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Laboratory results. * Maternal T cells in chimerism analysis. # Total chimerism 60% donor, 40% patient. Myeloid chimerism 100% patient, T and NK cell chimerism 100% donor.
Source publication
In high-burden countries,
Mycobacterium bovis
Bacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severe
Mycobacterium tuberculosis
infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burde...
Context in source publication
Context 1
... chest X-ray revealed absence of a thymus and showed bilateral areas of opacities (Figure 1). The immunologic panel confirmed the hypothesis of SCID (Table 1), later genetically characterized (missense mutation in exon 5, codon 226 CGC → CAC, leading to an arginine 226 substitu- tion by histidine; common cytokine receptor gamma chain of IL-2-IL2RG gene). This mutation has previously been described as causing human X-linked SCID [5]. ...
Similar publications
This systematic review critically investigates the administration of the Bacillus Calmette-Guérin (BCG) vaccine in neonates with severe combined immunodeficiency (SCID). The BCG vaccine, derived from Mycobacterium bovis, is a live attenuated vaccine recognized for its significant role in mitigating the impacts of tuberculosis (TB) in endemic areas....
Introduction: Bacillus Calmette-Guérin (BCG) vaccine, a live attenuated Mycobacterium bovis strain, is administrated to all newborn infants in endemic regions according to the current World Health Organization (WHO) recommendation. Case Presentation: We report a 10-month-boy who was a known case of severe combined immunodeficiency (SCID) admitted w...
Citations
... According to these findings, we believe that patients undergoing HSCT should be closely monitored for BCG-VAC even if they have received antimycobacterial prophylaxis. Even though no consensus exists at present, several studies advise that antimycobacterial prophylaxis should be initiated in patients with PIDs who undergo HSCT and this prophylaxis should be continued until immune reconstitution occurs after HSCT [15,20]. ...
Objective:
Bacillus Calmette-Guérin (BCG) vaccine derived from Mycobacterium bovis can cause BCG vaccine associated complications (BCG-VAC) especially in patients with primary immunodeficiencies (PID). No consensus exists for antimycobacterial prophylactic therapy for patients with PID who receive the BCG vaccine.
Aim:
This study aimed to define the risk factors in the development of BCG-VAC and effect of antimycobacterial prophylaxis in PID patients vaccinated with BCG.
Methods:
This is a retrospective cohort study. 104 patients diagnosed with PID who received the BCG vaccination were referred to pediatric pulmonology in a single center were enrolled. The demographic characteristics, type, dosage and duration of antimycobacterial prophylaxis regimen, treatment modalities for BCG-VAC were documented. Regression analysis was performed to evaluate the effect of covariates for predicting BCG-VAC in patients with PIDs.
Results:
Among 104 patients 21 (21.2%) developed BCG-VAC. The frequency of BCG-VAC was highest in patients with Mendelian susceptibility to mycobacterial disease (46.2%) followed by patients with severe combined immunodeficiency (22.4%) and those with chronic granulomatous disease (9.5%). Prophylactic therapy against mycobacterium was initiated for 72 patients (69.2%). Among patients who received the antimycobacterial prophylaxis, BCG-VAC developed in only four patients (5.6%), whereas 17 patients (53.1%) developed BCG-VAC in the non-prophylaxis group and this difference was statistically significant (p < 0.001). Multivariable regression analysis with age at diagnosis, type of PID, receiving antimycobacterial prophylaxis, median T cell number at the time of PID diagnosis and HSCT status showed that not receiving antimycobacterial prophylaxis and lower median T cell number were predictors, with antimycobacterial prophylaxis having the highest odds ratio for BCG-VAC prediction in patients with PIDs (p:<0.001, R2:0.64).
Conclusion:
The lower frequency of BCG-VAC in our cohort can be explained by two main reasons; relatively late BCG vaccination schedule and receiving antimycobacterial prophylaxis. It is reasonable to begin antimycobacterial prophylaxis in patients with PIDs who are susceptible to BCG-VAC.
... 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][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][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. ...
... 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. ...
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.
... In 1 patient (P293), dissemination of a subclinical BCG infection with the development of an acute erythroderma was assumed to be due to activation of the host's response with the donor's lymphocytes. In 74 of them (rows [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], immune reconstitution inflammatory syndrome (IRIS) 227 was presumably the underlying cause of BCG infection. Immunosuppression as part of the conditioning regimen together within the context of IRIS management led to BCG infection in 2 patients (P34 and P415). ...
... 14,15,40,42-44,114,120 Moreover, a previously resolved BCG infection relapsed in 2 patients, 45 and an already existing BCG infection worsened and resulted in serious systemic complications in 57 patients. [15][16][17][18][19]35,[46][47][48] However, the inflammatory responses to BCG were appropriately managed in most of these cases after full immune reconstitution and included prolonged antimycobacterial therapy, anti-inflammatory regimen, and/or surgical procedures for debridement of the abscess and suppurated lymph nodes. 14,16,17,35,40,42,44,47,48,114 This implies the fact that the possible incidence of IRIS should not be a contraindication for HSCT. ...
... [15][16][17][18][19]35,[46][47][48] However, the inflammatory responses to BCG were appropriately managed in most of these cases after full immune reconstitution and included prolonged antimycobacterial therapy, anti-inflammatory regimen, and/or surgical procedures for debridement of the abscess and suppurated lymph nodes. 14,16,17,35,40,42,44,47,48,114 This implies the fact that the possible incidence of IRIS should not be a contraindication for HSCT. Altogether, physicians should be aware of this syndrome and distinguish it from other mycobacterial infections owing to its different therapeutic approach. ...
Background:
Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis, which is mostly administered to neonates in regions where tuberculosis (TB) is endemic. Adverse reactions following BCG vaccination are rare, however immunocompromised individuals and in particular patients with primary immunodeficiencies (PIDs) are prone to develop vaccine-derived complications.
Objective:
We aimed to systematically review demographic, clinical, immunologic and genetic data of PIDs that present with BCG vaccine complications. Moreover, we performed a meta-analysis aiming to determine the BCG-vaccine complications rate for PID patients.
Methods:
We conducted electronic searches on Embase, Web of Science, PubMed and Scopus (1966 to September 2018) introducing terms related to PIDs, BCG vaccination, and BCG vaccine complications. Studies with human subjects with confirmed PID, BCG vaccination history and vaccine-associated complications (VAC) were included.
Results:
A total of 46 PIDs associated with BCG-VAC were identified. Severe combined immunodeficiency was the most common (466 cases) and also showed the highest BCG-related mortality. Most BCG infection cases in PID patients were reported from Iran (n=219, 18.8%). The overall frequency of BCG-VAC in the included 1691 PID cases was 41.5% (95% CI: 29.9, 53.2; I2=98.3%), based on the results of the random effect method used in this meta-analysis. Patients with Mendelian susceptibility to mycobacterial diseases had the highest frequency of BCG-VAC with a pooled frequency of 90.6% (95% CI: 79.7, 1.0; I2=81.1%).
Conclusions:
Several PID entities are susceptible to BCG-VAC. Systemic neonatal PID screening programs may help to prevent a substantial amount of BCG vaccination 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][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][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. ...
... 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. ...
... 4,5 Abu Arja et al reviewed 19 reported cases of BCG infection that had been reported in post-transplant patients with PID. [6][7][8][9][10][11][12][13][14][15] Three of them had no prior evidence of infection, yet developed either local or disseminated infection following HSCT as in our case. [6][7][8] Sixteen of them had infection prior to HSCT, and dissemination process had occurred before transplantation as a result of inadequate immunity. ...
... [6][7][8] Sixteen of them had infection prior to HSCT, and dissemination process had occurred before transplantation as a result of inadequate immunity. [8][9][10][11]14,15 BCG lymphadenitis occurred at post-transplant day 110 in our patient, and this reaction was closely associated with T-cell reconstitution on day 92. The timing of the HSCT and development of lymphadenitis in our case fits into the interval determined by previously reported cases (within 1-18 months following HSCT, in most cases within 4 months). ...
IRIS is a phenomenon describing localized inflammatory reactions at BCG vaccination site and development of lymphadenopathy as immune system recovers. It is a rare entity in children following haploidentical HSCT. We represent the successful treatment of a case with fluctuating lymphadenopathy due to BCG vaccine during immune reconstitution period following ex vivo T‐cell–depleted haploidentical HSCT.
... Administration of BCG vaccine soon after birth remains controversial, as it can be difficult to distiguish at birth infants who harbour an immunodeficiency, which would contraindicate use of the vaccine. 1,5,6 ...
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... Local adverse reactions, including erythema, induration or small ulceration around injection, are relatively common, and these reactions disappear in several weeks. Systemic adverse reactions are rare but increasingly reported in recent years [3][4][5]. Before 2009, we accepted some children patients with adverse reactions after BCG vaccination. ...
To study the clinical features of BCG infection in children.
51 cases confirmed with BCG infection from all over China were enrolled and followed up for at least 6 months. All cases were treated with anti-tuberculosis drugs. A random, open, group control study was designed in non-disseminated cases to evaluate curative effects of anti-tuberculosis drugs for early stage BCG infection. Disseminated cases were also closely monitored, and patients were given combined anti-tuberculosis drug therapy.
In 34 (66.7%) non-disseminated cases, 19 children with local infections were treated with Isoniazid (Group A) and 15 were treated with Isoniazid and Rifampin (Group B). In the first 3 months, Group B responded better to anti- tuberculosis drug therapy than Group A (P<0.05). At the end of 6 months drug therapy, improvement rate was 100% of Group B vs. 89.5% of Group A (P<0.05). 33.3% children were admitted with disseminated BCG disease and were initially treated with Isoniazid and Rifampin. Most of these children responded poorly to drug therapies: Both isolated strains and BCG vaccination strain showed resistance to isoniazid, but susceptible to other First-line anti-tuberculosis drugs (Rifampin, Ethambutol and Streptomycin).
INH does not perform well for treating BCG Chinese infections. Multiple drug regimens are necessary for treatment and preventing Drug-Resistance. Even for non-disseminated cases, preventive therapy using mono-isoniazid regimen is not suitable. BCG infections also occur in children without clear immunodeficiency, so parental education and awareness of health-care workers is essential for promptly recognition and handling BCG infections.
... The high mortality rate was ascribed to associated immunodeficiencies, delay in diagnosis or treatment, BCG resistance to pyrazinamide, and general resistance to present therapy for disseminated BCG infection in addition to a possible reporting bias. 2 Bone marrow transplant has been tried in children with disseminated BCG infection and immunodeficiency. 9,10 In our case, the immunological panel revealed hypogammaglobulinemia and grossly reduced T-cells. Mother was negative for ELISA-HIV. ...
Background: Bacille Calmette-Guerin (BCG), a live attenuated vaccine, is safe and given to all neonates in endemic countries; however may rarely cause disseminated disease, especially in immuno-deficient individuals.
Case characteristics: A 6 month old male infant, presented with vomiting, loose motions and failure to thrive. He was found to have features of severe acute malnutrition and abscess at BCG site. On investigations had features of disseminated tuberculosis in lung and skin and severe combined immunodeficiency.
Message: Infants with disseminated tuberculosis should be screened for underlying immunodeficiencies.
... In most cases, BCG infection was present prior to transplantation, and the decision to administer antituberculosis drugs depended on the clinical symptoms. Several authors have proposed drug combinations and management strategies for BCG infection [31,32,34]. In contrast to other BCG strains, M bovis from the Moreau/Rio de Janeiro strain is sensitive to isoniazid [36]. ...
Background:
Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine.
Methods:
We actively searched for cases by contacting all Brazilian referral centers.
Results:
We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases).
Conclusions:
In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.
... In most cases, BCG infection was present prior to transplantation, and the decision to administer antituberculosis drugs depended on the clinical symptoms. Several authors have proposed drug combinations and management strategies for BCG infection [31,32,34]. In contrast to other BCG strains, M bovis from the Moreau/Rio de Janeiro strain is sensitive to isoniazid [36]. ...
Background: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of
this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine.
Methods: We actively searched for cases by contacting all Brazilian referral centers.
Results: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were
male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P=.058)
before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P=.009). Most patients (60/70)
were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was
disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT).
Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either
alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases).
Conclusions: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis,
although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine
are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.
