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. 2020 Oct 27;41(1):147–162. doi: 10.1007/s10875-020-00892-6

Bacillus Calmette–Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation

Adeeb NaserEddin 1,2,✉,#, Yael Dinur-Schejter 1,3,#, Bella Shadur 4,5, Irina Zaidman 1, Ehud Even-Or 1, Diana Averbuch 6, Oded Shamriz 3, Yuval Tal 3, Avraham Shaag 7, Klaus Warnatz 8,9, Orly Elpeleg 7, Polina Stepensky 1
PMCID: PMC7591244  PMID: 33111199

Abstract

Purpose

Bacillus Calmette–Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients.

Methods

A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019.

Results

We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell–deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective.

Conclusion

BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell–deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.

Keywords: BCG vaccination, hematopoietic stem cell transplantation, immune reconstitution inflammatory syndrome, primary immune deficiency, severe combined immunodeficiency

Introduction

Mycobacterium tuberculosis (MTB) is a significant worldwide health threat [1]. Bacillus Calmette–Guerin (BCG) vaccine has been used widely since 1921 to prevent tuberculosis (TB) [1, 2], and a large proportion of the world’s population is vaccinated with BCG soon after birth. Nevertheless, the estimated prevalence of BCG side effects is 1:2500 and 1:100,000 for localized and disseminated complications, respectively [3]. BCG-related complications can be subdivided into local (vaccine area) or regional (adjacent lymph-node) vaccine-related complications referred to as BCGitis, versus distant (affecting one site) or disseminated (affecting > 1 site and/or blood) BCG infection, referred to as BCGosis [4, 5]. Either pattern can be a manifestation of an ongoing infection or can represent an immune reconstitution inflammatory syndrome (IRIS).

Since BCG is a live attenuated vaccine, complication rates are significantly increased in immunodeficient individuals [3, 6–11], especially so in patients with T cell defects, mendelian susceptibility to mycobacterial disease (MSMD), or chronic granulomatous disease (CGD) [5–7, 11], reflecting the main mechanisms of defense against mycobacteria. For T cell defects, this susceptibly is related to the inability to produce an effective Th1 response [3]. MSMD patients suffer from defects in the interleukin (IL)-12/IL-23/interferon (IFN) γ circuit [12] and CGD, caused by defects in the NADPH oxidase complex, adversely affect the macrophage’s and neutrophil’s ability to kill phagocytosed bacilli [6, 13]. Severe combined immunodeficiency (SCID) is the most common diagnosis among BCG-complicated primary immunodeficiency (PID) patients [3, 6] (42–51% of BCG-vaccinated SCID patients), with the highest mortality rate (41.2%) [6]. Lower T cell counts, younger age at vaccination [3], and natural killer (NK)-SCID [6] are risk factors for BCG-related complications.

Little is known about the prevalence and risks for BCG-related complications in the post-transplant setting. In this study, we summarize our experience with BCG vaccine-related complications in PID patients in the post-hematopoietic stem cell transplantation (HSCT) period.

Materials and Methods

This study was conducted at Hadassah Hebrew University Medical Center in Jerusalem. We retrospectively collected data from pediatric patients with inborn phagocytic or T cell defects who underwent HSCT between January 2007 and December 2019, after having received the BCG vaccine. Patients were divided into combined (T cell mediated) and phagocytic defects based on the international union of immunological societies (IUIS) classification of PIDs [14]. SCID was defined in T cell–deficient patients, who presented in the first year of life and had CD3 counts < 500 cells/μl [15]. PT9 without available pre-HSCT CD3 count, but with IL2RG mutation and a classical SCID phenotype, was also considered a SCID patient.

All patients had received their vaccines within the first week of life, as per the Russian and Palestinian schedules. A total of 32 of 36 patients had been vaccinated in the Palestinian Authority with the BCG Danish-1331 strain. Four patients (P9, P21, P32, and P35) had received the Moscow-368 strain in Russia. Prophylactic antimycobacterial treatment was given as per our protocol, which varied over time. Since 2013, patients with severe T cell deficiency and a history of BCG vaccine were given triple therapy (isoniazid, rifampin, and ethambutol), while rifampin was substituted during HSCT with ciprofloxacin to avoid drug interactions. Treatment of symptomatic BCG complications was tailored per patient. In general, antimycobacterial treatment was intensified, and in cases of lack of improvement under such a regimen, along with signs of hyperinflammation (fever, increase in inflammatory markers) steroid treatment was added.

We recorded baseline patient characteristics, timing, and nature of BCG complications, prophylactic and treatment regimens, immunological work up, transplant characteristics, and outcome. Graft-versus-host disease (GVHD) grading was based on the Glucksberg grading [16]. Genetic diagnosis was made via whole exome sequencing (WES) in 30 patients and confirmed by Sanger sequencing as described elsewhere [17]. For patients who were of the same kindred, diagnosis was done via WES in the index case and confirmed in family members by Sanger sequencing. Patients 25–26 were diagnosed via a CGD genetic panel. BCG-related complications were diagnosed based on clinical assessment of the treating physicians, supplemented with microbiology and pathology results whenever available. Complications were categorized as “infectious” when pre-transplant symptomatic disease further disseminated in the context of increased immune suppression, or disease manifestation emerged in the context of reduced immune function, or “inflammatory” when symptoms appeared for the first time shortly (within 45 days) after engraftment. In cases without symptomatic pre-transplant BCGosis, in which symptoms appeared prior to engraftment, it was impossible to discern worsening infection in the context of immune suppression from inflammatory reaction of donor T-cells, and therefore, we deemed these cases as “undetermined.” BCGitis was defined as local and/or the regional lymph node BCG infection, while BCGosis was defined as distant/disseminated disease [4].

Statistical analysis was conducted with the IBM_SPSS Statistics 27.0 version (IBM Inc., Armonk, NY). Cumulative survival curve was calculated using XLSTAT 2020.3.1 version. Fisher exact test was used for categorical variables. Mann-Withney U test and the Kruskal-Wallis H tests were used for 2 and 3 groups of independent numerical variables, respectively. Kaplan-Meier method was used for survival analysis. All statistical analyses conducted a 2-tailed test with a confidence level of 95%.

This study was approved by Hadassah’s Institutional Review Board.

Results

Patient and transplant characteristics

Thirty-six pediatric patients who underwent HSCT for phagocytic and T cell defects in Hadassah medical center between 2007 and 2019, and had received the BCG vaccine prior to transplant, were included in this study (Table 1). Fifteen (41.7%) developed post-transplant BCG-related complications: 6 patients (40%) had BCGitis, while 9 patients (60%) had BCGosis. Twenty-four patients were transplanted for T cell defects, while 12 had phagocytic defects. Genetic diagnoses are detailed in Tables 2 and 3. Baseline diagnoses significantly differed between complication groups: while only 47.6% of the BCG-uncomplicated patients had a T cell deficiency, 83.3% of the BCGitis and all BCGosis patients had a T cell defect (Table 1). This difference in baseline immune defect accounts for non-complicated patients’ older age at the time of transplant compared with patients with BCGitis or BCGosis (49.2 versus 23.3 and 9.9 months old, respectively, p = 0.002), as well as the increased use of prophylactic antimycobacterial treatment in this group, considering our institutional protocol (66.7% in the BCGosis group vs 16.7% and 23.8% in the BCGitis and non-complication groups, respectively, p = 0.05). Pre-transplantation BCGosis was a predictor for post-transplant disseminated disease (75% and 22.7% cumulative incidence of post-transplant BCGosis among patients with and without pre-transplant disease, respectively, p = 0.004 Fig. 1).

Table 1.

BCG complication groups

Non-complicated BCGitis BCGiosis p value
Number of pts (%) 21 (58.3) 6 (16.7) 9 (25.0)
Age at transplantation in months (STD) 49.2 (44.3) 24.3 (42.5) 9.9 (3.7) 0.002
Number of pts with a T cell defect (%) 10 (47.6) 5 (83.3) 9 (100) 0.013
Pre-transplant lymphocyte count, 106/L (STD) 3914 (3616) 3233 (3266) 9569 (17000) 0.715
Pre transplant immunophenotypinga
  CD3 cells/μl, mean (STD) 2780 (2803) 1416 (1616) 3614 (8480) 0.086
  CD4 cells/μl, mean (STD) 1134 (1376) 638 (849) 2719 (6116) 0.282
  CD8 cells/μl, mean (STD) 1258 (1472) 600 (764) 951 (1504) 0.326
  CD19 cells/μl, mean (STD) 917 (581) 779 (1434) 690 (694) 0.267
  NK cells/μl, mean (STD) 470 (565) 832 (993) 243 (427) 0.162
Number of pts with pre-transplant BCG-related complications (%) 1 (4.8) 0 3 (33.3) 0.06
Pts on pre-HSCT anti-mycobacterial treatment (%) 5 (23.8) 1(16.7) 6 (66.7) 0.05
Mean number of anti mycobacterial meds (STD) 2 (1) 3 3 (0.6) 0.191
Mean duration of treatment prior to HSCT (STD) 2.9 (3.3) 1.5 1.2 (1.4) 0.69
Day of neutrophil engraftment (STD, Num of patients)b 18.6 (6.1, 20) 16.6 (4.2, 5) 15.4 (6.0, 8) 0.401
Post transplant day of BCG complicationc NA 35 (14.4) 65.7 (145.4) 0.239
Day 100 lymphocyte count, 106/L (STD, Num of patients) 2967 (3282, 18) 4467 (1782, 6) 2275 (2935, 8) 0.013
Day 100 chimerism (STD, Num of patients) 95.5 (13.0, 18) 86.0 (31.3, 5) 53.4 (40.1, 8) 0.033
Number of pts with aGVHD Grade > 2 (%) 4 (19.0) 0 3 (33.3) 0.278
Number of pts with cGVHD (%) 1 (5.6) 2 (33.3) 0 0.187
Mean duration of follow-up (STD) 30.9 (28.0) 53.8 (30.6) 22.6 (18.0) 0.123
Last follow-up lymphocyte count, 106/L (STD, Num of pts) 3636 (2493, 19) 5283 (4321, 6) 3040 (2147, 9) 0.666
Last follow-up chimerism (STD, Num of pts) 89 (20.9, 18) 79.3 (33.1, 6) 47.4 (43.8, 8) 0.061
Last immunophenotyping cells/μl, Mean (STD)d
  CD3 2212 (1508) 5476 (4516) 2304 (932) 0.492
  CD4 727 (371) 2230 (1846) 1389 (866) 0.122
  CD8 1136 (1179) 2982 (2537) 872 (478) 0.268
  CD19 533 (452) 667 (776) 862 (990) 0.902
  NK 313 (348) 226 (258) 297 (446) 0.847
Num of pts on IVIG treatment at last follow-up (%) 4 (22.2) 0 1 (16.7) 0.794
Survival- Pts (%) 18 (85.7) 6 (100) 6 (66.7) 0.267
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aGVHD acute graft vs host disease, cGVHD chronic graft vs host disease, DLI donor lymphocyte infusion, IVIG intravenous immunoglobulins, NA non applicable, Pts patients, STD standard deviation

aPre-transplant lymphocyte immunophenotyping was recorded for 14 patients of the BCG-non complicated group, 5 patients of the BCGitis group, and 7 patients of the BCGiosis group

bNeutrophil engraftment defined as the first day of 3 consecutive days of ANC > 500

cFor patients with pre-transplant BCGosis, the first post transplant day of further BCG dissemination was noted

dLast follow-up lymphocyte immunophenotyping was recorded for 12 patients of the BCG-non complicated group, 4 patients of the BCGitis group, and 7 patients of the BCGiosis group

Table 2.

Clinical characteristics of BCG-complicated patients

Pt. Gender/consanguinity Age at diagnosis/Age at HSCT (months) Gene/Mutation Clinical presentation Pre-HSCT BCG related complications Pre HSCT anti BCG meds, duration (months) Pre-HSCT laboratory evaluation cells (μl) Pre-HSCT laboratory evaluation cells (μl) Donor match Graft source Conditioning GVHD px TNC dose (108/kg) Neut Engrafta (days) aGVHD (location, grade) cGVHD, extent, location Post transplant BCG complication Anti-BCG tx, duration, months Last donor chimerism (%) Outcome, Last follow-up (months)
ANC ALC CD3 CD4 CD8 CD19 NK Day Clinical presentationc Positive cultures, location Pathology
1 F/Yes 7/8 RAG1 c.1410_1413delCTTG FTT, C. diarrhea, Rec. chest infection, Pul. aspergillosis, Pancytopenia None None 300 300 6 6 78 0 195 MSD PBSC None None 8.9 NAb No Limited, eye 30 Inflammatory, Regional. Yes, skin BM:granulomas INH + RIF + ETM, 8 51 A + W, 105
2 F/Yes 0/6 DCLRE1C c.815G > T FTT, Omenn, rec. pneumoniae, CMV, E coli and stenotrophomonas sepsis, pseudomonas OM and cellulitis, candidal infections. None None 1200 1000 700 150 260 20 230 MRD PBSC Flu CSA 50 17 Skin I Limited, skin 19 Inflammatory, Regional Yes, LN Skin + LN: granuloma, ZN + INH + RIF + ETM, 12 100 A + W, 59
3 M/Yes 7/12 IKBKB c.207delC rec. pneumoniae, thrush BCGosis (bone marrow, skin, liver, spleen) INH + RIF + ETM + Cipro, 4 1200 23,500 20,915 16,450 3760 1880 1175 MRD BM Flu/Treo/TT/ATG CSA + MMF 4.9 13 GI III No 5 Infectious, Diss: Liver, spleen, skin, BM, kidney, CNS Yes, gast.asp. skin Liver+ BM +Skin: granuloma, ZN+ INH + RIF + ETM + Cipro, 16 7 Died of graft failure, diss BCGosis, 17
4 F/Yes 8/9 IL7Rα c.158G > A Rec. UTI, thrush, c.diarrhea BCGosis (lung, GI, liver, retroperitoneum) INH + RIF + ETM, 1 4300 200 0 0 0 180 0 MSD BM Flu/Treo/ATG CSA 10.9 26 GI IV No 2 Infectious, Diss: lung, liver, spleen, gi,, endocard Yes: sput, perit fl, skin GI: c. mild inflam, no granulomas, ZN+ ETM + RIF + INH + Doxy + Azythro + Cipro, 8 100 Died, diss BCGosis, 7
5 M/Yes 6/6 JAK3 c.2680 + 89 C > T FTT, rec pneumoniae and AOM, cholestatic hepatitis None INH + ETM + Cipro, 0.25 737 1277 0 0 0 1200 0 MRD PBSC None CSA + CS 7.6 8 Skin I No 3 Undetermined, Diss: skin, spleen, liver, eye, CNS, bones, lungs, kidney. Yes: skin Skin: mono infilt, no granulomas, ZN+ ETM + RIF + INH + Cipro/Moxi + Doxy, 24 17 A + W, 60
6 F/Yes 3/5 RAG1 c.210C > T FTT, c. diarrhea, Omenn, AOM None INH + RIF + ETM, 0.5 8400 50,400 NA NA NA NA NA MSD BM Flu/Treo/TT/ATG CSA 9.75 16 No No 4 Undetermined, Diss: LN, skin No NA ETM + INH + Cipro, 18 23 A + W, 17
7 M/Yes 13/15 PNP c.635 T > G FTT, rec pneumoniae and AOM, c. diarrhea None INH + ETM + Cipro, 0.6 17,200 200 24 4 6 22 148 MSD BM Flu/Treo CSA 9.76 9 No No 23 Inflammatory, Diss: skin, LN. Skin, LN: AFB pos.; culture neg. NA RIF + INH + ETM + Doxy + Levo, 10.5 100 A + W, 26
8 F/Yes 5/6 VPS45 c.671C > A Rec pneumoniae, skin abscesses, CMCC, delayed separation of cord, pancytopenia None None 200 3400 NA NA NA NA NA MSD BM Bu/Flu/TT/ATG CSA 6.91 11 No No 40 Inflammatory, Local Yes: skin NA INH+Cipro, 9 100 A + W, 20
9 M/No 5/14 IL2RG c.202G > A FTT, c. diarrhea, CMCC, AOM, maternal engraftment None None 2200 4500 NA NA NA NA NA MUD PBSC Bu/Flu/Alem CSA + MMF 23.6 14 GI I No 7 Undetermined, Diss: LN, skin, liver Yes: gast. asp., LN Skin, liver: granulomas, ZN+ INH + RIF + ETM + Cipro + Azithro, 12 100 A + W, 38
10 M/Yes 4/6 T-B-NK+ SCID Rec. pneumoniae. PJP pneumonia, c. diarrhea, rec bacteremiae, Omenn, CMCC BCGosis (liver, LN) None 100 700 672 189 504 7 21 MMUD CB Flu/Treo CSA + MMF 2.4 None No No 55 Infectious, Diss: Liver, LN No NA Azythro + Amikacin + Cirpo, 3 NA Died D + 88, non-engraftment
11 M/Yes 3/5 RAG1 p.Q407E CMV pneumonia +viremia, PJP pneumonia, Omenn None INH + RIF + ETM, 1.5 7200 1400 56 56 0 28 1260 MRD BM Flu/Treo/ATG CSA + MMF 9.5 20 No No 60 Inflammatory, Local No Skin: histiocytes, no granulomas INH + RIF + ETM, 12 100 A + W, 27
12 F/Yes 103/111 IL21R p.R201Q rec AOM, CMV viremia, rec pneumonia, PJP pneumonia, mucosal HSV None None 2800 4100 3280 1968 820 533 82 MSD BM Flu/Treo/TT/ATG CSA + MMF 9.69 14 No No 36 Inflammatory, Regional NA NA INH + RIF + ETM + Cipro, 5 100 A + W, 65
13 M/No 5/10 IL2RG p.R222V pneumonia, diarrhea None None 2700 9200 3036 1012 1840 3312 2392 MSD BM Flu/Treo/TT/ATG CSA 14.6 21 No No 25 Inflammatory, Local No NA INH + RIF + ETM, 5 25 A + W, 47
14 F/Yes 11/12 STIM1 c.436_437insG rec pneumoniae, FTT, hypotonia, ectodermal dysplasia, AIHA None None 2890 4540 NA 2350 2350 890 320 MSD BM Flu/Treo/TT/ATG CSA + MMF 8.4 21 No No 450 Infectious, Diss: LN. Yes: gast asp LN:hyperplasia, granuloma, ZN+ INH + RIF + ETM + Cipro, 13, ongoing 12 A + W, 27
15 F/Yes 8/10 JAK3 c.172G > A Rec. pneumoniae+ AOM diarrhea, ecthyma gangrenosum, pseudomonas bacteremia, Omenn None INH + ETM, 1 1500 800 72 40 40 648 40 MRD BM Flu/Treo/TT/ATG CSA + MMF 9.9 40 No No 42 Inflammatory, Diss: skin, LN. Yes: gast asp LN: granuloma, ZN neg INH + RIF + ETM, 10 ongoing 20 A + W,9
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aNeutrophil engraftment defined as the first day of 3 consecutive days of ANC > 500

bNeutrophil count did not fall below 500 cells/mm3

cExtent of infection was defined as local (injection site) reaction, regional (regional LN, ipsilateral to vaccine site), distant (any single site beyond local/regional), and disseminated (involvement of more than one distant site and/or blood/bone marrow involvement) (4)

a. acute, AIHA autoimmune hemolytic anemia, ALC absolute lymphocyte count, Alem Alemtuzumab, ANC absolute neutrophil count, AOM acute otitis media, ATG antithymoglobulin, A + W alive and well, Azithro Azithromycin, BCG Bacillus Calmette-Guerin, BM bone marrow, Bu busulfan, c. chronic, CB cord blood, Cipro Ciprofloxacin, CMCC chronic mucocutaneous candidiasis, CMV cytomegalovirus, CSA cyclosporin A, Diss disseminated, DLI donor lymphocyte infusion, Doxy Doxycillin, ETM ethambutol, F female, Flu Fludarabine, FTT failure to thrive, GI gastrointestinal, GVHD graft vs host disease, HSCT hemtopoietic stem cell transplantation, INH isoniazid, Levo Levofloxacin, LN lymph node, M male, MMF mycophenolate mofetil, Moxi Moxifloxacin, MMUD mismatched unrelated donor, MRD matched related donor, MSD matched sibling donor, MUD matched unrelated donor, NA non-available, PBSC peripheral blood stem cell, PJP pneumocyctis jirovci, Pt patient. Pul pulmonary, Rec recurrent. RIF Rifampicin, TNC total nucleated cells, Treo Treosulfan, TT thiotepa, ZN Zeihl Neilsen

Table 3.

Clinical characteristics of patients without BCG-related complications

Pt. Gender/consanguinity Age at diagnosis/Age at HSCT (Months) Gene/Mutation Clinical presentation pre- HSCT BCG related complications Pre-HSCT anti BCG treatment Pre-HSCT laboratory evaluation (cell/μl) Donor match Graft source Conditioning GVHD px TNC Dose (108/Kg) Neutrophil Engraft (Days)b aGVHD (location, grade) cGVHD, extent, location Last Donor chimerism (%) Outcome, Last follow-up (months)
Meds Duration pre HSCT/Total (months) ANC ALC CD3 CD4 CD8 CD19 NK
16 M/Yes 7/8 VPS45 Skin abscess, late cord detachment, pancytopenia None None - 100 2100 NA NA NA NA NA MSD BM Bu/Flu/TT/ATG CSA 5.48 22 None None 100 A + W, 30
17 M/Yes 6/8 RFX5 Pneumonia, oral ulcers, adenovirus, FTT, rash None None - 3200 1900 1178 171 988 342 304 MSD BM Flu/Treo/TT/ATG CSA + MMF 10 11 None None 96 A + W, 77
18 F/Yes 8/11 VPS45 IFI, otitis externa None None - 900 3300 1815 1188 924 775 33 MRD BM Flu/Treo/TT/ATG CSA + MMF 10.2 24 None None 61 A + W, 75
19 M/Yes 115/126 TPP2 c.432delG Rec OM, VZV, CMV, dev delay, seizures, Lnopathy, Evan syn None None - 2700 3400 2482 1360 1088 170 510 MSD CB + BM Flu/Treo/TT/ATG CSA 6.2 16 None None 100 A, interstitial lung disease, 68
20 M/NA 2/14 IL2RG c.664C > T Rec pneumoniae, diarrhea, Omenn None INH + ETM + RIF 1 /4 5700 4500 2790 720 1800 1350 225 MSD BM Flu/Treo/TT/ATG CSA + MMF 11.8 17 None None 64 A + W, 64
21 M/No 5/124 CGD Skin abscess, pneumonia, rec fevers, FTT None None - 8300 1100 NA NA NA NA NA MUD PBMC Flu/Treo/TT/ATG CSA + MMF 6.4 11 GI I Skin II limited, eye 100 A + W, 39
22 M/Yes 32/34 IL2RG c.664C > T FTT rec pneumonia osteomyelitis None INH + Cipro 0.25/2.5 700 1500 600 195 255 750 270 MSD BM Flu/Treo/TT/ATG CSA 8.5 28 None None 68 A + W, 51
23 M/Yes 7/20 IL2RG c.664C > T FTT, diarrhea None Cipro 0.25/0.83 5400 2300 713 690 207 1380 805 MRD PBMC Flu/Treo/TT/ATG CSA 7 36 None None 88 A + W, 49
24 M/Yes 62/69 NCF2 c.1171_1175delAAGCT Fever, LNitis, rec pneumonia, pleural granuloma, FTT, parotitis. None INH + RIF + Azithro 6/6a 7800 2400 NA NA NA NA NA MSD BM Flu/Bu/ATG CSA + MMF 4.3 17 None None 100 A + W, 93
25 F/Yes 82/92 CYBA c.58 + 4_ + 7delAGTG Rec pneumoniae, rec skin abscesses None None - 4200 6700 NA NA NA NA NA MSD BM Flu/Treo/TT/ATG CSA + MMF 4.3 20 None None 100 A + W, 29
26 F/Yes 118/137 CYBA c.58 + 4_ + 7delAGTG Rec fever and pneumoniae, skin abscess None None - 4900 3200 NA NA NA NA NA MSD PBSC Flu/Treo/TT/ATG CSA + MMF 13.5 16 None None 100 A + W, 20
27 M/No 35/60 IL2RG c.664C > T Recurrent pneumoniae FTT, Bronchiectais HSM None None - 5000 10,100 7777 855 5055 1515 2222 MUD BM Flu/Treo/ATG CSA + MMF 9.2 23 None None 2 Died, VOD, sepsis Day+86
28 F/Yes 12/15 LCK c.1129_1130insA Rec pneumoniae and AOM, FTT None None - 4100 1900 193 18 3 1330 336 MRD BM Flu/Treo/TT/ATG CSA + MMF 7 20 None None 25 A + W, 17, on IVIG
29 F/Yes 79/113 NCF2 Pneumonia, Lnitis FTT, None None - 10,990 3900 1872 655 206 1794 156 MSD PBSC Flu/Treo/TT/ATG CSA + MMF 11.4 16 None None 100 A + W, 9
30 M/Yes 3/37 MALT1 c.1799T > A Rec pneumoniae, skin abscesses, rec HSV None None - 5700 15,600 9322 4642 3831 869 100 MSD BM Flu/Treo/TT/ATG CSA + MMF 5.5 18 None None 100 A + W, 15, On IVIG
31 F/Yes 3/38 LCK c.1129_1130insA Rec pneumonia and AOM, CLD, FTT, HSM None None - 300 600 NA NA NA NA NA MMUD BM Flu/Treo/ATG CSA 5.5 10 None None 100 Died, sepsis Day+29
32 M/No 11/21 IL2RG c.664C > T Rec pneumonia None None - 2500 3100 1814 183 939 211 837 MMUD PBSC Flu/Treo/TT/ATG CSA + MMF 6 13 Skin III GI II None 100 A + W, 13, on IVIG
33 M/No 3/10 CYBB c.483 + 1G > A LNitis, liver abscess, serratia sepsis None None - 1900 8800 5764 3819 1588 1681 528 MMUD BM Flu/Bu/ATG CSA + MMF + MTX 5 19 None None 100 A + W, 5, on IVIG
34 M/Yes 9/10 VPS45 c.671C > A Rec aseptic meningitis, FTT, HSM, IFI None None 200 2000 NA NA NA NA NA MUD PBSC Flu/Bu/TT/ATG CSA + MMF 11.1 15 None None 100 A + W, 22
35 M/No 50/66 CYBB c.483 + 1G > A LNitis, lung abscesses Diss: LN, liver INH + ETM + RIF/Levo 7/10 3100 2100 1275 690 423 370 233 MUD BM Flu/Bu/ATG CSA + MMF 5.8 19 GI I None 100 A + W, 12
36 M/No 12/21 VPS45 c.671C > A Rec pneumoniae, rec fevers, LNitis, genital ulceration None None - 100 1700 1326 689 305 17 17 MMUD CB Flu/Treo/TT/ATG CSA + MMF 0.95 None None NA 0 Died, engraftment failure, sepsis day + 30
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aTreatment discontinued prior to transplant

bNeutrophil count did not fall below 500 cells/mm3

a. acute, ALC absolute lymphocyte count, ANC absolute neutrophil count, AOM acute otitis media, ATG antithymoglobulin, A + W alive and well, Azithro Azithromycin, BCG bacillus Calmette–Guerin, BM bone marrow, Bu busulfan, c. chronic, CB cord blood, Cipro Ciprofloxacin, CLD chronic lung disease, CMV cytomegalovirus, CSA cyclosporin A, Dev. delay developmental delay, Diss disseminated, DLI donor lymphocyte infusion, ETM ethambutol, F female, Flu Fludarabine, FTT failure to thrive, GI gastrointestinal, GVHD graft vs host disease, HSCT hemtopoietic stem cell transplantation, HSM hepatosplenomegaly, IFI invasive fungal infections, INH isoniazid, Levo Levofloxacin, LN lymph node, LNitis lympkhadenitis, LNopathy lymphandenopathy, M male, MMF mycophenolate mofetil, MMUD mismatched unrelated donor, MRD matched related donor, MSD matched sibling donor, MTX metrothrexate, MUD matched unrelated donor, NA non-available, OM otitis media, PBSC peripheral blood stem cell, Pt patient, Rec recurrent, RIF Rifampicin, TNC total nucleated cells, Treo Treosulfan, TT thiotepa, VZV varicella zoster

Fig. 1.

Fig. 1

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Cumulative Incidence for post-HSCT BCGosis. The cumulative risk of developing post-HSCT BCGosis in the first 500 days post-transplant. Cumulative incidence is 75.0% and 22.7% for patients with or without pre-transplant disease, respectively (p = 0.004)

Transplant variables are detailed in Tables 2 and 3. Donor, graft source and dose, conditioning regimen, and GVHD prophylaxis did not differ between groups. All transplants in this cohort were first transplants, and none of the patients required a second procedure.

Considering their increased rate of BCG-related complications, we analyzed T cell–deficient patients separately (Table 4). On a pooled analysis of BCGosis patients compared with non-complicated and BCGitis patients, those with BCGosis were younger at the time of transplant (mean age 9.9 vs 34.2 months, p = 0.045) and were more likely to have suffered from BCGosis prior to transplantation (33.3% of the BCGosis group vs none of the non-BCGosis group, p = 0.04). NK-cell counts prior to transplantation in BCGosis patients were significantly lower compared with the non-BCGosis group (243 vs 698 cells/μl, p = 0.03).

Table 4.

Characteristics of T cell deficiency patients

No BCGosis BCGosis p value
Num of pts (%) 15 (62.5) 9 (37.5)
Age at HSCT, months (STD) 34.2 (37.6) 9.9 (3.7) 0.045
Num of patients with SCID (%) 3 (20) 5 (55.6) 0.099
Num of patients with Omenn (%) 3 (20) 2 (22.2) 1.0
Pre-HSCT ALC 106/L (STD) 4060 (4302) 9569 (17000) 0.676
Pre HSCT Immunophenotyping cells/μl, mean (STD)a
  CD3 2425 (2843) 3614 (8480) 0.083
  CD4 859 (1235) 2719 (6116) 0.296
  CD8 1226 (1512) 951 (1504) 0.296
  CD19 844 (903) 690 (694) 0.765
  NK 698 (758) 243 (427) 0.03
Num pts with pre-HSCT BCGosis (%) 0 3 (33.3) 0.042
Pts on anti-mycobacterials primary prophylaxis (%)b 4 (26.7) 4 (66.7) 0.15
Day of neutrophil engraftment (STD, num of pts)c 18.9 (6.9, 14) 15.4 (6.0, 8) 0.206
Post-HSCT day of BCG complication (STD, num of pts) 34.0 (15.8, 5) 65.7 (145.4, 9) 0.257
Day 100 ALC, 106/L (STD, num of pts) 4223(2730, 13) 2275 (2935, 8) 0.017
Day 100 chimerism (STD, num of pts) 87.4 (23.8, 12) 53.4 (40.1, 8) 0.091
Number of pts with aGVHD grade > 2 (%) 1 (6.7) 3 (33.3) 0.13
Number of pts with cGVHD (%) 2 (18.2) 0 1
Mean length of follow-up (STD) 41.7 (30.2) 22.6 (18.0) 0.144
Last follow-up ALC, 106/L (STD, num of pts) 4006 (3417, 14) 3040 (2147, 9) 0.659
Last follow-up chimerism (STD, num of pts) 78.2 (28.8, 13) 47.4 (43.8, 8) 0.097
Last immunophenotyping cells/μl, mean (STD)d
  CD3 3114 (3208) 2304 (932) 1
  CD4 1117 (1202) 1389 (866) 0.329
  CD8 1720 (2034) 872 (478) 0.77
  CD19 496 (375) 862 (990) 0.558
  NK 331 (360) 297 (446) 0.558
Num of pts on IVIG at last follow-up (%) 3 (23.1) 1 (16.7) 1
Survival—number of pts (%) 13 (86.7) 6 (66.7) 0.326
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aGVHD acute graft vs host disease, BCG bacillus Calmette–Guerin, cGVHD chronic graft vs host disease, ALC absolute lymphocyte count, DLI donor lymphocyte infusion, IVIG intravenous immunoglobulins, num number, Pts patients, STD standard deviation

aPre-transplant lymphocyte immunophenotyping was recorded for 14 patients of the non-BCGosis group and 7 patients of the BCGosis group

bPercentage of patients receiving primary prophylaxis is calculated of the number of pre-transplant asymptomatic patients

cNeutophil engraftment–defined as the first day of 3 consecutive days of ANC > 500

dLast follow-up lymphocyte count was recorded for 10 patients of the non-BCGosis group and 7 patients of the BCGiosis group

In order to delineate other risk factors, T cell–deficient patients without a pre-HSCT history of BCG infection were analyzed separately: those who developed BCGosis had lower pre-HSCT CD3 (32 vs 2425 cells/μl, p = 0.02) and NK-cell counts (127 vs 698 cells/μl, p = 0.04), but also a shorter diagnosis to transplant interval (mean time 2.2 vs 10.7 months, p = 0.02) (Fig. 2).

Fig. 2.

Fig. 2

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Pre-HSCT immune variables in T cell–deficient patients with post-HSCT BCGosis. Baseline immune variables of T cell–deficient patients without a prior history of pre-HSCT BCGosis. Patients who developed post-HSCT BCGosis are compared with those who did not develop this complication: a CD3+ counts were scaled on a logarithmic scale. b NK cell counts were scaled on a linear scale

Among eight asymptomatic T cell–deficient patients receiving antimycobacterial prophylaxis prior to transplantation, 50% developed post-transplant BCGosis versus two-thirteenths (15.4%) of untreated patients (p = 0.15). Prophylactic regimens did not differ between patients who developed BCGosis and those who did not (mean number of medications 2.75 vs 2.25, p = 0.12, mean duration of prophylaxis 0.59 vs. 0.75 months, p = 0.88). However, patients who developed BCGosis despite prophylaxis had JAK3 (n = 2), RAG1, and PNP deficiencies, whereas T cell–deficient, uncomplicated patients had the IL2RG c.664C > T variant (n = 3) and RAG1, suggesting a milder disease phenotype. On the other hand, both T cell–deficient patients receiving antimycobacterial treatment for pre-transplant symptomatic BCGosis experienced further deterioration of their disease despite appropriate treatment with 3–4 medications for a period of 1–4 months. Both patients subsequently died of disseminated disease 7–17 months post-transplant.

Younger age at transplantation and a shorter diagnosis to transplant interval, observed in T cell–deficient patients who developed post-HSCT BCGosis, are potential markers for a more severe baseline condition. We therefore analyzed the patients with SCID separately (n = 8, 5 (55.6%) of the BCGosis group and 3 (20%) of the non-BCGosis group, p = 0.099; Table 4). In this cohort, there was no difference in patient’s age at transplant or in diagnosis to transplant interval (mean age 10.8 vs 9.3, p = 0.55, mean time from diagnosis to treatment 2.2 and 1.7 months, p = 0.34, in the BCGosis and non-BCGosis groups, respectively). However, pre-HSCT NK-cell count remained significantly lower in the BCGosis group compared with the non-BCGosis group (47 vs 597 cells/μl, p = 0.03). Patients with SCID who developed BCGosis had mutations in JAK3 (n = 2), PNP, IL7R, and IL2RG, whereas those who did not develop this complication had mutations in RAG1 (n = 2) and LCK.

Among patients with phagocytic defects, only PT8 with VPS45 experienced mild BCGitis (Table 2). PT35 with CYBB mutation and pre-HSCT BCGosis was treated with triple therapy prior and during transplant and had not suffered reactivation of BCG. He is currently 12 months post-HSCT with full donor chimerism (Table 3).

Pathogenesis of BCG-Related Complications

Four patients presented with infectious complications: PT3, PT4, and PT10 had severe BCGosis prior to transplantation, and their infection disseminated further during transplant-related immunosuppression. Both PT3 and PT4 had viable bacilli in pathology or microbiological specimens (Table 2). While PT4’s duodenal biopsy revealed chronic mild inflammation without granulomas, PT3’s initial biopsies revealed granulomas which were absent in subsequent biopsies, suggesting a declining immune function [18]. In another patient (PT14), deteriorating immune function following a decline in donor chimerism had uncovered a BCG infection, as evident by positive gastric aspirate cultures and granulomas with acid-fast bacteria (AFB) on lymph-node (LN) biopsy.

Eight patients presented with inflammatory complications (Table 2). These were characterized by initial local/regional disease on average day + 34.4 (range 19–60 days) post-HSCT, followed by further dissemination in 2 patients. Another 3 patients (PT5, PT6, PT9) without pre-transplant disease had developed symptoms prior to engraftment; thus, it was impossible to differentiate donor cell allo-reactivity from unmasked previously asymptomatic infection in the context of immune suppression in these cases.

Five patients demonstrated a switch from positive to sterile cultures following antimycobacterial treatment: while 4 of these patients (PT1, PT2, PT9, and PT15) had evidence of granulomatous inflammation, suggestive of IRIS [18], PT5 exhibited a switch from a mononuclear infiltrate with positive Ziehl-Neelsen (ZN) stain on an early skin specimen, into a foamy histiocytic infiltrate with multinucleated giant cells on a subsequent specimen. These changes are suggestive of a transition from active infection to IRIS following engraftment [18]. Of 12 patients receiving DLI, only one (PT15) suffered further worsening of her skin BCGosis 34 days following DLI.

Patient Outcomes

Mean follow-up was 32.6 months (range 0–105 months) and did not differ significantly between groups (30.9, 53.8, and 22.6 months for non-complicated, BCGitis and BCGosis groups, respectively, p = 0.12). Patients with BCGosis had significantly lower donor chimerism on day + 100 compared with non-BCGosis patients (53.4 vs 93.4% donor cells, p = 0.01) and at last follow-up (47.4 vs 86.6% p = 0.02). This difference remained as a mere trend in T cell–deficient patients (donor chimerism on day + 100: 53.4 vs 87.4%, p = 0.09, and donor chimerism at last follow-up: 47.4 vs 78.2%, p = 0.097, in BCGosis compared with non-BCGosis patients), even after excluding patients without pre-transplant disease (donor chimerism on day + 100: 51.0 vs 87.4%, p = 0.09, and chimerism at last follow-up: 45.3 vs 78.2%, p = 0.08). T cell patients with BCGosis also had lower lymphocyte counts on day + 100 (2275 vs 4223 cells/μl, p = 0.02). Other outcome measurements did not differ between groups (Table 4).

Overall survival (OS) in our cohort was 83.3% (30/36 patients) and was comparable between T cell–deficient and phagocytic defect patients (79.2% and 91.7%, p = 0.41). In T cell–deficient patients, OS did not significantly differ among complication groups (OS = 80.0%, 100% and 66.7% in the non-complicated, BCGitis and BCGosis respectively, p = 0.39; Fig. 3). However, none of the T cell–deficient patients with a history of pre-HSCT BCGosis survived transplant, whereas survival rate without such history was 90.5% (Fig. 4; p < 0.001).

Fig. 3.

Fig. 3

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Survival in T cell deficiency patients with BCG-related complications. A Kaplan-Meier survival curve of BCG-complication groups in T cell–deficient patients demonstrates a similar survival: Overall survival (OS) = 80.0%, 100.0%, and 64.8% in patients with no BCG-related complications, BCGitis and BCGosis, respectively, p = 0.393

Fig. 4.

Fig. 4

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Survival in T cell deficiency patients with pre-HSCT BCGosis. A Kaplan-Meier survival curve of T cell–deficient patients demonstrates a significantly reduced survival in patients with a pre-transplant history of BCGosis compared with those lacking such history. Overall survival (OS) = 0% vs 90.5%, p < 0.001

All three patients with T cell defects who suffered of pre-transplant BCGosis died in the post-transplant period (Table 2): PT3 with inhibitor of nuclear kappa b kinase subunit beta (IKBKB) mutation was given a prolonged quadruple antimicrobial regimen for pre-transplant BCGosis. Following an MRD transplant, he suffered secondary graft failure and died of disseminated BCGosis and septic shock 17 months post-HSCT, despite continued anti-mycobacterial treatment. PT4 with IL7Rα deficiency was treated for 1 month prior to transplant for BCGosis. Following her MSD transplant she failed to reconstitute her T cells and responded poorly to antimicrobials. She died 7 months post-HSCT of multiple bowel perforations related to her BCG infection. PT10 with unidentified SCID presented with multiple bacterial infections. Upon admission, he was noted to have BCG lymphadenitis and hepatitis and an urgent mismatched unrelated (MMUD) cord blood (CB) was performed for lack of a better donor. Unfortunately, the patient failed to engraft and despite full antimycobacterial treatment succumbed to BCGosis as well as enteroviral infection. Three patients (PT27, PT31, and PT36) in the non-BCGosis group died in the early post-transplant period of veno-occlusive disease (VOD), sepsis, and non-engraftment (Table 3).

Discussion

In this retrospective observational study, we compare 15 PID patients with BCG vaccine-related post-HSCT complications to 21 BCG-vaccinated patients without such complications. Patients with T cell deficiencies were at an increased risk of developing BCG-related complications compared with phagocytic defect patients. Indeed, post-HSCT, BCG-related complications have been reported in T cell deficiencies [3, 18–35] but have not so far been described in phagocytic defects. Despite the well-known association between CGD and BCG [6, 7, 13, 36], none of our 7 BCG-vaccinated CGD patients, including a patient with pre-transplant BCGosis, developed post-HSCT complications. These findings, in agreement with previous reports [13, 37], point to the central role of T cells in control of chronic mycobacterial infection and in mycobacterial-related IRIS [38].

History of pre-transplant disease is a major risk factor for post-HSCT BCGosis (Fig. 1; Table 4) as well as mortality (Fig. 4). In a review of the literature, 16/37 (43.2%) SCID patients with pre-transplant BCGosis died in the post-transplant period [18, 22–24, 27, 29, 31, 33, 39]. Increased mortality of pre-HSCT symptomatic patients was not found to be affected by antimycobacterial treatment [3]. Post-transplant treatment with anti-IL6 and Abatacept for prevention of inflammatory complications was recently reported in a small cohort [27] as both effective and safe. These results warrant further validation in larger, prospective studies.

Among T cell–deficient patients who had no pre-transplant BCGosis, lower baseline CD3 counts were found to be a risk factor for post-transplant BCGosis (Fig. 2). Poor T cell function was previously described as a risk factor for both BCG infection [3, 27] and future IRIS [40]. Lower NK-cell counts were found both in the T cell deficiency cohort, and in SCID patients specifically, and indeed, half of the patients in our SCID cohort who developed BCGosis had NK-SCID. This is compatible with a recent report [6], which identified a 2-fold higher number of NK negative SCID patients compared with NK positive SCID patients among the patients with BCG-related complications. NK cells have a role in control of mycobacterial infection, through the secretion of IFN-γ and TNFα as well as via direct contact [41, 42].

Various mechanisms have been ascribed to post-transplant BCG-related complications [6]. These can generally be divided into worsening of infection in the context of intensified immune suppression, versus increased inflammation in the context of an improved immune function. IRIS, defined as the restoration of an immune response against pathogen-specific antigens resulting in immunopathology, requires a functional immune system as a pre-requisite for diagnosis [43]. Features in our cohort consistent with IRIS included close association with engraftment and granuloma formation [18, 44], regardless of bacilli vitality. Features consistent with an infectious-driven process included active pre-transplant infection, poor immune reconstitution, and viable bacilli [18]. Nevertheless, distinguishing a predominant infectious process from an inflammatory reaction is challenging [45], since both mechanisms co-exist in the same patient during immune reconstitution. Gantzer et al. [18] demonstrated a switch from a diffuse histiocytic granuloma-negative infiltration with positive AFB to a CD3-rich, AF negative, granulomatous inflammation, as immunity was restored. Biopsy results can be helpful in distinguishing IRIS-related lesions from infectious worsening.

Three of five patients in our cohort who presented with Omenn syndrome developed IRIS. While there is not enough data to establish Omenn syndrome as a risk factor for post-HSCT BCG-related complications, it is possible that the switch from a Th2 milieu in Omenn syndrome [46], known to inhibit mycobacterial immune response [38], to a Th1 milieu in the post-HSCT period increased the risk of developing IRIS. Certainly, a shift from a Th2 to Th1/Th17 predominance is known to occur in multiple settings associated with IRIS [44, 45, 47].

There is no consensus regarding prophylactic treatment in PID patients [3]. In a previous retrospective analysis [3], only 3% of SCID patients receiving secondary prophylaxis developed BCG-related complications. However, prophylactic treatment did not improve OS. In our hands, post-exposure prophylaxis did not mitigate the risk for developing BCGosis. Nevertheless, as prospective controlled studies are lacking, we continue recommending a triple prophylactic regimen for profoundly T cell–deficient patients who have received the BCG vaccine. Another point to consider in prospective studies is the use of prophylaxis against inflammatory complications, as suggested in a recent report [27].

There are currently no guidelines for treatment of post-HSCT BCG disease, and diverse regimens have been used [3, 18–21, 24–28, 31, 33, 35, 39, 48, 49]. Treatment modalities other than anti-microbials include steroids [27, 29, 44, 47, 48], surgical treatment, [19, 20, 23, 27, 48] IFNγ, [18] and anti-IL1 and anti-IL-6R antagonists [27]. Our treatment protocol includes a triple regimen until clinical and radiological resolution of disease, as well as immune reconstitution. A recent report [27] eases safety concerns regarding anti-inflammatory treatment for IRIS on immune reconstitution. However, further studies are needed to better define the efficacy, safety, and need of such treatments in the post-transplant settings.

Finally, the WHO recommends avoiding BCG vaccination for immunodeficient infants [50]. These guidelines, however justified, are difficult to implement, due to immunization timing. Furthermore, neonatal screening does not encompass the wide range of BCG-associated PIDs and is currently not available in the countries with the highest burden of mycobacterial disease. Recommendations to postpone vaccination in at risk infants [50–52] must be weighed against the global health impact of BCG vaccination. Recently, the COVID-19 epidemic has stimulated new interest in the BCG vaccine for its possible non-specific protective effects through trained innate immunity, though evidence of efficacy of BCG vaccination against COVID-19 is lacking [53, 54]. Thus, while vaccine delay across all populations is neither practical nor advisable, we recommend that the possibility of PID should be considered prior to vaccination, especially in areas with a high prevalence of consanguinity.

Conclusion

BCG vaccination causes significant morbidity and mortality in PID patients, especially during post-transplantation immune reconstitution. Disseminated mycobacterial infection after HSCT is observed mainly in profound T cell deficiencies despite appropriate antibiotic treatment, with increased risk in NK-SCID. Pre-transplant infection is a significant negative prognostic factor. Taking a detailed medical and family history prior to administering the BCG vaccine is crucial and possibly lifesaving. Finally, there is a need for consensus guidelines for the prophylaxis and treatment of BCG disease in PID patients both prior to and following HSCT.

Acknowledgments

We thank our patients and their families, and our departmental nursing and administrative staff for their tireless commitment to patient care. Particularly, we thank Mrs. Maram Shweiki for her tireless work which enables optimal patient care. We also thank Professor Zeev Rotstein, Director of The Hadassah Medical Center, for his support of the department and our patients.

Authors’ Contributions

All authors have read and approved this manuscript. Yael Dinur Schejter, Adeeb NaserEddin, and Bella Shadur gathered the data, treated the patients, and wrote the manuscript. Oded Shamriz, Yuval Tal, Irina Zaidman, Ehud EvenOr, and Diana Averbuch gathered data and treated patients. Klaus Warnatz assisted in writing, assembly, and editing. Avraham Shaag and Orly Elpeleg provide the genetic diagnosis and segregation studies. Polina Stepensky treated the patients, designed, and supervised the study.

Funding

Adeeb NaserEddin received “Award for Excellence 2018” from Allergists For Israel organization. Bella Shadur’s position is supported by the Australian Government Research Training Program Scholarship and by Hadassah Australia. This work was supported by the Deutsche Forschungsgemeinschaft (Discovery and Evaluation of new Combined Immunodeficiency Disease Entities (DECIDE); grant DFG WA 1597/4-2) and the ERA-NetERARE Consortium EURO-CID.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Adeeb NaserEddin and Yael Dinur Schejter contributed equally to this work.

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