Severe cases of BCGosis-susceptible primary immunodeficiency diseases identified by next-generation sequencing: Implications for adjustment of BCG vaccination timing in China
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These authors contribute equally to this work.
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Fig. 1. Representative clinical features of cases #4 and #5. A: Recurrent ulceration in BCG vaccination site (black arrow) of case #4. B: Skin manifestations of case #5. Red arrow, skin eruptions in the neck and left arm. Black arrow, recurrent ulceration in BCG vaccination site. C: Left subaxillary lymph node enlargement (black arrow) and skin eruptions in convalescence (red arrow) of case #5. D: Granulomatous inflammation with acute active inflammation shown by skin biopsy of case #5. HE staining, 100×. E: Necrotic granulomatous inflammation shown by lymph node biopsy of case #5. HE staining, 200×. F: Positive acid-fast bacillus (black arrow) in lymph node biopsy of case #5. Acid-fast staining, 400×. G: Left subaxillary lymph node enlargement, ulceration, and granulation tissue formation (black arrow) of case #4. H: Quasi-circular lesion (red arrow) in the liver by enhanced MRI of case #4. I: Strong-positive acid-fast bacillus (black arrow) in the left subaxillary lymph node wound swab of case #4. Acid-fast staining, 400×. BCG, Bacillus Calmette-Guerin; HE, hematoxylin and eosin; MRI, magnetic resonance imaging.
Table 1. Summary of clinical features, pathogen tests, immunological assays, and next-generation sequencing of PID cases with BCG infections.
Case #, sex, age Clinical manifestation Pathogen test Immunological assay Next-generation sequencing Treatment Prognosis 1, female,
3 monthsDiarrhea after birth, pneumonia in two months, spleen abscess in three months Blood culture: Mycobacterium, PCR specific for BCG (+) T-SPOT.TB (−), subgroup of lymphocytes (450/μL): CD3+ T 1.6%, CD4+ T 0.8%, CD8+ T 0.8%, B 48.4%, NK 5.3% IL7R (AR): c.616C > T (NM_002185), p.R206X, homozygous; both parents are heterozygous Antibiotics, IVIG Death 2, male,
4 monthsRecurrent ulceration in BCG vaccination site after birth, skin eruptions in two months, pneumonia, liver abscess, and bone destruction in four months Blood culture: Mycobacterium, PCR specific for BCG (+) T-SPOT.TB (−), subgroup of lymphocytes (1150/μL): CD3+ T 0.4%, CD4+ T 0.2%, CD8+ T 0.2%, B 91.1%, NK 0.2% IL2RG (XR): c.306C > A (NM_000206), p.C102X, hemizygous; mother is heterozygous Antibiotics, including linezolid, IVIG Death 3, male,
6 monthsRecurrent ulceration in BCG vaccination site after birth, diarrhea, pneumonia, liver and spleen abscess, and multiple lesions in the brain in five months Acid-fast staining of gastric juice (+), Xpert MTB/RIF of cerebrospinal fluid (+) T-SPOT.TB (−), subgroup of lymphocytes (820/μL): CD3+ T 11.4%, CD4+ T 4.7%, CD8+ T 4.8%, B 83.2%, NK 0.3% IL2RG (XR): c.270-1G > C (NM_000206), hemizygous; mother is heterozygous Antibiotics, including linezolid, IVIG Recurrent infections 4, male
6 monthsRecurrent ulceration in BCG vaccination site after birth, left subaxillary lymph node enlargement and ulceration in five months, liver and spleen abscess in six months, microcephaly, growth retardation Acid-fast staining of wound swab in the left subaxillary lymph node: (++++), Xpert MTB/RIF of wound swab in the left subaxillary lymph node: (+) PPD (−), T-SPOT.TB (−), subgroup of lymphocytes (382/μL): CD3+ T 38.3%, CD4+ T 29.4%, CD8+ T 2.6%, B 38.9%, NK 14.2%, naïve CD4+ T 0%, memory CD4+ T 98.8% NHEJ1 (AR): c.532C > T (NM_024782), p.R178X, homozygous; both parents are heterozygous Antibiotics, including linezolid and ertapenem, isoniazid, rifampicin, IVIG Follow-up 5, male,
4 monthsRecurrent ulceration in BCG vaccination site after birth, skin eruptions in one month, left cervical lymph node enlargement in two months, skin eruptions in three months, multiple lymph node enlargement and pneumonia in four months Acid-fast staining of lymph node biopsy (+), culture of lymph node biopsy: MTB complex, next-generation sequencing for pathogens: MTB or BCG PPD (+++), T-SPOT.TB (−), respiratory burst assay: defective, subgroup of lymphocytes: CD3+ T 62.3%, CD4+ T 37.8%, CD8+ T 22.8%, B 32.3%, NK 4.4% CYBB (XR): c.87T > G (NM_000397), p.Tyr29∗, hemizygous, de novo; both parents do not have this mutation Antibiotics, including linezolid, isoniazid, IVIG Recurrent infections 6, male,
9 monthsRecurrent fevers since one month; urinary infection in three months, pneumonia in four months, recurrent fevers in five months, multiple lymph node enlargement, spleen abscess, and pleural effusion in nine months; elder brother died in one year and four months None PPD (+), T-SPOT.TB (−), respiratory burst assay: defective, subgroup of lymphocytes: CD3+ T 61.6%, CD4+ T 34.8%, CD8+ T 24.7%, B 32.1%, NK 5% CYBB (XR): c.374G > A (NM_000397), p.Trp125∗, hemizygous; mother is heterozygous Isoniazid, rifampicin, itraconazole, antibiotics Recurrent infections. His brother: death 7, female,
4 monthsRecurrent ulceration in BCG vaccination site after birth, left subaxillary lymph node enlargement in three months Acid-fast staining of lymph node ulceration fluids (+) PPD (−), T-SPOT.TB (−), subgroup of lymphocytes: CD3+ T 48.8%, CD4+ T 38.8%, CD8+ T 9.1%, B 43.9%, NK 8.2% IL12RB1 (AR): c.1791+2T > G (NM_005535), heterozygous; mother is heterozygous; deletion of exon 10 and exon 11 (qPCR), heterozygous; father is heterozygous Isoniazid, rifampicin, interferon-γ Stable conditions 8, male,
3 monthsNo vaccinated BCG because of his sister's death, no symptoms.
His sister: recurrent ulceration in BCG vaccination site after birth, left subaxillary lymph node enlargement in three months, spleen abscess in six monthsNone.
His sister: acid-fast staining of lymph node biopsy (+)None.
His sister:
PPD (−), subgroup of lymphocytes: CD3+ T 58%, CD4+ T 41%, CD8+ T 18%, B 36%, NK 4%IL12RB1 (AR): c.634C > T (NM_005535), p.R212X, heterozygous; mother is heterozygous; deletion of exon 10 and exon 11 (qPCR), heterozygous; father is heterozygous.
His sister had no gene testsNone.
His sister: isoniazid, rifampicinStable conditions.
His sister: deathBCG, Bacillus Calmette-Guerin; MTB, Mycobacterium tuberculosis; RIF, rifampicin; PPD, tuberculin pure protein derivative; IVIG, intravenous immunoglobulin; T-SPOT.TB, TB-specific T lymphocyte; AR, autosomal recessive; XR, X-linked recessive; qPCR, quantitative PCR. 
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