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Severe Axillary Lymphadenitis After BCG Vaccination: Alert for Primary Immunodeficiencies

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Abstract

The bacilli Calmette-Guérin (BCG) vaccine is administered to all newborns in countries where tuberculosis is endemic. Immunocompromised hosts, namely patients with human immunodeficiency virus infection or primary immunodeficiencies, are especially prone to serious complications from this vaccine. We report three cases of BCG disease in children with primary immunodeficiencies: one with a partial recessive interferon-γ receptor 1 deficiency, who developed BCG dissemination; and two relatives with ZAP70 deficiency, a severe combined immunodeficiency, both of whom presented with regional and distant BCG disease. All had severe axillary lymphadenitis. These clinical cases underline the importance of considering the diagnosis of immunodeficiency in a child with severe axillary lymphadenitis after BCG vaccination and of disseminated BCG disease in an immunodeficient child in the appropriate clinical setting. Moreover, BCG vaccination should be delayed in every newborn with a family history of primary immunodeficiency until the condition has been ruled out.

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... However, these publications are mostly based on case reports and retrospective studies. [7][8][9] There are several studies documenting PI with BCG-LA, including a case report of a patient who developed disseminated BCG with a partial recessive interferon-γ receptor 1 deficiency and two relatives with ZAP70 deficiency, and severe combined immunodeficiency syndrome (SCID). 7 Another study reported nine children with PI syndromes who developed persistent BCG-LA. ...
... [7][8][9] There are several studies documenting PI with BCG-LA, including a case report of a patient who developed disseminated BCG with a partial recessive interferon-γ receptor 1 deficiency and two relatives with ZAP70 deficiency, and severe combined immunodeficiency syndrome (SCID). 7 Another study reported nine children with PI syndromes who developed persistent BCG-LA. 9 A 2-year prospective cohort study found that multiple and recurrent BCG-LAs are associated with some immunological deficiency markers, such as low counts of CD3, CD8, CD19, CD16/CD56 and NK cells. ...
... The most frequent is BCG-LA, with a proportion varying from 0.1 to 1%. 4 In addition, some publications have reported that BCG-LA could be associated with PI in HIV-negative patients. [7][8][9][10] A study done by Santos and colleagues reported three cases of BCG disease in children with PI: one with a patient with a partial recessive interferon-γ receptor 1 deficiency who developed BCG dissemination, and two relatives with ZAP70 deficiency and an SCID, both of whom presented with regional BCG-LA. The authors recommended in this study that BCG vaccination should be delayed in all newborns with a family history of PI, until these conditions have been ruled out. ...
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Objectives: Vaccination against tuberculosis with live-attenuated Bacillus Calmette-Guérin (BCG) is widely used even though its effectiveness is controversial. BCG-lymphadenitis (BCG-LA) is its most common complication. Some studies have proposed that BCG-LA can be associated with primary immunodeficiencies (PIs). This study's aim is to see whether patients who developed BCG-LA (named as 'LA') developed more infections than BCG-vaccinated children without BCG-LA (named as 'NON-LA'). Methods: From January 2009 to April 2014, 31 LA children were seen at the outpatient clinic of the General Hospital of Tijuana, Mexico. Among them, 22 (70.97%), 5 (16.13%) and 4 (12.9%) had axillary, supraclavicular, or both BCG-LA, respectively. No treatment was given and complications were not seen. Per LA subject, a NON-LA not >1 month of age difference and same gender was paired and followed for 3 years to look for ambulatory infections (AINFs), acute otitis media (AOM) and hospitalizations. Surveillance per patient was performed by phone monthly, and they were seen at the clinic every 4 months. All patients were HIV-negative and had no family history of PI. Statistical analyses used were relative risk (RR) with confidence intervals (CI), t test for independent variables and z test. Results: In total 62 subjects were enrolled: 31 LA paired with 31 NON-LA. Between them, there were no differences in age, day care attendance and breastfeeding. There were no differences in the total number of AINF per patient (LA: 18.61 avg. ± 5.03 SD versus NON-LA: 18.19 avg. ± 4.17 SD, RR = 1.06, 95% CI = 0.33-0.66), AOM total episodes (LA: 30 versus NON-LA: 26, RR = 0.87, 95% CI = 0.31-0.68) and hospitalizations (LA: 5 versus NON-LA: 4, RR = 1, 95% CI = 0.25-0.74). Conclusions: This cohort strongly suggests that BCG-LA in healthy children is not associated with more episodes of AINF and hospitalizations, when paired and compared with children BCG-vaccinated without BCG-LA.
... AEFI demands special consideration in PID because they can represent the first manifestation of these diseases, in many cases resulting in the "red flag" for the initial diagnosis [4][5][6]. Lymphadenitis, seizures, paralysis, failure to thrive, dissemination of a vaccine strain to other organs and death have been reported after vaccination in PID patients. Several reports describe several AEFI following Bacille Calmette-Guérin (BCG) vaccination in severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), interferon-gamma receptor 1-and ZAP-70-deficiency [4][5][6][7][8][9][10][11][12][13][14]. ...
... Lymphadenitis, seizures, paralysis, failure to thrive, dissemination of a vaccine strain to other organs and death have been reported after vaccination in PID patients. Several reports describe several AEFI following Bacille Calmette-Guérin (BCG) vaccination in severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), interferon-gamma receptor 1-and ZAP-70-deficiency [4][5][6][7][8][9][10][11][12][13][14]. Moreover, a comprehensive review of the published mycobacterial complications in patients with CGD revealed that 45/72 (62.5%) are BCG-related [11]. ...
... 4 Other congenital defects of the phagocyte number included two cases of congenital neutrophenia, two cases of Shwachman-Diamond syndrome and one unspecified defect in the phagocytes. 5 Although is not included as a PID by Bousfiha et al., [1], PFAPA is one of the most common autoinflammatory conditions. of complications in 349 patients exposed to BCG, with an overall increase in the risk of localized or disseminated reactions of 400 and 33,000, respectively compared to the normal population. This study also reported a 2.03-fold increase in BCG complications among SCID patients receiving BCG before the first month of age compared to those vaccinated later in life [15]. ...
Article
Background: Adverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a "red flag" for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients. Methods: Medical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria. Results: Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients. Conclusions: Our study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT).
... Safety is a main consideration prior to vaccination in patients with IEI [1]. Adverse events after live attenuated vaccination have been documented in patients with a range of IEIs [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. National guidelines, based on cohort studies, case series and expert opinion offer some advice; however, highquality evidence regarding best practice is lacking [1,[23][24][25][26][27]. ...
... In mild/moderate combined IEI, Vakkilainen et al. found sustained antibody responses to MMR but decreased antibody responses to varicella vaccine when compared to healthy controls in patients with cartilage hair hypoplasia (CHH), though cell mediated responses varicella vaccine were sustained [6]. Physician concerns about safety of live attenuated vaccines may derive from their potential to cause vaccine-associated disease including vaccine derived rubella virus associated granulomas in CIDs, as well as from conflicting guidelines on their use in patients with mild-moderate IEI [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]41]. For example, in partial CID, the CDC recommends avoidance of all live vaccines, while the Canadian Immunization Guide suggests that patients with a CD4 + T cell count > 0.500 × 10 9 /L and normal mitogen responses can receive MMR and univalent varicella vaccines [1,23,24,26,27]. ...
Article
Full-text available
Background and objectives Safety and effectiveness concerns may preclude physicians from recommending vaccination in mild/moderate inborn errors of immunity (IEI). This study describes attitudes and practices regarding vaccination among physicians who care for patients with mild/moderate B cell or mild/moderate combined immunodeficiencies (CID) and vaccination completeness among patients diagnosed with IEIs. Methods Canadian physicians caring for children with IEI were surveyed about attitudes and practices regarding vaccination in mild/moderate IEI. Following informed consent, immunization records of pediatric patients with IEI evaluated before 7 years of age were reviewed. Vaccine completeness was defined at age 2 years as 4 doses of diphtheria-tetanus-pertussis (DTaP), 3 doses pneumococcal conjugate (PCV), and 1 dose measles-mumps-rubella (MMR) vaccines. At 7 years 5 doses of DTP and 2 doses MMR were required. Results Forty-five physicians from 8 provinces completed the survey. Most recommended inactivated vaccines for B cell deficiency: (84% (38/45) and CID (73% (33/45). Fewer recommended live attenuated vaccines (B cell: 53% (24/45), CID 31% (14/45)). Of 96 patients with IEI recruited across 7 centers, vaccination completeness at age 2 was 25/43 (58%) for predominantly antibody, 3/13 (23%) for CID, 7/35 (20%) for CID with syndromic features, and 4/4 (100%) for innate/phagocyte defects. Completeness at age 7 was 15%, 17%, 5%, and 33%, respectively. Conclusion Most physicians surveyed recommended inactivated vaccines in children with mild to moderate IEI. Vaccine completeness for all IEI was low, particularly at age 7. Further studies should address the reasons for low vaccine uptake among children with IEI and whether those with mild-moderate IEI, where vaccination is recommended, eventually receive all indicated vaccines.
... On average, in this study, lymphadenitis was presented at 4.28 months of age. In most studies, lymphadenitis developed within 2 -6 months after birth (2,15,16,23,(26)(27)(28). In our study, the commonest involved lymph node was the ipsilateral axillary node, followed by the supraclavicular lymph node. ...
... In our study, the commonest involved lymph node was the ipsilateral axillary node, followed by the supraclavicular lymph node. The regional distribution of lymphadenitis was similar to the reports of other studies (3,7,12,15,16,23,28). In our study, the suppurative and nonsuppurative lymphadenopathy rates were equal, similar to studies from the UK (5) and India (6). ...
Article
Full-text available
Background: Tuberculosis (TB) is one of the most important infectious diseases worldwide. Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine, entered into the childhood immunization program by the World Health Organization (WHO) in 1974 to prevent TB. One of the relatively common complications of BCG vaccination is regional lymphadenitis. Objectives: This study aimed to determine the lymphadenitis incidence in BCG-vaccinated children in southwest Iran. Methods: In a prospective descriptive study, infants born from March to June 2017 were evaluated for BCG vaccine complications at two, four, six, nine, and 12 months of age in Ahvaz, southwestern Iran. Results: The study enrolled 1,506 infants (794 males and 712 females). Among the vaccinated infants, four (0.26%) had injection site reactions, and 106 (7.03%) presented lymphadenitis (66 males and 40 females). The lymphadenitis rate was significantly higher in males than in females (P = 0.024). The mean age at presentation was 4.28 ± 0.79 months. Suppurative lymphadenitis was seen in 53 (50%) cases and nonsuppurative lymphadenitis in 53 (50%) cases. About 80% of nonsuppurative lymphadenitis resolved entirely or partially after a one-year follow-up. Of 53 cases with suppurative lymphadenitis, 46 (43.4%) developed spontaneous drainage, and seven (6.6%) were drained by needle aspiration. No significant relationship was found between the BCG inoculation site and lymphadenitis rate. No other complications such as osteomyelitis or disseminated BCG infection were observed after one year of follow-up. Conclusions: The relatively high incidence of BCG lymphadenitis in this study may be due to the vaccine strain, young vaccinees, and improper vaccination techniques. In most cases, nonsuppurative lymphadenitis regressed spontaneously, and suppurative lymphadenitis was drained spontaneously or by needle aspiration.
... Notably, presence of acid fast bacilli within the cytoplasm (intracellularly) is an uncommon yet interesting phenomena (16). Our patient fulfilled all diagnostic criteria of disseminated BCG infection, including presence Mycobacterium bovis BCG substrain on his skin as indicated by PCR, showing typical histopathological changes with granulomatous inflammation and positive tuberculosis complex-PCR in gastric washing, having systemic symptoms and more than two areas of involvement beyond the site of BCG vaccination (hepatosplenomegaly, pulmonary and skin involvement) (3,17). Patients with unrecognized primary immunodeficiency frequently experience severe complications of live bacterial or viral vaccines (for example BCG and rotavirus) in early infancy. ...
... Patients with unrecognized primary immunodeficiency frequently experience severe complications of live bacterial or viral vaccines (for example BCG and rotavirus) in early infancy. Unusual vaccine adverse events could be the first signs of primary immune deficiencies (2,3,8,12,17); some authors have estimated the incidence of primary immune deficiencies from unusual systemic adverse events of live vaccines in early infancy (2). These complications may partly be the consequence of lack of standard newborn screening programs for primary immunodeficiency. ...
Article
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Introduction: There are increasing reports of serious adverse events of bacillus Calmette-Guerin (BCG) vaccination in infants with unrecognized primary immunodeficiency disorders (PIDs) in our country. Among these adverse events skin manifestations occur less frequently and are less noticed. Case Presentation: We report on an 11-months-old boy with prolonged fever and diffuse hyper pigmented subcutaneous nodules. Due to lymphopenia, oral thrush and severe adverse reaction to BCG vaccination, the possibility of primary immunodeficiency was considered for him and immunological investigations were done. Conclusions: Subcutaneous nodules in the absence of a local reaction at the site of BCG vaccination may be the sole manifestation of disseminated BCG disease.
... However, severer lesions caused by M. bovis BCG strains can be found in patients with immunodeficiency, who should be treated with a combination regimen of drugs, such as isoniazid, rifampin, ethambutol, and ciprofloxacin. (1, [3][4][5] The treatment of disease caused by BCG can be complicated by resistance to pyrazinamide, which is inherent to all strains of M. bovis, as well as by intermediate resistance of some strains to isoniazid and by the emergence of acquired resistance during inappropriate therapy. (5,6) ...
... Ethambutol was introduced after a literature review, which showed that this drug is introduced in severer forms of infection with M. bovis BCG. (1, [3][4][5] The infant was also referred to the department of ophthalmology for evaluation because of the risk of ethambutol-induced optic neuritis. In the second month of treatment, there was optic disc blurring bilaterally. ...
Article
Full-text available
We report a rare case in a female infant (age, 3.5 months) with primary immunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurative lymphadenitis after Mycobacterium bovis BCG vaccination. The strain of M. bovis BCG identified was found to be resistant to isoniazid and rifampin. The patient was treated with a special pharmacological regimen involving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, and IFN-γ, after which there was complete resolution of the lesions.
... However, severer lesions caused by M. bovis BCG strains can be found in patients with immunodeficiency, who should be treated with a combination regimen of drugs, such as isoniazid, rifampin, ethambutol, and ciprofloxacin. (1, [3][4][5] The treatment of disease caused by BCG can be complicated by resistance to pyrazinamide, which is inherent to all strains of M. bovis, as well as by intermediate resistance of some strains to isoniazid and by the emergence of acquired resistance during inappropriate therapy. (5,6) ...
... Ethambutol was introduced after a literature review, which showed that this drug is introduced in severer forms of infection with M. bovis BCG. (1, [3][4][5] The infant was also referred to the department of ophthalmology for evaluation because of the risk of ethambutol-induced optic neuritis. In the second month of treatment, there was optic disc blurring bilaterally. ...
Article
Full-text available
We report a rare case in a female infant (age, 3.5 months) with primary immunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurative lymphadenitis after Mycobacterium bovis BCG vaccination. The strain of M. bovis BCG identified was found to be resistant to isoniazid and rifampin. The patient was treated with a special pharmacological regimen involving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, and IFN-γ, after which there was complete resolution of the lesions. Resumo Relatamos um caso raro em uma lactente com três meses e meio de idade, portadora de imunodeficiência primária (defeito no eixo IFN-γ/IL-12), que apresentou linfadenite supurativa após a vacinação por Mycobacterium bovis BCG, cepa essa resistente a isoniazida e rifampicina. Após o tratamento com um esquema medicamentoso especial com isoniazida (de forma estratégica e limitada), etambutol, estreptomicina e IFN-γ, houve a cura completa das lesões. Descritores: Vacina BCG; Interferon gama; Tuberculose resistente a múltiplos medicamentos.
... Infants with PID might therefore receive BCG or OPV before receiving a diagnosis of PID, increasing the risk for disseminated mycobacterial disease and iVDPV infection. ZAP70 gene deficiency is very rare and manifests with typical clinical features of SCID early in life (8). Approximately one half of BCG-vaccinated SCID patients have developed BCGassociated manifestations (9). ...
Article
Oral poliovirus vaccine (OPV) has proven to be highly effective in the global effort to eradicate poliomyelitis because of its ability to induce both humoral and intestinal immunity, ease of administration, and low cost (1). Sabin-strain OPV contains live attenuated virus and induces immunity by replicating in the intestinal tract, triggering an immune response that clears the vaccine virus. However, among undervaccinated communities and persons with immunodeficiency, OPV mutations that arise during prolonged replication can result in the emergence of genetically divergent, neurovirulent vaccine-derived polioviruses (VDPVs). In addition, OPV has resulted in rare cases of vaccine-associated paralytic poliomyelitis (VAPP) among vaccine recipients or their close contacts (1). Identification of circulating polioviruses relies on surveillance of acute flaccid paralysis (AFP) and environmental surveillance of wastewater (i.e., sewage). In 2022, type 3 VDPV (VDPV3) was detected in stool specimens from an infant with primary immunodeficiency disorder (PID) through a pilot surveillance program to identify VDPVs in children with PIDs. Integrated AFP, environmental, and immunodeficiency-associated VDPV (iVDPV) surveillance is critical to detecting and containing all polioviruses and achieving the goal of global polio eradication.
... It is mostly associated with immunodeficiency, but can occur in healthy, immune-competent children. 13,[16][17][18] Various immunodeficiency conditions have been associated with increased susceptibility to disseminated mycobacterial infections. Those conditions are secondary immunodeficiency, primary immunodeficiencies such as SCID and CGD, hyper-IgM syndrome, and defects of the IL12-IFNγ axis (MSMD). ...
Article
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BACKGROUND Bacillus Calmette-Guérin (BCG) vaccine-related complications are frequently observed in children in Oman. There are a few regional studies on BCG complications, but none from Oman. OBJECTIVE Evaluate the spectrum of BCG-vaccine related complications and immune status in Omani children. DESIGN Retrospective cross-sectional study. SETTING Referral tertiary hospital. METHODS Children aged younger than 13 years old and with complications of BCG vaccination recorded from 2006-2018 were included in this study. Clinical characteristics, treatment, immune workup and outcome were reviewed from hospital records. MAIN OUTCOME MEASURES Different BCG vaccine-related complications categorized by the site of involvement. SAMPLE SIZE 226. RESULTS Of the 226 children had BCG-vaccine related complications, 99% received BCG vaccine immediately after birth. The median age of presentation was 4 months. The most common complication was isolated BCG lymphadenitis (85%, n=192), followed by BCG-related osteomyelitis (10.2%, n=23) and disseminated BCG infection (4.9%, n=11). The median age of presentation of disseminated BCG was 5 months, with different organs involved. Out of 11 children with disseminated BCG infection, 72.7% (n=8) had primary immune deficiency (PID), including chronic granulomatous disease (CGD, n=5), severe combined immunodeficiency (SCID) (n=2); 1 patient had Mendelian susceptibility to mycobacterial disease (IFNGR2 deficiency); 2 patients with PID not yet identified and the 1 with a non-specific PID had blood or saliva samples sent for whole-exome sequencing. CONCLUSION Because of the spectrum of BCG vaccine-related complications, including the most severe in children with PID, we suggest that delaying the BCG vaccine from birth to 6 months may prevent disseminated BCG diseases and their complications in children with PID because any PID will have been identified before 6 months. Further studies are needed to guide this recommendation. LIMITATIONS Single center-based study that may not provide a full overview of all BCG vaccine-related complications in Oman. Unavailability of details of some microbiological results and an inability to determine the detailed management for all patients. CONFLICT OF INTEREST None.
... It is mostly associated with immunodeficiency, but can occur in healthy, immune-competent children. 13,[16][17][18] Various immunodeficiency conditions have been associated with increased susceptibility to disseminated mycobacterial infections. Those conditions are secondary immunodeficiency, primary immunodeficiencies such as SCID and CGD, hyper-IgM syndrome, and defects of the IL12-IFNγ axis (MSMD). ...
Preprint
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BACKGROUND: BCG vaccine-related complication is frequently observed in children and it was not studied well in Oman. OBJECTIVE: To study the spectrum of BCG-vaccine related complications and immune status in Omani children. DESIGN: Retrospective observational study SETTING: This study was conducted in a tertiary hospital in Oman which gets a referral of cases from different Oman. This study covers a 12-year experience between 2006-2018. METHOD: Children less than 13 years of age who present or referred with complications of BCG vaccination. Clinical characteristics, treatment, immune workup, and outcome were reviewed from the hospital record. SAMPLE SIZE: A total of 226 children with complications related to the BCG vaccine MAIN OUTCOME MEASURES: Different BCG vaccine related complication were categorized according to the site of involvement. RESULTS: 226 children had BCG-vaccine related complications and 99% received BCG vaccine immediately after birth. The mean age of presentation was 6 months. The most common complication was isolated BCG lymphadenitis (85%). Then BCG related osteomyelitis (10.2%) and disseminated BCG infection (4.9%). Simple BCG lymphadenitis was managed conservatively and some of those with suppurative lymphadenitis required needle aspiration (37 patients: 60.7%). However, seventeen patients (8.9%) required surgery due to the persistence of lymph nodes beyond 6 months. BCG osteomyelitis required surgery and anti-TB medications which showed recovery except in one patient with persistent ankle deformity. The mean age of presentation of disseminated BCG was 9 months, different and variable organs were involved. Among patients with disseminated BCG infection, primary immune deficiency (PID) found in 82% (9/11 patients) including CGD, Severe Combined Immunodeficiency (SCID) and, Mendelian susceptibility to mycobacterial diseases (MSMD). CONCLUSION: considering delay the BCG vaccine from birth to 6 months will give time to diagnosed children with primary immune deficiency and will prevent these children from having disseminated BCG diseases with its own complication. LIMITATIONS: This is a single center based study which will not give a whole idea of all BCG related complication.
... Given the substantial role of the immune system in the development of complications after BCG vaccination, especially severe axillary lymphadenitis, and that BCG is injected at advanced ages, family history of immunodeficiency should also be taken into account. If the immune system of the infant is weak, the vaccination could be delayed (35). ...
Article
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Background: Lymphadenitis is the most common complication of BCG vaccination in children. Interferon-gamma (IFN-γ) plays a key role in immune response to Mycobacterial infections. In this study, the relationship of serum levels of IFN-γ and its receptor (CD119) to development of Bacillus Calmette Guerin (BCG) axillary lymphadenopathy was investigated. Materials and Methods: In this case-control study, 45 children with axillary lymphadenopathy and 45 healthy children matched by age and sex were included. Two ml peripheral blood was collected in tubes containing anticoagulants. Then, level of IFN-γ was measured by ELISA and the level of CD119 expression in the peripheral blood mononuclear cell (PBMC) was measured by flow cytometry. Data were analyzed using SPSS software version 22.0. Results: Totally, 90 children were enrolled in this study, which consisted of 30 girls and 60 boys. The mean age of participants was 14.5±6.5 months in case group and 15.2±7.1 months in control group, respectively (p=0.61). The level of IFN-γ was significantly lower in case group than in control group (p<0.001), but no significant difference was observed in PBMC percentage between the two groups (p>0.05). There was no significant relationship of age and sex to BCG (INF and PBMC) lymphadenopathy (p>0.05). Conclusion: Based on the results, IFN-γ level was significantly lower in the BCG lymphadenopathy group than in the control group. Levels of IFN-γR (CD119 cellular level in PBMC) in two groups did not show a significant relationship.
... Mutations in ZAP70 were identified initially in patients of Mennonite descent and subsequently in other ethnicities, including Hispanics, Japanese, Kurdish, Turkish, Portuguese, Caucasian, Mexican, Malagasy, and Iranian patients (3)(4)(5)(6)(7)(8)(9). World map of ZAP-70 deficient patients is available in Figure S1. ...
Article
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Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.
... laboratory tests and imaging and pathological reports of patients), was filled for all enrolled patients. Furthermore, based on the predominant presentation and infectious location of each patient, we grouped the infections into 6 main categories including upper respiratory infections (25), lower respiratory infections (26)(27)(28), gastrointestinal infections, skin infections, soft tissue infections, and severe or life-threatening infections (meningitis, sepsis, osteomyelitis) (23,29,30). ...
Article
Recurrent infections seem to be a common complaint in children who are referred to general practitioners and pediatricians offices. Detection of primary immunodeficiencies (PID) etiology is very important for achieving appropriate diagnosis and treatment of these patients. The absence of appropriate treatment could lead to subsequent complications, in a hospital inpatient and/or outpatient settings. This study was performed in a group of children with recurrent infections to identify patients with underlying PID. A cross-sectional study was designed to evaluate the final clinical diagnosis obtained in 100 pediatric patients with a history of recurrent infections referred to Children s Medical Center, Tehran, Iran, during one year (2011-2012). History taking and physical examination, complementary laboratory tests including immunological investigations were done to confirm the main causes of disease according to our previously published stepwise approach to recurrent infections. Among all studied patients, 21% (11 males and 10 females) were diagnosed to have PID. Parental consanguinity (p = 0.001) and soft tissue infections (p = 0.004) were significantly higher in PID group, comparing to other causes of recurrent infections. Gender and location of infections were also linked to the type of PID including antibody deficiency, combined immunodeficiency and phagocytosis disorders. The real rate of PID as a cause of recurrent infection appears to be much higher than what is generally considered in a se-lected group of pediatric patients; so, following the suggested stepwise guideline can im-prove timely diagnosis and appropriate treatment of these patients.
... Although the efficacy of BCG vaccine in the prevention of miliary or meningeal tuberculosis among children has been noted consistently, the use of BCG vaccine is not without risk (4). Patients with human immunodeficiency virus infection or primary immunodeficiency and immunocompromised hosts are prone to serious complications from this vaccine (5). Complications after BCG vaccine are include local reactions in 0% to 5% of recipients and systemic complications such as osteitis and disseminated infection. ...
... Although the efficacy of BCG vaccine in the prevention of miliary or meningeal tuberculosis among children has been noted consistently, the use of BCG vaccine is not without risk (4). Patients with human immunodeficiency virus infection or primary immunodeficiency and immunocompromised hosts are prone to serious complications from this vaccine (5). Complications after BCG vaccine are include local reactions in 0% to 5% of recipients and systemic complications such as osteitis and disseminated infection. ...
... Although the efficacy of BCG vaccine in the prevention of miliary or meningeal tuberculosis among children has been noted consistently, the use of BCG vaccine is not without risk (4). Patients with human immunodeficiency virus infection or primary immunodeficiency and immunocompromised hosts are prone to serious complications from this vaccine (5). Complications after BCG vaccine are include local reactions in 0% to 5% of recipients and systemic complications such as osteitis and disseminated infection. ...
Article
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Background: Although the efficacy of Bacillus Calmette-Guerin (BCG) vaccine in the prevention of tuberculosis has been noted consistently, the use of BCG vaccine is not without risk. In this study we aimed to evaluate immunologically, children with complication of BCG vaccination in North of Iran.Materials and Methods: This case-control study began in 30 Jan 2013 and was completed in 2 Jul 2015. In case group 35 patients with moderate to severe complications of BCG vaccination for Tuberculosis (TB), have been enrolled.Thecontrol group included 35 patients with mild complication and patients had no complications due to BCG vaccine. Routine and specific tests for evaluation of immunological function were performed.Results: Out of total number of 35 patients in case group, 3(8.6%) patients had severe complication, also they diagnosed as BCG-osis; 32(91.42%) cases had moderate symptoms‎. In the control group 25 (71.4%) patients had mild complications and 10(28.57%) patients had no complications. The mean of IL-23 level in the two groups had significant difference (P= 0.027). There was a significant relationship about interleukin and interferon deficiency among patients with severe complications. Patients with mild to moderate complications of BCG vaccine were not associated with immunodeficiency. Patients with severe complications of BCG vaccine, were associated with Mendelian susceptibility to mycobacterial disease (MSMD) primary ‎immunodeficiency (PID).Conclusion: Severe complications of BCG vaccine could be due to MSMD and it may be associated with immune ‎deficiency in IL 12/23.‎ BCG vaccination must be deferring in newborns in families with a history of death following presumed BCG or early death or recurrent infection, until suitable screening immunological tests exclude the PID.
... These include 7 autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and 2 X-linked (NEMO and CYBB) genes. [78][79][80][81][82] Thus, BCG is contraindicated in all these disorders. Because TB is a major problem in developing countries and in patients with HIV infection, there is great interest and need for an inactivated vaccine. ...
Article
Immunocompromised patients have increased susceptibility to vaccine-preventable infections. Thus, vaccination is a critical issue in this population. Vaccines are usually classified as live versus inactivated or subunit (nonviable) vaccines. In general, inactivated vaccines are safe in immunocompromised patients and should be given per the routine schedule except when they are unlikely to have any benefit as in severe antibody deficiency or combined immunodeficient patients and patients receiving immunosuppressive therapy or immunoglobulin replacement. However, viable vaccines usually carry the risk of causing disease, especially in severely immunocompromised patients. Therefore, much greater caution must be exercised with the use of viable vaccines and administration is individualized on the basis of the estimated risk of infections if not vaccinated versus the potential adverse effects of the vaccine itself. In this review, we make clear recommendations on the basis of available evidence regarding both routine and specialized vaccines, viable and nonviable, and the degree of immune compromise in all the categories of immunodeficiency disorders.
... Serious adverse events following BCG vaccination are likely to indicate immunodeficiency states. [8][9][10][11] Incidence of mild complications is said to be less than 1 per 1000 vaccinations whereas serious events like disseminated disease is less than 1 per million vaccinations. 12 Treatment options that have generally been taken in past for BCG adenitis include conservative follow up, anti-tubercular therapy, oral antibiotics mainly Erythromycin, needle aspiration, incision drainage and excision of lymphadenitis. ...
Article
Full-text available
BCG adenitis, the enlargement of regional lymph nodes after BCG vaccination is one of the common complications seen. BCG adenitis may present at varied time interval after the vaccine administration. Different medical and surgical treatment modalities have been reported for its management. We report our management experience of BCG adenitis seen over a period of 1 year.
... Cutaneous involvement is usually in the form of skin and subcutaneous nodules along with necrotic ulcers [3]. The condition is often fatal and is associated with immunodeficiency states like human immunodeficiency virus (HIV) infection, inherited immunodeficiency states like severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD) and in those with mutations in genes involved in regulation of interleukin-12-gamma interferon axis [4][5][6][7][8][9]. Disseminated BCG disease in the absence of immunodeficiency is termed as idiopathic [8]. ...
Article
Full-text available
A seven month old healthy male infant was brought with papular skin lesions all over the body, which became ulcerative with increasing fever and redness within 1 week duration. On examination, Bacilli Calmette Guerin (BCG) scar was ulcerated with discharge; infant was irritable with tachycardia and tachypnea. Investigations revealed pancytopenia, and acid fast bacilli was positive in skin lesions and at BCG scar site. There was progressive worsening of infant's condition, culminating in death.
... Thus, BCG vaccination should be delayed when a primary immunodeficiency is suspected and/or a newborn has a family history of primary immunodeficiency. Primary immunodeficiency such as IL-12/IFN-γ axis defects, granulomatous disease, severe combined immunodeficiencies (SCID) and idiopathic CD4 lymphopenia, increase the susceptibility of individuals to mycobacterial infections (Santos et al. 2010). ...
Article
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The introduction of vaccination worldwide dramatically reduced the incidence of pathogenic bacterial and viral diseases. Despite the highly successful vaccination strategies, the number of cases among vaccine preventable diseases has increased in the last decade and several of those diseases are still endemic in different countries. Here we discuss some epidemiological aspects and possible arguments that may explain why ancient diseases such as, measles, polio, pertussis, diphtheria and tuberculosis are still with us.
... The occurrence of BCG complication particularly disseminated BCG due to vaccine should alert the pediatrician to the possibility of PID [21]. Further efforts must be taken by increasing the coverage of Iranian PID registry via electronically registration and even referral system in order to estimate the PID and reduce the number of undiagnosed cases [22]. ...
Article
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There are considerable variations in the number of adverse reaction reports related to vaccine from different countries. The aim of this study was to review the development of adverse reactions to bacille Calmette-Guérin (BCG) vaccination among hospitalized patients in an Iranian referral hospital. We identified hospitalized patients with BCG complications in Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran during January 2007-April 2009. Data on demographics, clinical features, laboratory findings, personal history (including vaccination history), family history, and outcomes were retrieved from medical records. There were 46 cases with BCG complication during the 2 years period. All of the children received vaccination at birth. Twenty-eight patients (61%) were male. The mean age of the patients was 13.5 ±11.3 months (range, 1 to 52 months; median, 10 months). The majority of children (57%) with BCG complication were less than 1 year old. Among hospitalized patients due to BCG complications, suppurative lymphadenitis was occurred in 28 children (61%) and lymphadenopathy was seen in 9 children (20%). Disseminated BCG was detected in 8 patients (17%) and only 1 child (2%) was presented with abscess. In 7% (n = 3) of children, the family history of BCG complications were positive. The most common side effect of the BCG vaccine in our study was suppurative lymphadenitis. Disseminated BCG infection in complications leading to hospitalization in our study was 17%. With regard to the difficulty in implementing such a guideline in settings where BCG is given to all newborns, registration of Iranian primary immunodeficiency disorders (PID) patients would be helpful to increase the awareness of medical community of Iran to investigate underlying disease. In addition, BCG vaccination should postpone in each newborn with a family history of PID until the definite condition has been ruled out.
... CID may also be caused by a number of other genetic defects (72), some of which are associated with mycobacterial diseases in a small proportion of patients, implying a more modest susceptibility to mycobacterial infection. Two patients with ZAP70 deficiency were found to display BCG-itis (81). One patient with major histocompatibility complex class II deficiency had M. avium complex infection (82), and one patient had BCG-osis (73). ...
Article
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
... Biopsy specimen of lesions was also positive for BCG-PCR. According to the identification of Mycobacterium bovis, BCG substrain, from the patient's bone involvement by culture and standard PCR, as well as typical histopathologic changes with granulomatous inflammation, in addition to systemic symptoms and more than 2 areas of involvement beyond the site of BCG vaccination (hepatosplenomegaly and bone involvement) our patient fulfilled all diagnostic criteria of disseminated BCG infection (7,8). ...
Article
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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 with multi-focal fusiform painful swelling in his hands. He had undergone bone marrow transplantation 7 weeks before admission. Multidisciplinary management was done to treat this rare post-transplant occurrence of Bacillus Calmette-Guérin complication. Conclusions: BCG vaccination administrated routinely in Iran, given that of no screening program for primary immune deficiency currently achieved in our country, exact attention to reschedule of immunization programs in suspicious newborn (with primary immune deficiency) always is necessary and is one of the most effective strategy to prevent BCG complication.
... However, positive acid-fast bacilli smears or M tuberculosis complex cultures were found in some cases. Therefore, suspicion of M bovis infection should be based on the clinical history and physical examination, and the possibility of disseminated disease should be considered in any diagnosed case of SCID [33]. ...
Article
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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.
... However, positive acid-fast bacilli smears or M tuberculosis complex cultures were found in some cases. Therefore, suspicion of M bovis infection should be based on the clinical history and physical examination, and the possibility of disseminated disease should be considered in any diagnosed case of SCID [33]. ...
Article
Full-text available
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.
... Apesar disso, quase a totalidade dos pacientes com IDP atendidas na UNIFESP recebeu todas as vacinas recomendadas para sua idade pelo Ministério da Saúde (21) . Um médico clínico ou obstetra, no entanto, deve estar apto a orientar uma gestante com história familiar sugestiva de imunodeficiência (ID) para que a criança, ao nascer, tenha a vacinação por bacilo Calmette-Guérin (BCG) adiada, até que se defina sua imunocompetência (26) . ...
Article
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To evaluate medical knowledge of primary immunodeficiency in the city of São Paulo (SP). A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator. Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (±17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations). There is a deficit in medical knowledge of primary immunodeficiency in the city of São Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases.
... Regarding outcome, resolution was noted in 97% of the group with local complications (3% with residual lymphadenopathy) and zero mortality in contrast to 100% mortality in the disseminated group with underlying immune defects. Disseminated BCG related complications were suggested as an alert for underlying immune defects whether Human Immunodeficiency virus or primary immunodeficiencies [12]. ...
Article
Full-text available
Background: Bacillus Calmette ET Guerin (BCG) vaccine, compulsory in endemic areas, remains the only available vaccine for prevention of Tuberculosis (TB) despite its modest protective value. Complications may arise in healthy/ immunocompromized hosts. Methods: Children presenting with BCG vaccine related complications in the form of local/distant complications were enrolled from 2007-2010 at Cairo University Pediatric hospital. Objectives: assess outcome of BCG related complications in a group of children with post vaccination incidents, identify risk factors for complications among vaccinated children and identify cases of underlying Primary Immunodeficiency (PID) among presenting cases. Results: Fifty one eligible patients were included, forty three were proved immunocompetent, and eight had underlying primary immunodeficiency disorders. Presentations included localized axillary lymphadenopathy, cervical sinuses, granulomatous lesions and disseminated forms Faulty injection sites were strongly associated with complications (p value < 0.001).Patients without underlying PID had larger scar size and younger age at presentations (p values: 0.02, 0.0001 respectively).Resolution of lesions was observed in 97 % (95% CI 97% ± 3%) of cases without underlying PID versus fatal outcome in all cases with underlying immune defects. Conclusion: Local BCG related complications do not necessarily indicate underlying PID, disseminated complications are more serious and warrant further investigations. If PID is suspected, vaccination should be deferred to avoid its potentially fatal outcome.
... 3,-7 The incidence of regional lymphadenitis is variable ranging from as low as one in 10,000 to as high as 38 in 1000. 1,[7][8][9][10] The management of this complication is still controversial and varies from no treatment, surgical incision and drainage, surgical excision, administration of anti-tuberculous drugs or a combination of these. In Saudi Arabia, a national policy for vaccination was adopted and the BCG vaccine is administered to all newborns at birth. ...
Article
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To evaluate the safety of Bacillus Calmette-Guerin (BCG) in Saudi infants and outline our management for BCG related lymphadenitis. The records of infants who developed BCG related complications were retrospectively reviewed from March 2008 to March 2011 at the Maternity and Children Hospital, Dammam, Saudi Arabia for age, gender, birth weight, presentation, and outcome. All our patients were immunized with the BCG vaccine within 48 hours after birth, and the total number of vaccinated newborns was obtained from the vaccination registry. During a 3-year period (March 2008 to March 2011), 26,000 newborns received BCG and 81 (51 males and 30 females) developed complications. This gives an incidence of 3.12 complications/1000 newborns. Their presentations were: left axillary lymphadenitis (n=62), supraclavicular lymphadenitis (n=9), collection at immunization site (n=6), and one each (left cervical lymphadenitis, bilateral axillary lymphadenitis, left arm abscess, left axillary lymphadenitis and collection at immunization site). Two were immunocompromized and 6 with local collection were aspirated. The arm abscess had drainage. Simple lymphadenitis (n=6) were treated expectantly, while those with suppurative lymphadenitis (n=68) had excision (n=65) or incision and drainage (n=3) without anti-tuberculous treatment. Bacillus Calmette-Guerin is safe but is associated with a relatively high incidence of suppurative lymphadenitis. Non-suppurative lymphadenitis can be treated conservatively, while suppurative lymphadenitis should be treated with excision. This is safe, avoids rupture, and shortens the recovery period without anti-tuberculous treatment. Although, the use of BCG vaccine may be associated with side effects, the potential morbidity and mortality from tuberculosis outweighs that from BCG related complications.
... 10 It has been shown that some PIDs tend to remain undiagnosed until the appearance of the presumed complications, including BCGosis. 6,11 Meanwhile a number of PIDs are susceptible to severe mycobacterial disease following vaccination with BCG, including severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial diseases. 12 There are a number of reports that investigated underlying PIDs in those with disseminated BCG (Table 1). ...
Article
Full-text available
Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases.
... Although there are antibiotics for effectively treating TB, strains of Mycobacterium tuberculosis resistant to multiple drugs are increasing annually, compromising our ability to treat TB (5). The only available vaccine, an attenuated strain of Mycobacterium bovis Bacille Calmette-Guérin (BCG), is effective in preventing serious complications of TB in infants and small children, but this vaccine does not confer long-lasting immunity to infection (6,29,69), its efficacy in preventing TB in adults is variable, and the vaccine can cause disseminated disease in immunocompromised individuals (64). ...
Article
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Live recombinant attenuated Salmonella vaccine (RASV) strains have great potential to induce protective immunity against Mycobacterium tuberculosis by delivering M. tuberculosis antigens. Recently, we reported that, in orally immunized mice, RASV strains delivering the M. tuberculosis early secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens via the Salmonella type III secretion system (SopE amino-terminal region residues 1 to 80 with two copies of ESAT-6 and one copy of CFP-10 [SopENt80-E2C]) afforded protection against aerosol challenge with M. tuberculosis. Here, we constructed and evaluated an improved Salmonella vaccine against M. tuberculosis. We constructed translational fusions for the synthesis of two copies of ESAT-6 plus CFP-10 fused to the OmpC signal sequence (OmpCSS-E2C) and amino acids 44 to 338 of antigen 85A (Ag85A294) flanked by the signal sequence (SS) and C-terminal peptide (CT) of β-lactamase (BlaSS-Ag85A294-BlaCT) to enable delivery via the Salmonella type II secretion system. The genes expressing these proteins were cloned as an operon transcribed from Ptrc into isogenic Asd+/MurA+ pYA3681 lysis vector derivatives with different replication origins (pBR, p15A, pSC101), resulting in pYA4890, pYA4891, and pYA4892 for SopENt80-E2C/Ag85A294 synthesis and pYA4893 and pYA4894 for OmpCSS-E2C/Ag85A294 synthesis. Mice orally immunized with the RASV χ11021 strain engineered to display regulated delayed lysis and regulated delayed antigen synthesis in vivo and harboring pYA4891, pYA4893, or pYA4894 elicited significantly greater humoral and cellular immune responses, and the RASV χ11021 strain afforded a greater degree of protection against M. tuberculosis aerosol challenge in mice than RASVs harboring any other Asd+/MurA+ lysis plasmid and immunization with M. bovis BCG, demonstrating that RASV strains displaying regulated delayed lysis with delayed antigen synthesis resulted in highly immunogenic delivery vectors for oral vaccination against M. tuberculosis infection.
Article
Background: Lymphadenitis is the most common complication following BCG vaccination observed in 0.1% to 1% of children. Objectives: The presence of immunodeficiency can increase the probability of lymphadenitis or contribute to its exacerbation, so the early detection of immunodeficiency in those developing lymphadenitis can help prevent its many catastrophic complications. Methods: This study was performed on patients referred to Taleghani Hospital of Gorgan city in 1396. Forty children with lymphadenitis and 40 healthy children entered the study. Serum samples were taken to measure white blood cell counts and the antibodies, including IgE, IgG, IgM, and IgA. Purified protein derivative (PPD) test was done in both groups. Results: In this study, there were 40 patients with lymphadenitis, of whom 24 were boys (60%), and 16 were girls (40%), and in the control group were 22 boys (55%) and 18 girls (45%). There was no statistically significant difference between the two groups. Lymphadenitis was ipsilateral to the vaccine injection site in all 40 cases, and it was in the anterior axillary region in 82%. Abscess at the lymphadenitis site occurred in 25% of cases. The mean size of induration following PPD in the lymphadenitis group was larger than the control group (5.86 mm and 3.04 mm, respectively) (P = 0.004). There were five patients (12.5%) under one year of age with lymphopenia (lymphocyte count 3,000 >), but no lymphopenia was observed in the control group. The mean average IgA and IgM levels were different between the case and control groups (P = 0.001), (P = 0.016), respectively. There was no statistical difference in IgG and IgE levels between both groups (P = 0.92 and P = 0.762, respectively). Conclusions: This study shows that the size of indurations following PPD injection is higher in those with post-vaccination lymphadenitis. Although the probability of a primary immunodeficiency disorder in the cases of our study was low considering the normal immunoglobulin levels and CBC report, further studies with a larger sample size and more specific investigations, such as flow cytometry and specific antibody response, are needed.
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Purpose: In Mycobacterium tuberculosis endemic regions, BCG vaccine is administered early after birth to confer protection against severe form of tuberculosis disease. Previous reports suggest that BCG adverse events, even localized ones (BCGitis), can be the first manifestation of immunodeficiency. We investigated children with a history of BCGitis who needed drug treatment looking for possibly pathogenic variants in inborn errors of immunity genes (IEI-genes). Methods: Forty-four probands were evaluated. The exome sequences obtained by Next-Generation Sequencing were filtered for variants in the 344 IEI-genes described by the International Union of Immunological Societies (IUIS) and classified according to the recommendations of the American College of Medical Genetics. The identified candidate variants were validated by Sanger sequencing. Results: Out of the 44 probands, 36 were sporadic cases and 8 were familial cases. Thirty-one in 44 (70.5%) presented immunoallergic or other infectious clinical conditions besides BCGitis; 19 in 44 (43.2%) presented variants classified as pathogenic or likely pathogenic in 17 different IEI-genes, of which 35.3% were genes related to defects in intrinsic and innate immunity, including Mendelian Susceptibility to Mycobacterial Disease (MSMD) genes (IRF8, IFNGR1, JAK1, STAT1, TLR3 and TBK1). Remaining genes were distributed in another five IUIS classifications groups (CARD14, CFH, CHD7, FOXN1, NFAT5, NLRP3, NOD2, PMS2, STAT3, TNFRSF13B and TNFSF12). Conclusion: The high prevalence of pathogenic or likely pathogenic variants found in IEI-genes may be associated with BCGitis, which should be considered a sign of an inborn error of immunity.
Article
World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of Inborn Errors of Immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR-National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007-2019 was done. IEI were identified in n=52/90 (57.7%) patients presenting with BCG complications. Of these, n=13(14.4%) patients were diagnosed with Severe Combined Immune-deficiency, n=15(16.7%) with Chronic Granulomatous disease, n=19(21.1%) with Inborn errors of IFN-γ immunity, n=4(4.4%) with Combined immunodeficiency and n=1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.
Article
Evaluation of antibodies produced after immunization is central to immune deficiency diagnosis. This includes assessment of responses to routine immunizations as well as to vaccines administered specifically for diagnosis. Here, we present the basic concepts of the humoral immune response and their relevance for vaccine composition and diagnosis of immune deficiency. Current vaccines are discussed, including nonviable protein and glycoprotein vaccines, pure polysaccharide vaccines, polysaccharide-protein conjugate vaccines, and live agent vaccines. Diagnostic and therapeutic applications of vaccine antibody measurement are discussed in depth. Important adverse effects of vaccines are also presented.
Chapter
The assessment of humoral immune function is essential for the diagnosis of immune deficiency in the great majority of cases. An integral component of this assessment is the measurement of antibodies produced during intentional immunization. This includes routine infant and childhood vaccination, as well as the administration of boosters and additional vaccines in the process of immune deficiency diagnosis. This chapter discusses fundamental concepts in the humoral immune response in relation to the principles of vaccine antibody measurement. All general vaccine types in current use are discussed, including protein and glycoprotein vaccines, pure polysaccharide vaccines, and polysaccharide–protein conjugate vaccines. The current status of the practical diagnostic applications of measurement of antibody in response to the routinely used vaccines is presented in depth. Less commonly used vaccines will also be discussed briefly. Of course, vaccines are often also used therapeutically in immune deficient patients. This chapter also discusses indications and contraindications to routine immunization in this population.
Article
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.
Article
Bacille Calmette‐Guérin (BCG), a live attenuated vaccine prepared using Mycobacterium bovis, can prevent tuberculosis in children and is routinely administered to infants in China and many other countries. A serious complication following vaccination is disseminated BCG infection. The risk is greatly increased in patients with severe combined immunodeficiency disease (SCID), a syndrome characterized by deficiency of both humoral and cellular immunity. We report a case of disseminated BCG infection in an infant with SCID caused by two novel janus kinase 3 (JAK3) gene mutations.
Article
Caso clínico: niña de 10 años que presentaba lesiones cutáneas de diferentes características, de evolución tórpida y asintomáticas; la de mayor tamaño se localizaba en la cara externa del deltoides derecho en forma de placa eritematosa de 20 por 10 cm con bordes sobreelevados presentando en su centro micropápulas que coalescen dejando una zona de atrofia central. Esta había comenzado en etapa neonatal luego de la vacunación por el bacilo de Calmette y Guérin. Desde hacía tres años presentaba una segunda lesión más pequeña en cara externa de muslo derecho de similares características y otras de carácter múltiple en dorso con forma de micropápulas rojo vinosas. Los exámenes de valoración general fueron normales, al igual que la radiografía de tórax y de los miembros. El test de la tuberculina mostró una induración de 15 mm y las baciloscopias fueron negativas. La biopsia de la lesión de piel del deltoides mostró granulomas caseosos y las técnicas moleculares diagnosticaron Mycobacterium bovis atenuado. Con ese diagnóstico, recibió tratamiento antituberculoso por diez meses con buena tolerancia y con mejoría de las lesiones.
Article
A seven month old healthy male infant was brought with papular skin lesions all over the body, which became ulcerative with increasing fever and redness within 1 week duration. On examination, Bacilli Calmette Guerin (BCG) scar was ulcerated with discharge; infant was irritable with tachycardia and tachypnea. Investigations revealed pancytopenia, and acid fast bacilli was positive in skin lesions and at BCG scar site. There was progressive worsening of infant's condition, culminating in death.
Article
Background: Adverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a "red flag" for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients. Methods: Medical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria. Results: Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients. Conclusions: Our study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT).
Article
We report on a case of disseminated BCGitis with an unusual presentation in a 4-month-old infant revealing a syndrome of Mendelian susceptibility to mycobacteria due to a partial dominant mutation of the interferon gamma receptor 1 gene. Copyright © 2015. Published by Elsevier SAS.
Article
One of the actual problems for nowadays is tuberculosis’ sickness and death rate. Ukraine as well as other CIS countries is the countries with high rate of tuberculosis sickness – indicator for 100 k populations is more than 30 cases. The most difficult situation for tuberculosis is in Southeast Ukraine region. In period of years 2005-2013 total sickness rate was between 84,1 (2005 y.) and 70,9 (2013 y.) for 100k population, death rate – 25,3 and 18, 0 accordingly. Among children of age 0 month – 14 years old sickness rate is 9,3 (2011 y.) vs. 11, 1 (2013) cases for 100 k. children population. Annual risqué of children tuberculosis infection is 0,5 – 2,0 %. Analysis of unfavourable termination by tuberculosis of Donetsk region children let determinate that among dead children 80 % are unvaccinated children.
Article
We describe here a girl who was vaccinated at birth with BCG (Bacillus Calmette-Guerin) vaccine according to national immunization schedule in Poland. After the age of 2.5 m.o., she developed disseminated BCG infection. Primary immunodeficiencies (PID), such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), hyper IgM syndrome (HIGM), hyper IgE syndrome (HIES) were excluded. The diagnostic tests exploring IFN-gamma/IL-12 axis were performed. The 818del4, the most common basis of IFNGR1 deficiency was found.
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Pyrazinamide (PZA) is an effective antitubercular drug that becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by pyrazinamidase (PZase), encoded by mycobacterial pncA. A strong association was noted between the loss of PZase activity and PZA resistance. The causative organisms in extrapulmonary tuberculosis are rarely cultured and isolated. To detect pncA mutations in specimens from extrapulmonary tuberculosis as confirmative diagnosis of mycobacterial infection and alternative susceptibility test to PZA. Specimens were collected from clinically proven extrapulmonary tuberculosis. pncA was sequenced and compared with wild-type pncA. pncA from 30 specimens from 23 donors were successfully amplified (56.6% in specimens, 59% in donors). Six mutations in pncA were detected (20.0% in amplified specimens, 26.1% in specimen donors) at nucleotide positions of 169, 248 and 419. The mutation at position 169 results in substitution of aspartic acid for histidine, a possible allelic variation of M. bovis that have intrinsic PZA resistance. The mutation at position 248 changes proline into arginine and that at position 419, arginine into histidine. DNA-based diagnosis using pncA may be simultaneously useful for the early diagnosis of mycobacterial infection and the rapid susceptibility to PZA in extrapulmonary tuberculosis. A potential implication of pncA allelic variation at 169 might be suggested as a rapid diagnostic test for M. bovis infection or Bacille Calmette-Guérin (BCG) reactivation.
Article
Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency disease, which renders patients prone to recurrent severe infections in early childhood. Herein, we present a five-month-old boy with SCID who was referred to our center with recurrent diarrhea, respiratory infection and lymphadenopathy. Immunological studies showed hypogammaglobulinemia and low number of T-cells, which was compatible with the diagnosis of T- B+ SCID. An advanced cytomegalovirus pneumonitis was detected based on the results of lung necropsy. Cultures and polymerase chain reaction studies of bone marrow aspirates and spleen specimen were indicative of Mycobacterium bovis. This report emphasizes the importance of lymphadenopathy as a sentinel sign of immunological disorders. Underlying immunodeficiency diseases such as SCID should be considered in the differential diagnosis of an infant with infections and lymphadenopathy, particularly in the regions with routine national Bacillus Calmette-Guérin (BCG) vaccination.
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Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guerin (BCG) vaccine and environmental non-tuberculous,mycobacteria (NTM), has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the inter;fel on gamma receptor ligand-binding chain (IFNgR1), interferon gamma receptor signalling chain (IFNgR2), interleukin 12 p40 sllbunit (IL-12p40), and interleukin 12 receptor betal chain (IL-12Rb1) genes have been identified in a number of patients with disseminated BCG or NTM infection. Although genetically distinct, these conditions are immunologically related and highlight the Essential role of interferon gamma-mediated immunity in the control of mycobacteria in man.
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Stéphanie Boisson-Dupuis, Jacinta Bustamante, Jamila El-Baghdadi, Yildiz Camcioglu, Nima Parvaneh, Safaa El Azbaoui, Aomar Agader, Amal Hassani, Naima El Hafidi, Nidal Alaoui Mrani, Zineb Jouhadi, Fatima Ailal, Jilali Najib, Ismail Reisli, Adil Zamani, Sebnem Yosunkaya, Saniye Gulle-Girit, Alisan Yildiran, Funda Erol Cipe, Selda Hancerli Torun, Ayse Metin, Basak Yildiz Atikan, Nevin Hatipoglu, Cigdem Aydogmus, Sara Sebnem Kilic, Figen Dogu, Neslihan Karaca, Guzide Aksu, Necil Kutukculer, Melike Keser-Emiroglu, Ayper Somer, Gonul Tanir, Caner Aytekin, Parisa Adimi, Seyed Alireza Mahdaviani, Setareh Mamishi, Aziz Bousfiha, Ozden Sanal, Davood Mansouri, Jean-Laurent Casanova, Laurent Abel. (2015) Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. Immunological Reviews 264:10.1111/imr.2015.264.issue-1, 103-120 CrossRef I. Sologuren, S. Boisson-Dupuis, J. Pestano, Q. B. Vincent, L. Fernandez-Perez, A. Chapgier, M. Cardenes, J. Feinberg, M. I. Garcia-Laorden, C. Picard, E. Santiago, X. Kong, L. Janniere, E. Colino, E. Herrera-Ramos, A. Frances, C. Navarrete, S. Blanche, E. Faria, P. Remiszewski, A. Cordeiro, A. Freeman, S. Holland, K. Abarca, M. Valeron-Lemaur, J. Goncalo-Marques, L. Silveira, J. M. Garcia-Castellano, J. Caminero, J. L. Perez-Arellano, J. Bustamante, L. Abel, J.-L. Casanova, C. Rodriguez-Gallego. (2011) Partial recessive IFN- R1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds. Human Molecular Genetics 20, 1509-1523 CrossRef Guillaume Vogt, Ariane Chapgier, Kun Yang, Nadia Chuzhanova, Jacqueline Feinberg, Claire Fieschi, Stéphanie Boisson-Dupuis, Alexandre Alcais, Orchidée Filipe-Santos, Jacinta Bustamante, Ludovic de Beaucoudrey, Ibrahim Al-Mohsen, Sami Al-Hajjar, Abdulaziz Al-Ghonaium, Parisa Adimi, Mehdi Mirsaeidi, Soheila Khalilzadeh, Sergio Rosenzweig, Oscar de la Calle Martin, Thomas R Bauer, Jennifer M Puck, Hans D Ochs, Dieter Furthner, Carolin Engelhorn, Bernd Belohradsky, Davood Mansouri, Steven M Holland, Robert D Schreiber, Laurent Abel, David N Cooper, Claire Soudais, Jean-Laurent Casanova. (2005) Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nature Genetics 37, 692-700 CrossRef
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Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis.
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Bacille Calmette-Guérin (BCG)--a live, attenuated vaccine--is routinely given to neonates in settings where tuberculosis is endemic, irrespective of human immunodeficiency virus (HIV) exposure. HIV-infected infants and other immunodeficient infants are at risk of BCG-related complications. We report the presentation, treatment, and mortality of children who develop BCG disease, with emphasis on HIV-infected children. In addition, we present a revised classification of BCG disease in children and propose standard diagnostic and management guidelines. This retrospective, hospital-based study was conducted in the Western Cape Province, South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged <13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. Mortality was assessed at the end of the study period. BCG disease was diagnosed in 25 children; 22 (88%) had local disease, and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodeficient children. The proposed pediatric BCG disease classification reflects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIV-infected and HIV-uninfected children is essential.
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Primary immunodeficiency diseases (PIDs) represent a large and heterogeneous group of more than 120 different entities, most of which have now been genetically characterized (77). Increased susceptibility to infections is the predominant man- ifestation of almost all forms of PID, particularly in infants and children, demonstrating the paramount importance of the im- mune system in defense against infection. It has long been known that the nature of an immune defect is related to the etiology of an infection. Prime examples are recurrent respi- ratory infections with pyogenic bacteria in patients with anti- body deficiencies, opportunistic infections with fungi and viruses in infants with SCID (severe combined immunodefi- ciency), Neisseria meningitidis infections as a hallmark of de- fects in late-complement components, recurrent staphylococ- cal infections in patients with neutrophil disorders, and susceptibility to weakly virulent mycobacterial diseases and to Salmonella in patients with deficiencies of the interleukin-12 (IL-12)/IL-23-gamma interferon (IFN-) axis. Studies of PID patients have actually contributed to clarification of the anti- infection roles of several mechanisms and components of the immune response, as PIDs offer unique opportunities to link phenotypes to immunological functions and to ascribe various classes of immunity to defenses against different microbes. Thus, studies of agammaglobulinemic patients were crucial in elucidating the role of antibodies in immunity to extracellular bacteria and enteroviruses, as were studies of children with Kostmann's syndrome (congenital severe neutropenia) and chronic granulomatous disease (CGD) in defining the critical role of neutrophils and studies of SCID patients in showing the relevance of T-cell immunity in resistance to intracellular pathogens. More recently, as clinical phenotypes are being mapped to gene defects, respective pathophysiologies can be better understood, often with the help of murine knockout models. Here we offer an observational approach to host/parasite relationships, based on clinical features of PID patients. After an exhaustive review of the main infectious manifestations of PID patients described in large published series as well as in our own series, we propose a novel classification of PIDs ac- cording to the degrees of clinical susceptibility to infectious agents observed with PID patients, attempting to link selective susceptibility to specific mechanisms and to established genetic defects. Evidence for a causal association between a particular infection and a given PID is available in some cases, but in others, only a small number of patients have been studied. The data were organized in tables that classify susceptibility to each infection as high (when it is a major manifestation of disease), intermediate (when it appears in some cases but not as a rule), and low (when it is seldom seen). We believe that organizing available information in this manner may also be helpful for the physician, whose identification of a given infection may help determine a putative immunodeficiency.
Article
Selective susceptibility to weakly pathogenic mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a Mendelian disorder but its molecular basis remained elusive. Recently, mutations in the interferon-gamma receptor ligand-binding chain (IFN gamma R1), interferon-gamma receptor signaling chain (IFN gamma R2), Signal Transducer and Activator of Transcription-1 (STAT-1), interleukin-12 p40 subunit (IL-12 p40), and interleukin-12 receptor beta 1 chain (IL-12R beta 1) genes have been identified in a number of patients with severe BCG or NTM infection. Dominant or recessive alleles causing complete or partial cellular defects have been found to define nine different inheritable disorders. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man. The genetic and immunologic heterogeneity of this syndrome makes accurate diagnosis challenging but vital as decisions about the most appropriate treatment are best taken based on an accurate molecular diagnosis.
Article
BCG vaccination is mandatory in France before six years of age and for occupational exposure. It reduces by 80 % the risk of disseminated tuberculosis (meningitis and miliary forms) in infants and children. The spread of M. tuberculosis is not affected by BCG vaccination. The main adverse effects of BCG vaccination are adenitis (1/1000), osteitis and disseminated BCG infection in infants less than 6 months old with severe combined immunodeficiency (about 12 cases/year in France). The switch from the Mérieux BCG strain to the more immunogenic Copenhagen strain must be monitored for safety. The incidence of tuberculosis in France fell gradually from 1964 to 1997 and has now stabilized at about 10 cases per 100000 inhabitants per year. This apparent stability masks major disparities among districts and population groups, however. Migrants from highly endemic countries are the most at risk. In 2003 the incidence of tuberculosis was 5.6/105 in French-born people, 31.7/105 among North African immigrants and 187.7/105 among immigrants from sub-Saharan Africa. The incidence is higher than 10/105 in three French regions, namely the Paris area (26.4), Provence-Alpes-Côte d'Azur (10.8) and Alsace (10.3). The highest incidence is found among immigrants, with a rate of 114.3/105 in the Paris region (198.9/105 in Paris itself). France has met the UICTMR criteria regarding national BCG vaccination policy. The yearly rate of tuberculous meningitis is now less than 1/107 in children and has been steady since 1996. Four options are now conceivable : - To stop BCG vaccination : this would probably increase the rate of disseminated tuberculosis in infants and children (16 estimated) - To maintain universal vaccination : this is not theoretically justified for most children, given the current French epidemiological situation ; in addition, production of multipuncture BCG will be halted in 2006, to be replaced by the new intradermal BCG procedure, which is more difficult to administer to newborns and infants. - The third option is targeted BCG vaccination. The targets could be the three regions with the highest incidence, but it would only cover 55 to 85 % of cases and would omit 15 to 45 % of children at risk. - The best strategy is to target all children who are at an increased risk of tuberculosis (about 100000 children) because of exposure to potentially infectious adults (children with a personal or familial history of tuberculosis, families from highly endemic countries, and travellers to such countries). Targeted vaccination would be acceptable if the fight against tuberculosis were to be updated with the same rigor in every region.
Article
Vries for the Clinical Working Party of the European Society for Immunodeficiencies (ESID)* Department of Paediatrics, Jeroen Bosch Hospital (loc GZG),'s-Hertogenbosch, the Netherlands Summary Efficient early identification of primary immunodeficiency disease (PID) is important for prognosis, but is not an easy task for non-immunologists. The Clinical Working Party of the European Society for Immunodeficiencies (ESID) has composed a multi-stage diagnostic protocol that is based on expert opinion, in order to increase the awareness of PID among doctors working in different fields. The protocol starts from the clinical presentation of the patient; immunological skills are not needed for its use. The multi-stage design allows cost-effective screening for PID within the large pool of poten-tial cases in all hospitals in the early phases, while more expensive tests are reserved for definitive classification in collaboration with an immunologist at a later stage. Although many PIDs present in childhood, others may present at any age. The protocols presented here are therefore aimed at both adult phy-sicians and paediatricians. While designed for use throughout Europe, there will be national differences which may make modification of this generic algo-rithm necessary.
Article
Two infants, one with a T-cell-signaling defect resulting in a primary immunodeficiency syndrome and the other with severe combined immunodeficiency (SCID), are described. Both infants developed cutaneous infections secondary to their bacillus Calmette–Guérin (BCG) vaccinations. Both patients were from countries where BCG is routinely administered in infancy. The infant with the T-cell-signaling defect developed a disseminated infection involving the skin, while the infant with SCID developed a localized cutaneous infection at the site of his BCG immunization. These two cases resemble other reported cases of cutaneous BCG infection following routine vaccination in immunocompromised patients. Mycobacterium bovis infection should be considered in patients with cutaneous eruptions who have received BCG vaccination, especially those who are immunocompromised.
Article
Members of the European Society for Immunodeficiencies (ESID) and other colleagues have updated the multi-stage expert-opinion-based diagnostic protocol for non-immunologists incorporating newly defined primary immunodeficiency diseases (PIDs). The protocol presented here aims to increase the awareness of PIDs among doctors working in different fields. Prompt identification of PID is important for prognosis, but this may not be an easy task. The protocol therefore starts from the clinical presentation of the patient. Because PIDs may present at all ages, this protocol is aimed at both adult and paediatric physicians. The multi-stage design allows cost-effective screening for PID of the large number of potential cases in the early phases, with more expensive tests reserved for definitive classification in collaboration with a specialist in the field of immunodeficiency at a later stage.
Article
Nine children with immunodeficiency syndromes who developed persistent or disseminated Bacillus Calmette-Guérin (BCG) infections after BCG vaccination at birth were observed in Santiago, Chile, over a period of 10 years. This represents a risk for persistent or disseminated BCG infections of 3.4/1,000,000 vaccinated newborns. This may closely reflect the incidence of severe combined immunodeficiency syndromes, cellular immunodeficiency syndromes and chronic granulomatous disease in the study area. The clinical presentation and course of the infection varied considerably depending on the underlying immunodeficiency syndrome. Two patients with severe combined immunodeficiency presented with cutaneous nodules in the absence of any local reaction at the site of BCG vaccination. Both patients died of disseminated BCG infection within the first year of life. Four patients with cellular immunodeficiency syndromes presented with regional lymphadenitis resistant to treatment after the fifth month of life. Three of these patients had specific unresponsiveness to tuberculin and survived from 5 to 6 years of age. Two boys with X-linked chronic granulomatous disease presented with regional lymphadenitis in the first 3 months of life. A girl with autosomal recessive chronic granulomatous disease presented at 18 months of age with regional lymphadenitis. All three patients with chronic granulomatous disease had positive tuberculin reactions and died from infections other than BCG.
Article
The attenuated bacille Calmette-Guérin (BCG) vaccine is administered to prevent tuberculosis. Complications of vaccination are uncommon. We report a new case of disseminated BCG disease and review 27 additional cases identified from a review of >5,000 reports published between 1980 and 1996. Twenty-four of the 28 total cases were associated with an immune deficiency, including nine cases of AIDS. Seventy-one percent of the cases occurred in children younger than 2 years old. Sixty-eight percent of the patients were male. About one-half of the patients were vaccinated in a developed nation, but 85% of the cases were reported from a developed nation. Response to therapy was poor, with an overall mortality rate of 71%. We made two new observations. Disseminated BCG disease has historically been a disease of infants, but cases now occur in adults and older children coinfected with human immunodeficiency virus. Cases also occur after revaccination of individuals who were anergic following the initial administration of BCG vaccine. Disseminated BCG disease is an uncommon but devastating complication of vaccination that should be considered in the appropriate clinical setting. Immunocompromised infants and patients with late-stage AIDS are at greatest risk and respond poorly to standard therapies.
Article
Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin vaccine and environmental non-tuberculous mycobacteria, has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon-gamma-receptor receptor ligand-binding chain, interferon-gamma-receptor signalling chain, IL-12 p40 subunit and IL-12-receptor beta 1 chain genes have been identified in a number of patients with disseminated mycobacterial infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon-gamma-mediated immunity in the control of mycobacteria in man.
Article
Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.
Article
Interferon gamma receptor 1 (IFNgammaR1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFNgammaR1 deficiencies. We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form. We identified 22 patients with recessive complete IFNgammaR1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3.1 years [SD 2.5] vs 13.4 years [14.3], p=0.001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0.0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4.1 [SD 0.8] vs 2.0 [1.1], p=0.004), had shorter mean disease-free intervals (1.6 years [SD 1.4] vs 7.2 years [7.6], p<0.0001), and lower Kaplan-Meier survival probability (p<0.0001). M avium complex osteomyelitis was more frequent in dominant than in recessive patients (22/28 [79%] vs 1/8 [13%], p=0.002), and this disorder without other organ involvement arose only in dominant patients (9/28 [32%]). Disease caused by rapidly growing mycobacteria was present in more recessive than dominant patients (7/22 [32%] vs 1/38 [3%], p=0.002). Recessive complete and dominant partial IFNgammaR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases. A strong correlation exists between IFNGR1 genotype, cellular responsiveness to interferon gamma, and clinical disease features.
Article
Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.
Article
Tuberculosis is the leading cause of death from a curable infectious disease. On the basis of results of surveys of the prevalence of infection and disease assessments of the effectiveness of surveillance systems and death registrations there were an estimated 8.9 million new cases of tuberculosis in 2004 fewer than half of which were reported to public-health authorities and WHO. About 3.9 million cases were sputum-smear positive the most infectious form of the disease. The WHO African region has the highest estimated incidence rate (356 per 100 000 population per year) but the majority of patients with tuberculosis live in the most populous countries of Asia; Bangladesh China India Indonesia and Pakistan together account for half (48%) the new cases that arise every year. About 80% of individuals newly diagnosed with the disease every year live in the 22 most populous countries. (excerpt)
Article
Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders. Although genetically different, these conditions are immunologically related, as all result in impaired IL-12/23-IFN-gamma-mediated immunity. These disorders were initially thought to be rare, but have now been diagnosed in over 220 patients from over 43 countries worldwide. We review here the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-gamma circuit.
Article
A few known primary immunodeficiencies confer predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines (regional disease, known as BCG-itis, or disseminated disease, known as BCG-osis), or more virulent mycobacteria, such as Mycobacterium tuberculosis (pulmonary and disseminated tuberculosis). We investigated the clinical and genetic features of a 12-year-old boy with both recurrent BCG-osis and disseminated tuberculosis. The patient's phagocytic cells produced no O(2)(-). A hemizygous splice mutation was found in intron 5 of CYBB, leading to a diagnosis of X-linked chronic granulomatous disease. Chronic granulomatous disease should be suspected in all children with BCG-osis, even in the absence of nonmycobacterial infectious diseases, and in selected children with recurrent BCG-itis or severe tuberculosis.
Article
The world is witnessing an escalation of the tuberculosis (TB) epidemic, particularly in sub-Saharan Africa and South-East Asia. The problem has been compounded by the evolution of the human immunodeficiency virus pandemic, the increase in multidrug-resistant TB and the emergence of extensively drug-resistant TB. This has led to renewed interest in vaccines aimed at preventing tuberculosis. The current Bacille Calmette-Guérin (BCG) vaccine prevents the invasive complications of childhood tuberculosis, such as meningitis and miliary disease, but provides variable protection against adult pulmonary disease. This review discusses the history of the BCG vaccine, the reasons for its variable efficacy, protective immunity and TB, and the evolution of and obstacles to development of new candidate vaccines. Several new TB vaccines have demonstrated promising results in animal models; a number have gone into phase I clinical trials in humans, and it is anticipated that phase III trials will commence by 2009. Licensing of an effective new TB vaccine by 2015 is thus a possibility.
Other Well-defined Immunodeficiency Syndromes
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Disseminated bacille Calmette-Guerin disease after vaccination: case report and review
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