio-logic image after institution of ATT. Synchronous infection was de ned as a diagnosis of TB disease within 3 months of MDS diagnosis [17][18][19] Statistical analysis All statistical analyses were performed using SPSS 22.0 (SPSS, Chicago, IL, USA). Chi-square and Fisher's exact test were used for Categorical variables, while the Student's t-test or ANOVA test were used for Continuous variables. OS was measured from the date of diagnosis of MDS to the date of death or last follow-up, the survival strati ed by synchronous and non-synchronous of MDS and TB infection was analyzed by Kaplan-Meier method and log-rank test. The signi cance level was set at 0.05 and all p values were two-tailed.

1, Epidemiology of tuberculosis infection
Between 2014 and 2019, a total of 1347 patients were diagnosed with MDS in our center, including 113 patients were MDS with single lineage dysplasia (MDS-SLD), 9 patients were 5q-syndrome, 209 patients were MDS with multi lineage dysplasia (MDS-MLD), 94 patients were MDS-unspeci ed (MDS-U), 416 patients were MDS with excess blasts 1 (MDS-EB1), and the rest 407 patients were MDS with excess blasts 2 (MDS-EB2). Among them, thirty-four patients were diagnosed with TBI. The overall incidence of TBI in patients with MDS during the study period was 2.5 %, and the numbers of TB cases among each WHO subtype of MDS were as follows: SLD, n = 2 (1.77%); MLD, n = 5 (2.39%); MDS-U, n = 2 (2.13%); MDS-EB1, n = 12 (2.88%); MDS-EB2, n = 13 (3.19%); Patients with MDS-EB seemed more likely to develop TBI than patients with other sub-type (3.04% vs. 2.1%, p = 0.334; odds ratio, 1.45; 95% con dence interval, 1.39-4.41) but the difference was not signi cant. P=0.04 ). The median time to AML was signi cantly shorter in the synchronous group (7.68 months) than those in non-synchronous group (23.83 months, P<0.01). However, other clinical characteristics, such as gender, age, blood cell count, and organs involved in TBI, were not signi cantly different between the two groups. The baseline characteristics of the patients were given and compared in Table 1.

3, Diagnosis of TBI
Only 4 patients (11.76%) had both positive acid-fast bacilli staining of samples including sputum and lymphoid tissue and culture for TB in our study, and 22 patients had just positive tissue staining without culture results. The remaining 8 patients were clinical-radiological TBI. Besides, the interferon-γ release test of all patients in our study was positive. The organ most common involved with TBI was lung, followed by lymph nodes, which were seen in 70.5% (24/34) and 41.18% of patients respectively. TBI occurred only in lung and lymph node in 13 and 9 patients respectively, and 13 (38.24%) patients had pulmonary involvement also had concomitant extra-pulmonary tuberculosis (lymph nodes, 5; Pleural cavity, 4 ), two patients had lumbar tuberculosis, one patient had TBI of the skin there was no signi cant difference in organs involved between the two groups.

4, The treatment and outcome of patients with TBI and MDS
Most patients received supportive care for MDS (22/34, 64.71%), eleven patients received decitabine therapy, and only 1 patient received hematopoietic stem cell transplantation (HSCT). For 22 patients received support care,10 have transformed to AML, but in those received decitabine therapy, only 2 patients proceeded to AML. In synchronous group, 10 patients received supportive care and 5 patients received decitabine therapy, while in non-synchronous group, 12 patients received support care and 7 received active therapy, and there were no signi cant difference between the two groups.
Thirty-three patients received ATT, among which 26 received standard ATT (isoniazide, rifampin, ethambutol, and pyrazinamide) and 7 (21.2%) patients received uoroquinolone based ATT. Twenty-four patients had response to ATT, and 9 patients had no response manifesting as lasting fever, six patients were in synchronous group and 3 in non-synchronous group. Two patients died of TBI without control, and 16 patients died due to MDS progression, among which 9 patients had transformed into AML, and 4 patients died of complication related to treatment. For patients were still alive, 7 have progressed disease, and 3 patients have transformed into AML, 5 patients are still on ATT.

Discussion
Compared with the general population [20], patients with MDS have a higher risk of developing TB infection. Previous studies have found that persistent cytopenia caused by ineffective hematopoiesis and defects in the lymphatic system such as a decrease in the absolute value of T lymphocytes [21], as well as a decrease in the ratio of CD4 / CD8 were main reason [22,23].
While in real world, TBI were seldom suspected in MDS patients, several reasons may be involved. First, clinical manifestations of MDS with TBI are not speci c [24][25][26], long standing fever with constitutional symptoms, even enlarged lymph nodes is often attributed to MDS itself or progression to acute leukemia [16,27], as well as other pathogenic microbial infections, such as bacteria and fungi. Second, the limitations of most of the existing diagnostic methods make the exact diagnosis rate of TBI low [28], and severe cytopenias further precludes the use of invasive diagnostic modalities to obtain a de nitive evidence for TB [27]. Thirdly, Other serious co-morbidities of MDS have attracted our attention, making us neglect the symptoms of TBI. In our study, some patients showed persistent fever and enlarged lymph nodes in the mediastinum, but due to a signi cant cytopenia, histological staining could not be performed as soon as possible, which extended the diagnosis time.
As a precursor disease of AML, MDS has similar clinical manifestations with low-proliferative AML, but MDS with TBI is very different from AML. In our study, not all TBI were secondary to MDS treatment, nearly half of TBI were found synchronously with MDS. Further analysis showed that MDS patients with synchronous TBI have higher risk strati cation, higher AML transformation rate, and shorter survival time, suggesting that these patients may have different genetic susceptibility bases. Previous studies have showed that some gene mutations and polymorphisms are associated with susceptibility to MDS, Among which, HLA-DRB1, GATA2 are also associated with TBI susceptibility [29,30]. Unfortunately, there have not enough data about gene polymorphism and mutation in our retrospective study to further analysis.
MDS combined with TBI could led to the rescheduling of therapy. In our study, most patients had higher risk group, but they received supportive treatment because of combined TBI, and the number of patients who received demethylatting drugs and HSCT were lower than the overall patients in the same period, but the AML transformation and disease progression were higher than the overall patients [31], so we speculated that failure to receive active treatment may be one reason for the rapid progression of patients with MDS and TBI. Previous study has found that HMA as a bridge to high dose therapy in AML patients with TBI could be a useful strategy [27], in our study, patients received decitabine also have a lower AML transformation rate (2/11 vs. 10/22, P = 0.03), which also suggested that patients may bene t from active therapy.

Conclusions
TBI is not uncommon among patients with MDS, patients with synchronous TBI and MDS progress faster and have shorter OS than those who developed TBI after MDS diagnosis, which may be associated with genetic susceptibility and lack of active therapy. Ethics and publication of this study was approved by the Ethics Committee of the First A liated Hospital, College of Medicine, Zhejiang University on January 30, 2020. The committee waived the requirement for informed written consent due to the retrospective and anonymous nature of the data and the fact that this research presented no risk of exposure to the subjects. Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.