Genomic, phenotypic and demographic characterization of Mycobacterium tuberculosis in Israel in 2021

Abstract

According to World Health Organization WHO, Tuberculosis (TB) is the second cause of death from infectious disease worldwide. During 2021, 10.6 million people were infected with TB, and 1.6 million people died. TB is caused by pathogens belonging to the Mycobacterium tuberculosis complex (MTBC), mainly by Mycobacterium tuberculosis (M.tb). Members of this complex are acid-fast bacilli, which can cause intrapulmonary and extra pulmonary TB, and can be divided into various lineages, based on genomic markers. The main public health threat comes from drug resistant M.tb strains, which are responsible for about 25% of TB death and treatment failure worldwide. Treating drug resistant TB patients significantly raises the costs of TB treatment. This study provides an overview of the demographic and drug susceptibility characteristics of newly diagnosed TB patients in Israel in 2021. The State of Israel has a very low level of TB endemicity and is at a pre-elimination phase. Notably, only 11.7% of the newly diagnosed TB patients were born in Israel. In this report, of the 154 new laboratory-confirmed TB patients, 66.7% had pulmonary TB, while 16% had extrapulmonary TB. Males accounted for 52% of the patients, with the most prevalent age group being 21-40. Most patients were citizens of Israel (53.9%), while 37.7% had no Israeli citizenship. Among non-citizens, there was a predominance of males and patients aged 21-40. The susceptibility profile showed a high resistance rate to streptomycin (18.2%) and to a lower extent to isoniazid (13.6%), pyrazinamide (8.4%), rifampicin (7.8%), and ethambutol (3.2%). Only 2 cases of XDR-TB and 10 MDR-TB strains were detected in Israel in 2021, with both XDR strains and 5 out of 10 MDR strains belonging to the Beijing lineage. Most of Beijing isolates were resistant to at least one tested drug. Genomic sequencing of 134 out of 156 strains and bioinformatics analysis using the MTBseq program and WHO mutation catalogue shows a good match with only 9 discrepancies between phenotypic and genotypic susceptibility profiles in first line drugs. The most common lineage is Delhi-Cas (23%) followed by the Beijing lineage (17%). Most patients from the Delhi-Cas lineage were born in Africa, while patients with Beijing isolates were born in different countries. Minimum spanning tree analysis identified 15 clusters. The study highlights the need for ongoing surveillance of TB using molecular and phenotypic tools to further decreasing the spreading level of the disease and develop effective treatment strategies.

Keywords: Israel; Mycobacterium tuberculosis complex (MTBC); extensively drug-resistant M.tb (XDR-TB); migrants; multidrug resistant M.tb (MDR-TB); next generation sequencing (NGS); whole genome sequencing (WGS).

Figure 1

Demographic characterizations of newly laboratory identified TB patient is Israel, year 2021: Age distribution among new TB diagnosed males and females (A), Citizenship status among TB males and females (B), age distribution among citizens vs. non-citizens (C).

Figure 2

Country of birth of newly diagnose TB patients in Israel in 2021: Cases from different countries were colored as indicated inset.

Figure 3

Phenotypic susceptibility profile of newly diagnosed TB patients in Israel in 2021: (A) Susceptibility to selected drugs from first and second line and (B) Drug resistance combinations. *excluding MDR-TB isolates.

Figure 4

MTBC lineage of newly diagnosed TB patients (A), and place of birth distribution among the lineages (B) in Israel in 2021. NA - the isolates were not sequenced. (n=154). Dehli-CAS, the major lineage in Israel consists mainly of patients from Africa. In contrast, patients infected with Beijing lineage, were born in many countries and regions including Israel, Africa, FSU, Central Asia and Western Asia, South America, Philippines, South Asia and Europe.

Figure 5

Minimum spanning tree of MTBC in Israel in 2021: The size of the circles is proportional to the number of isolates in the cluster. The color of the circles is according to lineages, the length of the lines connecting the circles is proportional to the number of SNPs. The numbers along the line connecting the circles indicate the SNPs numbers. A cluster of cases is defined when the distance between all isolates in the cluster is equal to or less than 12 SNPs, (n=138).