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Increase in Childhood Nontuberculous Mycobacterial Infections after BCG Coverage Drop - a Nationwide Population-Based Retrospective Study, Finland, 1995 to 2016
Abstract
Background:
Epidemiological data on childhood nontuberculous mycobacterial (NTM) disease is scarce and the protective effect of Bacillus Calmette-Guérin (BCG) vaccination remains debated. In 2006 the BCG policy in Finland changed from universal to selective. We aimed to study the effect of the BCG coverage decrease on the incidence of childhood NTM infections in Finland.
Methods:
We conducted a nationwide, population-based, retrospective study of NTM notifications recorded to the National Infectious Diseases Register between 1995 and 2016 and identified native-born children aged 0-4 years infected with NTM. Poisson log linear model was used to estimate the change in the incidence rate of cohorts born during universal or selective BCG policy between 1995 and 2015.
Results:
We identified 97 native-born children infected with NTM under the age of five (median age 27 months, female to male ratio 2:1). The most common species was Mycobacterium avium (N=69; 71%). The estimated incidence rates of NTM in universal-BCG and selective-BCG cohorts were 0.2 and 3.9 per 100,000 person-years, respectively. The incidence rate ratio of selective-BCG cohorts compared to universal-BCG cohorts was 19.03 (95% CI, 8.82-41.07, p<0.001).
Conclusions:
After the infant BCG coverage in Finland decreased, childhood NTM infections increased drastically. Since there is no other apparent cause for the increase, this indicates that BCG offers protection against childhood NTM disease. This observation adds to the understanding of childhood NTM epidemiology and might explain why the disease is emerging in some countries.
... NTM rarely cause disease except when immune function is impaired [3], elderly patients and chronic lung disease. However, some NTM are pathogenic, and recently there has been a reported increase in NTM lymphadenitis [4,5] and Buruli ulcers [6,7]. ...
... Absence of NTM sensitization was associated with higher efficacy of BCG against pulmonary and severe forms of tuberculosis in a systematic review [8]. Surprisingly, the discontinuation of universal BCG vaccination in these countries has seen an increase of NTM lymphadenitis in children, suggesting BCG was also protecting against NTM in that setting [4]. NTM appear to be immune modulators influencing host interactions in BCG efficacy, TB burden, and NTM disease. ...
... It is possible that BCG is protective against NTM colonisation. A twenty-year retrospective study of NTM notifications in children demonstrated increased odds of NTM disease when universal BCG vaccination was halted in Finland [4]. Therefore, BCG could also protect against colonisation. ...
There is inadequate understanding of the epidemiology of Non-Tuberculous Mycobacteria (NTM) among infants in high tuberculosis burden countries. The objective of this study was to document the incidence and diversity of NTM disease or colonisation in sputum specimens from infants with presumptive TB, the risk factors, and clinical characteristics, in a high TB and HIV burden setting in Western Kenya. A cohort of 2900 newborns was followed for 1–2 years to assess TB incidence. TB investigations included collection of induced sputa and gastric aspirates for culture and speciation by HAIN®, Tuberculin Skin Testing (TST), HIV testing, and chest radiography. The American Thoracic Society Criteria (ATS) were applied to identify NTM disease. Among 927 (32% of 2900) with presumptive TB, 742 (80%) were investigated. NTM were isolated from 19/742 (2.6%) infants. M. fortuitum was most frequently speciated (32%). Total person-time was 3330 years. NTM incidence was 5.7/1,000 person-years, 95% CI (3.5, 8.7). Infants diagnosed with TB were more likely to have NTM isolation (odds ratio 11.5; 95% CI 3.25, 41.0). None of the infants with NTM isolated met the criteria for NTM disease. The incidence of NTM isolation was comparable to similar studies in Africa. NTM isolation did not meet ATS criteria for disease and could represent colonisation. TB disease appears to be structural lung disease predisposing to NTM colonisation.
... Several studies also report that the increase in foreign-born TB cases is associated with a rise in the proportion of extrapulmonary TB (EPTB) [3,[5][6][7]. In the European region, EPTB has increased from 16,4% of all TB cases in 2002 to 22,8% in 2016 [6,8]. In the Netherlands, England, Australia and Norway, EPTB currently accounts for as much as 40% of all TB cases [1,2]. ...
... Histopathological findings suggestive of TB may support the EPTB diagnosis, but these are also present in other diseases including sarcoidosis and non-tuberculosis mycobacteria (NTM) infections. The incidence of NTM infections is also increasing in western countries [19][20][21][22]. Due to these diagnostic challenges, a definite diagnosis of EPTB is often difficult to obtain. ...
Background:
Extrapulmonary tuberculosis (EPTB) poses diagnostic challenges due to the paucibacillary nature of the disease. The immunochemistry-based MPT64 antigen detection test (MPT64 test) has shown promising results for diagnosing EPTB in previous studies performed in low-resource settings, with higher sensitivity than microscopy and culture. The aim of this study was to investigate the performance of the MPT64 test in a routine clinical setting in a high-income low TB prevalence country.
Methods:
Extrapulmonary samples sent for TB diagnostics to microbiology and pathology laboratories at three regional tertiary care hospitals in Norway in a one-year period were included and subjected to the MPT64 test in parallel to the routine TB diagnostic tests.
Results:
Samples from 288 patients were included and categorised as confirmed TB cases (n = 26), clinically diagnosed TB cases (n = 5), non-TB cases (n = 243) and uncategorised (n = 14), using a composite reference standard (CRS). In formalin-fixed biopsies, the sensitivity (95% CI) of the MPT64 test, microscopy, PCR-based tests pooled, and culture was 37% (16-62), 20% (4-48), 37% (16-62) and 50% (23-77), respectively, against the CRS. The MPT64 test showed a good positive predictive value (88%) and an excellent specificity (99, 95% CI 92-100) in formalin-fixed biopsies. In fine-needle aspirates, pus and fluid samples, the test performance was lower.
Conclusions:
The MPT64 test was implementable in pathology laboratories as part of routine diagnostics, and although the sensitivity of the MPT64 test was not better than culture in this setting, the test supplements other rapid diagnostic methods, including microscopy and PCR-based tests, and can contribute to strengthen the diagnosis of EPTB in formalin-fixed biopsies in the absence of culture confirmation.
... 11 Reports showed increase in NTM infection in children under 5 years of age after stopping universal neonatal BCG vaccination in various countries including Czech Republic, Sweden and Finland. [12][13][14][15] In Sweden and Finland where information of strains was reported, the most common strains were MAC or M. avium. 12,15 The effectiveness may vary between NTM diseases and species, age groups and BCG strain, however data from various countries show that there is an effect on the incidence of NTM infection in children. ...
... [12][13][14][15] In Sweden and Finland where information of strains was reported, the most common strains were MAC or M. avium. 12,15 The effectiveness may vary between NTM diseases and species, age groups and BCG strain, however data from various countries show that there is an effect on the incidence of NTM infection in children. 11 Interestingly, all children in this study were previously vaccinated with BCG, over 5 years of age and in cases where the organism was identified, M. haemophilum was identified as a causative organism. ...
Background:
Nontuberculous mycobacteria (NTM) lymphadenitis is an under-recognized entity, and data of the true burden in children are limited. Without a high index of suspicion, diagnosis may be delayed and microbiological detection is challenging. Here, we report a cluster of NTM lymphadenitis experienced in Korean children.
Methods:
Subjects under 19 years of age diagnosed with NTM lymphadenitis during November 2016-April 2017 and April 2018 were included. Electronic medical records were reviewed for clinical, laboratory and pathological findings. Information regarding underlying health conditions and environmental exposure factors was obtained through interview and questionnaires.
Results:
A total of ten subjects were diagnosed during 18 months. All subjects were 8-15 years of age, previously healthy, male and had unilateral, nontender, cervicofacial lymphadenitis for more than 3 weeks with no significant systemic symptoms and no response to empirical antibiotics. Lymph nodes involved were submandibular (n = 8), preauricular (n = 6) and submental (n = 1). Five patients had two infected nodes and violaceous discoloration was seen in seven subjects. Biopsy specimens revealed chronic granulomatous inflammation and acid-fast bacteria culture identified Mycobacterium haemophilum in two cases and NTM polymerase chain reaction was positive in two cases. Survey revealed various common exposure sources.
Conclusion:
NTM lymphadenitis is rare but increasing in detection and it may occur in children and adolescents. Diagnosis requires high index of suspicion and communication between clinicians and the laboratory is essential for identification of NTM.
... Other studies have also suggested an increase in the prevalence rates of NTM over the last four decades (29). Previous studies indicated that Bacille Calmette-Guérin (BCG) vaccination confers cross-protection against NTM, thus in countries without a nationwide BCG immunization program, a rise in NTM cases is expected (30)(31)(32)(33). However, BCG is compulsory for all newborns in China since 1978, and BCG coverage in Zhejiang Province in 2017 was more than 90% (34). ...
Background
As one of the high multi-drug resistance tuberculosis countries, it is critical for China to understand patterns of drug resistance to better formulate effective treatment regimens.
Methods
The anti-TB Drug resistance surveillance has been conducted in Zheijang Province in years 1999, 2004, 2008, 2013, and 2018 respectively. We compared the prevalence of DR-TB from the latest survey with that of the previous four surveys in terms of all four first-line anti-TB drugs. We also examined the prevalence of rifampin-resistant TB (RR-TB) between the last two surveys and routine surveillance data.
Results
Among 996 patients surveyed in 2018, the prevalence of RR-TB in new and previously treated TB cases was 2.5 and 4.3%, respectively. The prevalence of RR-TB among previously treated cases was much higher than for new cases in the four surveys from 1999 to 2013, while there was no significant difference between these groups in the 2018 survey. The percentage of TB cases resistant to fluoroquinolones in new patients was 3.8%. The prevalence of non-tuberculous mycobacteria increased over time; the prevalence of RR-TB among new cases slowly decreased. The prevalence of RR-TB in both new and previously treated TB cases from the latest two surveys was consistent with routine surveillance data.
Conclusions
This consistency between routine surveillance and periodic surveys for TB cases implies that with universal testing in Zhejiang Province, data from routine surveillance could be used instead of periodic surveys to improve access to timely and appropriate treatment for DR-TB. Levels of resistance were lower than whole-country and global estimates, further indicating the value of universal drug susceptibility testing.
... In pediatric patients, NTM usually manifests as lymphadenitis, which is most often of the cervical lymph nodes 2-6 . The most common age group affected by NTM lymphadenitis is children of 1-5 years of age, and the disease is often indolent 1,[7][8][9][10] . The annual incidence of NTM lymphadenitis has been reported to reach as high as 3.7 new cases per 100,000 children in children less than 5 years of age 1 . ...
Non-tuberculous mycobacterial (NTM) infection is an emerging infectious entity that often presents as lymphadenitis in the pediatric age group. Current practice involves invasive testing and excisional biopsy to diagnose NTM lymphadenitis. In this study, we performed a retrospective analysis of 249 lymph nodes selected from 143 CT scans of pediatric patients presenting with lymphadenopathy at the Montreal Children’s Hospital between 2005 and 2018. A Random Forest classifier was trained on the ten most discriminative features from a set of 1231 radiomic features. The model classifying nodes as pyogenic, NTM, reactive, or proliferative lymphadenopathy achieved an accuracy of 72%, a precision of 68%, and a recall of 70%. Between NTM and all other causes of lymphadenopathy, the model achieved an area under the curve (AUC) of 89%. Between NTM and pyogenic lymphadenitis, the model achieved an AUC of 90%. Between NTM and the reactive and proliferative lymphadenopathy groups, the model achieved an AUC of 93%. These results indicate that radiomics can achieve a high accuracy for classification of NTM lymphadenitis. Such a non-invasive highly accurate diagnostic approach has the potential to reduce the need for invasive procedures in the pediatric population.
... While the primary use of BCG is for the prevention of tuberculosis [24], there is increasing evidence that BCG vaccination provides protection against non-tuberculous mycobacteria (NTM) infections; this includes resurgence of such infections after discontinuation of BCG [25][26][27]. BCG protection also extends to leprosy [28] and Buruli's ulcer [29]. This is unsurprising as BCG, a live attenuated vaccine, shares epitopes with mycobacteria other than M. tuberculosis [30]. ...
BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.
... The primary use of BCG is for the prevention of tuberculosis (152). There is increasing evidence that BCG provides protection against NTM infections (153)(154)(155). This extends to leprosy (156). ...
This article prosecutes a case against the zoonotic pathogen Mycobacterium avium ss. paratuberculosis (MAP) as a precipitant of Alzheimer’s disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne’s disease; in humans, it is the putative cause of Crohn’s disease. Beyond Crohn’s, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson’s disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.
... forma universal a la basada en grupos de riesgo, con lo que la cobertura de vacunación disminuyó de 98 a 6%.45 En Suiza, luego de descontinuar la aplicación universal de la BCG en 1975, la incidencia de casos de enfermedad por MNT aumentó de 0.06 a 5.7 casos por 100,000 habitantes.46 ...
Artículo de revisión IntroduccIón El género Mycobacterium comprende más de 170 especies, las cuales se pueden clasificar en tres grupos de importancia clínica: 1) el complejo Myco-bacterium tuberculosis (M. bovis, M. africanum, M. microti, M. canetti, M. caprae, M. pinnipedii, M. suricattae y M. mungi); 2) micobacterias que causan lepra (M. leprae y M. lepromatosis); y 3) micobacte-rias atípicas o no tuberculosas (MNT). 1 Las MNT son en su mayoría no patógenas; sin embargo, pueden llegar a causar enfermedad en el humano. 2 Comparten características antigénicas con el complejo M. tuberculosis, por lo que inducen una respuesta inmune y un cuadro clínico similar al ocasionado por éste. Sin embargo, diferenciar entre un proceso ocasionado por MNT y uno causado por M. tuberculosis es importante, ya que el tratamiento es distinto. 3 De acuerdo con reportes epidemiológicos, la enfermedad causada por MNT ha aumentado en los últimos 20 años, aunque la información disponible en cuanto a los menores de 15 años es escasa. La presente revisión comprende la epidemiología y el efecto de la vacunación universal con la vacuna BCG, así como una descripción de la presentación clínica y la aproximación diagnóstica y terapéutica en niños. EpIdEmIología La enfermedad causada por MNT no es de declara-ción epidemiológica obligatoria en la mayoría de los países, por lo que la información exacta sobre ella y su distribución geográfica es difícil de determinar con precisión. La transmisión persona-persona se ha reportado en casos de fibrosis quística, aunque es poco frecuente, por lo que se acepta que los reservorios naturales o Financiamiento: Ninguno. Conflicto de intereses: Ninguno. Este artículo puede ser consultado en versión completa en Resumen Las micobacterias se pueden clasificar en tres grupos de relevancia clínica; de ellos, las micobacterias no tuberculosas comprenden un grupo heterogéneo que puede ocasionar enfermedad en el humano. Los carga real de enfermedad por este grupo de micobacterias se desconoce, aunque de acuerdo con algunas series parece haber aumentado en los últimos 20 años. Diferenciar entre un proceso relacionado con M. tuberculosis y uno con micobacterias no tuberculosas es imperativo, ya que los esquemas de tratamiento son diferentes. En niños, la información es escasa, por lo que la presente revisión tiene como objetivo orientar al clínico en el abordaje diagnóstico-terapéutico de estos casos. Palabras clave: Micobacterias no tuberculosas, tratamiento, micobacteriosis pulmonar. Nontuberculous mycobacterial infection in children AbstrAct Mycobacteria can be classified into three groups of clinical relevance, of which nontuberculous mycobacteria comprise a heterogeneous group that can cause disease in humans. The actual burden of disease is unknown, although according to some series it seems to have increased in the last 20 years. Differentiating between a process related to M. tuberculosis and one related to nontuberculous mycobacteria is mandatory, since the treatment schemes are different. In children, information is scarce; therefore, the present review aims to guide the clinician in the diagnostic-therapeutic approach of these cases.
... Similarly, in a large retrospective population-based study in Finland, where BCG policy changed from universal to selective vaccination strategy in 2006, childhood NTM infections increased drastically, with an incident rate ratio of 19.03 (95% CI 8.8-41.07; P < 0.001) (98). These population-based studies support the hypothesis that BCG offers cross-protection against NTM disease in humans. ...
First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.
... cine, has demonstrated cross-reactive immune responses against M. avium in both human PBMC and mouse lymphocytes 51 , and is protective against challenge with M. avium in mice [52][53][54] . Furthermore, retrospective epidemiological evidence from Finland suggests that cessation of universal BCG administration in infants across the nation has coincided with a significant increase of NTM infection and disease in children 55 . Route of administration of BCG is an active and promising area of research, including the exciting publication by P. A. Darrah and colleagues whereby intravenous (i.v.) and intradermal (i.d.) BCG immunizations in nonhuman primates were evaluated for efficacy against Mtb challenge 56 . ...
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. An immunocompromised host status, either genetically or acutely acquired, presents a large risk for progressive NTM infections. Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models. We optimized an aerosol challenge model using a clinical NTM isolate: M. avium 2-151 smt, observed bacterial growth kinetics, colony morphology, drug sensitivity and histopathology, characterized the influx of pulmonary immune cells, and confirmed the immunogenicity of ID91 in both mouse models. To determine prophylactic vaccine efficacy against this M. avium isolate, mice were immunized with either ID91 + GLA-SE or bacillus Calmette–Guérin (BCG). Immunocompromised Beige mice displayed a delayed influx of innate and adaptive immune cells resulting in a sustained and increased bacterial burden in the lungs and spleen compared to C57BL/6 mice. Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM.
... In 2006, the BCG policy changed from universal at birth to selective vaccinations of children at high TB risk only [12]. Consequently, the BCG coverage of infants dropped from more than 98% to an estimated 6-10% and the ensuing birth cohorts have grown up predominantly without BCG protection [13,14]. Simultaneously, immigration from countries with high TB incidence has caused a major transition of TB morbidity from the old indigenous to the young foreign-born population [11]. ...
Introduction
In 2006, the Bacillus Calmette–Guérin (BCG) vaccination policy in Finland changed from universal to selective.
Aim
We assessed the impact of the policy change on tuberculosis (TB) morbidity in children under 5 years and epidemiological trends of paediatric TB in Finland.
Methods
We conducted a nationwide, population-based, retrospective registry study of all newly diagnosed active TB cases younger than 15 years in Finland from 1995 to 2015 by linking data from the National Infectious Diseases Register, Finnish Care Register for Health Care, medical patient records and Finnish Population Information System. We compared the TB incidence rate ratio of under 5 year-olds with universal and selective BCG vaccinations with a Poisson log-linear model and analysed incidence trends among those younger than 15 years with a negative binomial model.
Results
We identified 139 paediatric TB cases: 50 native (including 24 second-generation migrants) and 89 foreign-born children. The TB rate of under 5 year-olds remained stable after changing to selective BCG vaccination (incidence rate ratio (IRR): 1.3; 95% confidence interval (CI): 0.7–2.3). TB rate in the native population under 15 years increased slightly (IRR = 1.06; 95% CI: 1.01–1.11).
Discussion
Paediatric TB cases in Finland were concentrated in families with migrant background from high-TB incidence countries. The native TB morbidity in under 5-year-olds did not increase after the BCG policy revision, suggesting that selective vaccinations can prevent TB in the most vulnerable age group in low-incidence settings. Second-generation migrants under 15 years in Finland with high TB risk are probably increasing.
... Interestingly, a recent report indicated that BCG given intravenously to macaques provided much greater protection against TB [64]. There is increasing but largely epidemiologic evidence that BCG may also provide protection against NTM infections [65][66][67][68][69][70]. Thus, BCG has the potential to protect against NTM such as MAP and perhaps help prevent the initiation or exacerbation of autoimmune diseases that may be associated with them. ...
Sjogren’s syndrome (SS) is a common, systemic autoimmune disorder primarily affecting the exocrine glands resulting in xerostomia and xerophthalmia. SS may also manifest with polyarthralgia, polyarthritis, polymyalgia, cutaneous/other organ vasculitis, interstitial lung disease, and/or various other disorders. The primary autoantibodies associated with SS and used as adjuncts to diagnosis are anti-Ro (SSA) and anti-La (SSB). The pathogenesis of SS is considered to involve genetic susceptibility and environmental triggers. An identified genetic susceptibility for SS lies in variants of the tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene, the product of which is known as A20. Deficiency or dysfunction of A20 is known to induce macrophage inflammatory response to mycobacteria, potentially increasing the repertoire of mycobacterial antigens available and predisposing to autoimmunity via the paradigm of molecular mimicry; i.e., providing a mechanistic link between genetic susceptibility to SS and exposure to environmental non-tuberculous mycobacteria (NTM). Mycobacterium avium ss. paratuberculosis (MAP) is an NTM that causes Johne’s disease, an enteritis of ruminant animals. Humans are broadly exposed to MAP or its antigens in the environment and in food products from infected animals. MAP has also been implicated as an environmental trigger for a number of autoimmune diseases via cross reactivity of its heat shock protein 65 (hsp65) with host-specific proteins. In the context of SS, mycobacterial hsp65 shares epitope homology with the Ro and La proteins. A recent study showed a strong association between SS and antibodies to mycobacterial hsp65. If and when this association is validated, it would be important to determine whether bacillus Calmette-Guerin (BCG) vaccination (known to be protective against NTM likely through epigenetic alteration of innate and adaptive immunity) and anti-mycobacterial drugs (to decrease mycobacterial antigenic load) may have a preventive or therapeutic role against SS. Evidence to support this concept is that BCG has shown benefit in type 1 diabetes mellitus and multiple sclerosis, autoimmune diseases that have been linked to MAP via hsp65 and disease-specific autoantibodies. In conclusion, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and SS, including the presence of antibodies to mycobacterial hsp65 in SS, the homology of hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or anti-mycobacterial therapeutics should be studied in SS.
... In 2013, a nearly six-fold increase in NTM cases were reported in America compared to the 1980s (Donohue and Wymer, 2016), with similar trends in the United Kingdom, Denmark, and Germany (Ratnatunga et al., 2020). Some studies have attributed this rise of NTM infections to a vaccination policy change from a blanket BCG vaccination to a limited vaccination only for specific groups (SAGE Working Group of BCG Vaccines and WHO Secretariat, 2017; Kontturi et al., 2018). ...
Mycobacterial disease is an immense burden worldwide. This disease group includes tuberculosis, leprosy (Hansen’s disease), Buruli Ulcer, and non-tuberculous mycobacterial (NTM) disease. The burden of NTM disease, both pulmonary and ulcerative, is drastically escalating globally, especially in developed countries such as America and Australia. Mycobacteria’s ability to inhibit or evade the host immune system has contributed significantly to its continued prevalence. Pre-clinical studies have highlighted promising candidates that enhance endogenous pathways and/or limit destructive host responses. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents, small molecules, and autophagy-activating vaccines may be beneficial in restricting intracellular mycobacterial infection, even with multidrug-resistant strains. This review will examine how mycobacteria evade autophagy and discusses how autophagy could be exploited to design novel TB treatment strategies, such as host-directed therapeutics and vaccines, against Mycobacterium tuberculosis and NTMs.
... It remains unclear whether this represents a true increase or reflects increased awareness and/or improvements in diagnostic methods [6]. The possible protective effect of bacille Calmette-Guerin (BCG) vaccination against NTM remains under debate and cessation of universal vaccination over past decades in most European countries has been pointed out as one of the contributing factors for the increase of NTM infections [7,8]. ...
Nontuberculous mycobacterial lymphadenitis often presents a diagnostic challenge. This study aimed to evaluate the role of fine-needle aspiration cytology in the diagnosis of nontuberculous mycobacterial lymphadenitis in children. We conducted a retrospective review of fine-needle aspiration cytology performed in patients < 17 year-old with subacute lymphadenitis from 2003 to 2016 in a tertiary hospital in Spain. Confirmed nontuberculous mycobacterial lymphadenitis (isolation of nontuberculous mycobacterial in culture from fine-needle aspiration cytology or biopsy samples) and probable nontuberculous mycobacterial lymphadenitis (“granulomatous inflammation” in cytopathologic examinations from fine-needle aspiration cytology or biopsy and clinical-epidemiological history compatible with nontuberculous mycobacterial) were selected. Forty-one patients with nontuberculous mycobacterial lymphadenitis were included: 14 confirmed and 27 probable. Fine-needle aspiration cytology was done in all of them. For 34 patients with excised lymphadenopathy, cytopathology from fine-needle aspiration cytology was concordant with biopsy in 100% cases. Culture results were available from 78.0% (32/41) of patients with fine-needle aspiration cytology and from 85.3% (29/34) with excisional biopsy. Among 22 patients with microbiological results from fine-needle aspiration cytology and biopsy, fine-needle aspiration cytology allowed advanced results in concordance with biopsy or with positive isolation not found in biopsy in 90.1% (20/22) of patients. Sensitivity of nontuberculous mycobacterial cultures obtained by fine-needle aspiration cytology compared to biopsy was 45.5% vs. 36.4% (p = 0.07). Two patients with previous skin alterations presented fistulas after fine-needle aspiration cytology (4.9%); no other complications were described.
Conclusion: Fine-needle aspiration cytology provides quick cytopathologic information and is an accurate and safe technique for the diagnosis of nontuberculous mycobacterial lymphadenitis, especially in cases with challenging work-up.What is Known:
• Nontuberculous mycobacterial (NTM) infection is an important cause of subacute lymphadenitis in children.
• Fine-needle aspiration cytology (FNAC) is an available technique for the diagnosis of lymphadenitis of unknown etiology.
What is New:
• FNAC is an accurate and safe technique for the diagnosis of NTM lymphadenitis in children.
• FNAC can provide reliable samples for cytopathological studies and even a better sensitivity for microbiological culture than excisional biopsy in the study of suspected NTM lymphadenitis.
... Because such environmental factors are comparatively restricted, it may be possible to investigate causality for the major changes having affected this part of the population. Such factors include increased intake of vitamin D after the policy-based fortification of milk products with vitamin D since 2002 and a doubling of the fortification dose in 2010 (20)(21)(22), decreased Calmette-Guérin vaccine coverage (from .98% to 6%) after changes in the National Immunization Program in 2006 regarding the vaccine's target population (23,24), decreased exposure to rotavirus infections after commercial availability of the rotavirus vaccine since 2006 and introduction of the vaccine to the National Immunization Program in 2009 (25)(26)(27)(28)(29)(30), and increased use of peroral probiotics by infants and young children during the study period (31)(32)(33). ...
Objective:
The incidence of type 1 diabetes has been rising for decades, particularly among young children. Between 2006 and 2011, the incidence rate (IR) reached a plateau in Finland. In this observational, register-based cohort study, we assess recent trends in the disease rate in Finnish children.
Research design and methods:
Based on data from the Finnish Pediatric Diabetes Register, we studied the incidence of type 1 diabetes among children younger than 15 years of age between 2003 and 2018. We assessed sex-specific IRs per 100,000 person-years (PY) by 4-year time periods in three age-groups (0.50-4.99, 5.00-9.99, and 10.00-14.99 years).
Results:
Among the 7,871 children with newly diagnosed type 1 diabetes, the median age at diagnosis increased from 7.88 to 8.33 years (P = 0.001), while the overall IR decreased from 57.9/100,000 PY in 2003-2006 to 52.2/100,000 PY in 2015-2018, yielding an IR ratio (IRR) of 0.90 (95% CI 0.85-0.96, P = 0.001). This decline was mainly due to the decrease in the youngest age-group (IRR 0.77 [95% CI 0.68-0.87]; P < 0.001), being significant both among boys and girls. In the middle age-group, a significant decrease was observed only among girls. No changes were observed in the oldest children.
Conclusions:
The incidence of type 1 diabetes decreased among young Finnish children between 2003 and 2018. Current findings imply that environmental factors driving the immune system toward islet autoimmunity are changing in young children.
... Interestingly previous studies had observed a reduction in the number of pulmonary NTM and TB cases in several countries after the implementation of national BCG vaccination policy. This suggests that BCG confers cross-protection against NTM, and in countries without a nationwide BCG immunization program, a rise in NTM cases is expected [82][83][84][85]. Importantly, unlike TB, pulmonary NTM infections are more prevalent in women (59%) and the elderly (median age 66) than younger men, with MAC being the most common NTM species [13]. ...
Pulmonary diseases due to mycobacteria cause significant morbidity and mortality to human health. In addition to tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Although more than 170 NTM species are present in various environmental niches, only a handful, primarily Mycobacterium avium complex and M. abscessus, have been implicated in pulmonary disease. While TB is transmitted through inhalation of aerosol droplets containing Mtb, generated by patients with symptomatic disease, NTM disease is mostly disseminated through aerosols originated from the environment. However, following inhalation, both Mtb and NTM are phagocytosed by alveolar macrophages in the lungs. Subsequently, various immune cells are recruited from the circulation to the site of infection, which leads to granuloma formation. Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to Mtb and NTM infections are different. Striking differences also exist in the disease presentation between TB and NTM cases. While NTM disease is primarily associated with bronchiectasis, this condition is rarely a predisposing factor for TB. Similarly, in Human Immunodeficiency Virus (HIV)-infected individuals, NTM disease presents as disseminated, extrapulmonary form rather than as a miliary, pulmonary disease, which is seen in Mtb infection. The diagnostic modalities for TB, including molecular diagnosis and drug-susceptibility testing (DST), are more advanced and possess a higher rate of sensitivity and specificity, compared to the tools available for NTM infections. In general, drug-sensitive TB is effectively treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics. However, the treatment of drug-resistant TB requires the additional, newer class of antibiotics in combination with or without the first and second-line drugs. In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical and not entirely successful. In general, the treatment duration is much longer for NTM diseases, compared to TB, and resection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotics treatment. Here, we discuss the epidemiology, diagnosis, and treatment modalities available for TB and NTM diseases of humans.
... Secondly, evidence suggests there is increasing incidence of childhood NTM disease. A nationwide, populationbased study showed a significant increase in childhood NTM infection following a change in national policy on BCG vaccination from "universal" to "selective" (113). This study suggests that while BCG may provide some degree of protection to children from NTM infection, unvaccinated children, and other populations with respiratory deficits like CF could be a susceptible to this disease. ...
The incidence and number of deaths from non-tuberculous mycobacterial (NTM) disease have been steadily increasing globally. These lesser known “cousins” of Mycobacterium tuberculosis (TB) were once thought to be harmless environmental saprophytics and only dangerous to individuals with defective lung structure or the immunosuppressed. However, NTM are now commonly infecting seemingly immune competent children and adults at increasing rates through pulmonary infection. This is of concern as the pathology of NTM is difficult to treat. Indeed, NTM have become extremely antibiotic resistant, and now have been found to be internationally dispersed through person-to-person contact. The reasons behind this NTM increase are only beginning to be elucidated. Solutions to the problem are needed given NTM disease is more common in the tropics. Importantly, 40% of the world's population live in the tropics and due to climate change, the Tropics are expanding which will increase NTM infection regions. This review catalogs the global and economic disease burden, at risk populations, treatment options, host-bacterial interaction, immune dynamics, recent developments and research priorities for NTM disease.
... Mycobacteria are commonly divided into Mycobacterium tuberculosis complex, which causes tuberculosis (TB), and nontuberculous Mycobacteria (NTM), which cause opportunistic lung diseases in patients with pre-existing pulmonary disease and/or mild to severe immunosuppression. Over the past three decades, NTM detection has increased in clinical laboratory, probably due to both improved culture techniques and the actual increase in NTM incidence (Johnson and Odell, 2014;Kontturi et al., 2018). Unlike TB, the detection of NTM in pulmonary specimen does not always denote the disease itself since NTM are common environmental germs. ...
Objectives
Aspergillus and Mycobacterium are opportunistic pathogens that can cause severe pulmonary diseases. To date, the clinical significance of their concomitant isolation and potential interactions in the lung remains poorly understood. The aim of this study was to assess the prevalence of their concomitant isolation from respiratory samples, and to depict the related clinical and microbiological characteristics.MethodsA retrospective monocentric study was conducted from January 2011 to December 2017, including all in-patients from whom positive cultures of Aspergillus and Mycobacterium were obtained on respiratory samples within a 3-month period. Clinical, radiological and laboratory data were analyzed. Patients were categorized by a clinical and microbiological committee as “infected” or “colonized” by both pathogens according to current guidelines.ResultsOverall, 140 patients had ≥1 respiratory samples positive for Mycobacterium and concomitantly sent for fungal culture, and 708 were positive for Aspergillus, concomitantly sent for mycobacterial culture. Only 50 had at least one positive culture for both Mycobacterium sp. and Aspergillus sp. Men represented 63% of patients, mean age was 61 years. A third of patients were immunocompromised and 92% had underlying lung diseases. Aspergillus was primarily found as a colonizing agent. Proportion of Mycobacterium Avium Complex (p = 0.02) was higher in patients co-carrying Aspergillus spp.Conclusion
In this first study focusing on co-isolation of Mycobacteria and Aspergillus in patient’s respiratory samples, co-infection remains rare. Further studies are warranted in order to precise the exact relationship between these opportunistic pathogens and the clinical impact of co-isolations.
... In toddlers, it is likely that NTM infect the cervical LNs via gingival tears that are caused by tooth eruption [5], theoretically enabling NTM entry into tissues drained by the cervical LNs after oral exposure to NTM-laden dirt or tap water. Adaptive immunity is required for children to resist NTMI, as evidenced by the accelerated progression of NTMI in children with human immunodeficiency virus infection and low circulating CD4 + T-cell counts [6] and the association of BCG vaccine exposure with lower rates of NTM disease [7]. To address which aspect of adaptive immunity is altered in children in whom clinical disease develops after NTMI, we carried out the current study, which demonstrated that T H cells from children with NTM lymphadenitis have an attenuated capacity for T H 1/T H 17 differentiation. ...
Nontuberculous mycobacteria (NTM) infect children with increasing frequency worldwide. Using blood and lymph node tissue (LN) from children with NTM lymphadenitis, and uninfected LN from community controls, we evaluated TH cells in functional assays of TH1/TH17-differentiation, and measured the concentration of their associated cytokines at the site of infection. Circulating TH cells from infected children were attenuated in their TH1/TH17-differentiation capacity, and expressed less IFNγ/IL17 following polyclonal stimulation. Similar differences were observed at the site of infection, where most cytokine concentrations were unchanged relative to controls. Our data are consistent with a model wherein TH1/TH17-differentiation is attenuated in NTM-infected children.
... It is unclear whether shared antigens can elicit protection against the diverse NTM that cause disease (11). Reports of increased incidence of extrapulmonary NTM in Sweden and Finland after the end of bacillus Calmette-Guérin (BCG) vaccination to protect against TB suggest that BCG may provide collateral protection against extrapulmonary NTM (12,13). However, no evidence is available regarding its effect on pulmonary NTM. ...
Background
Live vaccines potentially have non-specific effects that protect against other infections than those the vaccines are targeted against. The national vaccination program (NVP) in Finland was changed on September 1st, 2006: before BCG vaccine was given to all newborn babies and afterwards to babies in risk groups only. We used this natural experiment to study the non-specific effects of BCG in the frame of NVP using before-after design.
Methods
We compared the incidence of several outcomes obtained from Finnish health registers between children born between July 1st, 2004, and June 30th, 2006 (BCG-eligible) and an age- and season-matched reference cohort born between July 1st, 2007, and June 30th, 2009 (BCG-non-eligible) using Poisson regression. These cohorts were restricted to full-term children whose parents were born in Finland. Follow-up began at birth and lasted 3 months, which is the scheduled age for DTaP-IPV-Hib vaccination, and from 4 months until first birthday. The outcomes included all infections, pneumonia and injuries as a negative control outcome.
Results
The incidence rate ratio (IRR) of the BCG-eligible cohort (N = 93,658) compared to BCG-non-eligible cohort (N = 94,712) for hospital-diagnosed infections was 0.89 (95 %Cl 0.86–0.93) for the 3-month follow-up. The decrease was mainly caused by respiratory infections. In 4–12 months follow-up the BCG-eligible had slightly more infections than BCG-non-eligible children (IRR 1.03, 1.01–1.06).
Conclusions
BCG vaccination was associated with a lower incidence of all hospital-diagnosed infections during the first three months of life. The difference cannot be attributed to lung tuberculosis, since only few paediatric cases occurred in Finland during 2000s. The disappearance of non-specific effect after administration of an inactivated vaccine is compatible with previous studies.
This study aimed to investigate the association between Bacille Calmette-Guérin (BCG) vaccination and nontuberculous mycobacterial pulmonary disease (NTM-PD). Patients in the prospective NTM-PD cohort were matched to healthy controls to measure the association between BCG and NTM-PD development. The clinical course of NTM-PD patients was also evaluated to investigate the association between BCG and NTM-PD progression. BCG scars were not associated with NTM-PD development (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 0.96-4.34) or progression (adjusted OR, 1.61; 95% CI, 0.92-2.81). In conclusion, BCG vaccination was not associated with the development or progression of NTM-PD.
The Bacille Calmette-Guérin (BCG) vaccine has been in use for nearly 100 years and is the only available vaccine against tuberculosis currently. However, its efficacy remains controversial. In this chapter we review the history, efficacy, immunology, delivery and the future role of the BCG vaccine in protection against TB.KeywordsBCGVaccineNon-specific immunityBCG adverse effectsBCG policyBCG eligibilityBCG protectionBCG efficacy
Background
Non‐tuberculous mycobacteria (NTM) can cause chronic lung infection particularly in patients who have structural lung disease such as cystic fibrosis (CF). We evaluated the incidence and management of NTM infections in patients with CF in our center.
Methods
A retrospective cohort study was carried out on CF patients having at least one positive NTM isolate between 2012‐2020.
Results
Ten patients (2.1 %) had at least one positive NTM culture from respiratory samples. All of them were vaccinated with Bacille Calmette‐Guérin (BCG) vaccine which it is in the national vaccination program in our country. Eight patients had Mycobacterium abscessus complex (MABSC), one had Mycobacterium avium and one had Mycobacterium szulgai growth in their respiratory samples. Three patients had transient, 2 had persistent and 5 had active NTM infection (NTM pulmonary disease). Patients with NTM pulmonary disease received antibiogram directed antimycobacterial therapy. In patients with NTM pulmonary disease, the median ppFEV1 and BMI decreased by 17% and 1%, respectively, at the time of the first NTM isolation when compared with the values one year before first NTM isolation. Culture conversion was not seen in any patient infected with MABSC.
Conclusions
The NTM infection incidence is lower in our country than those countries where the BCG vaccine is not routinely applied. The BCG vaccine may be a protective factor for NTM infection. Further studies are needed about the prevalence of NTM infections, facilitating and protective factors and appropriate management of NTM infections in patients with CF.
Aim
A review published in 2015 showed that 331 Bacillus Calmette‐Guérin (BCG) osteitis cases were globally reported in 1976‐2012. The 222 Finnish cases from 1960 to 1988 formed two‐thirds of all cases. The present narrative review summarises epidemiological, clinical and immunological findings obtained from this Finnish cohort in relation to data from other countries.
Methods
Six reports including 93 BCG osteitis cases, which were not included in the 2015 review, were identified from PubMed.
Results
In all, 424 BCG osteitis cases have been published. Population‐based data were available only from Finland and Taiwan. The BCG osteitis incidence in Finnish infants was 6.4/100 000/year in 1960‐1988 compared to 3.4/100 000/year in Taiwanese infants in 1998‐2012. The incidence in Finland increased to 36.9/100 000 in 1971‐1977, and the vaccinations were temporarily discontinued. Over half of lesions were in lower limbs and nearly all were solitary in both cohorts. The outcomes after surgery and chemotherapy were good. Immunology of BCG osteitis was studied only in the Finnish cohort. There were deviations from population data in polymorphisms of genes regulating Toll‐like receptors 1, 2 and 6, mannose‐binding lectin and interleukin‐17A.
Conclusion
BCG osteitis after vaccination is rare. Preliminary findings in innate immunity raise a question of genetic background.
The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG’s effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.
Background:
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and a well-known cause of lymphadenitis, skin and soft tissue infections. The aim of this study was to evaluate the epidemiology of extrapulmonary pediatric NTM infections occurring from 2000 to 2017 in Queensland, Australia.
Methods:
All cases of NTM and TB are notifiable under the Queensland Public Health Act (2005) and associated regulations (2005). Data from 2000 to 2017 inclusive was collected from the Notifiable Conditions Database, a laboratory based notification system that covers private and public laboratory systems. Pediatric population demographic data were obtained from the Australian Bureau of Statistics by researching the number of children 0-14 years of age in Queensland from 2000 to 2017; both annual and averaged population was determined. The statistical software SPSS and Tableau was used for analysis.
Results:
The mean age of diagnosis was 2.5 years with a majority of the cohort being women. Mycobacterium avium was the most commonly diagnosed pathogen. Geographic regions with the highest numbers of cases were predominantly tropical and coastal areas. M. haemophilum emerged as a more common pathogen from 2011 following a period of major flooding.
Conclusion:
Characteristics of the cohort of children susceptible to NTM disease appears consistent with previous reports. However, changes in the epidemiology of NTM infection (such as incidence, species, and geographic distribution) in children may be linked to environmental and weather factors.
Background:
Bacille Calmette-Guérin (BCG) vaccine is protective in children but its efficacy wanes with age. Consequently, determining if BCG revaccination augments anti-TB immunity in young adults in TB endemic regions is vital.
Methods:
200 healthy adults, BCG vaccinated at birth were tested for their IGRA status. Of these, 28 IGRA+ and 30 IGRA- were BCG revaccinated and 24 IGRA+ and 23 IGRA- subjects served as unvaccinated controls. T and innate cell responses to mycobacterial antigens were analyzed by 14-colour flow cytometry over 34 weeks.
Results:
IFN-γ and/or IL-2 Ag85A and BCG-specific CD4+ and CD8+ T-cell responses were boosted by revacciantion at 4 and 34 weeks respectively and were >2-fold higher in IGRA+ compared to IGRA- vaccinees. Polyfunctional Ag85A, BCG and Mtb latency Ag (LTAg)-specific CD4+ T-cells expressing up to 8 cytokines were also significantly enhanced in both IGRA+ and IGRA- vaccinees relative to unvaccinated controls, most markedly in IGRA+ vaccinees. A focussed analysis of Th17 responses revealed expansion of Ag85A, BCG and LTAg-specific total IL-17A+IL-17F+IL-22+ and IL-10+ CD4+ T-cell effectors in both IGRA+ and IGRA- subjects. Also, innate IFN-γ+ NK/γδ/NKT responses were higher in both IGRA+ and IGRA- vaccinees compared to controls. This is the first evidence that BCG revaccination significantly boosts anti-mycobacterial Th1/Th17 responses in IGRA+ and IGRA- subjects.
Summary:
These data show that BCG revaccination is immunogenic in IGRA- and IGRA+ subjects implying that Mtb pre-infection in IGRA+ subjects does not impact immunogenicity. This has implications for public health and vaccine development strategies.
Funding:
This work was funded principally by DBT-NIH (BT/MB/Indo-US/HIPC/2013).
Objective:
Cervicofacial lymphadenitis caused by nontuberculous mycobacteria (NTM) is commonly treated with surgery or antimicrobial therapy. The aim of this study was to analyze the utility of our new blood-based diagnostic method and the treatment protocol, surgery or observation alone, in NTM lymphadenitis in children.
Methods:
All patients under 16 years of age with cervicofacial NTM lymphadenitis diagnosed and treated at Children's Hospital or at the Department of Otorhinolaryngology, Helsinki University Hospital (Helsinki, Finland) in 2007-2017 were retrospectively reviewed.
Results:
Fifty-two patients, 33 (63%) of whom were girls, were included in the study. The median age at initial presentation of the NTM lymphadenitis was 2.9 years. The novel blood-test had been performed on 49 (94%) of the patients and in all of them it was indicative of NTM infection. A sample for mycobacterial culture was available from 34 patients, and Mycobacterium avium was the most common species detected. Most patients (n = 33, 63%) were treated conservatively with observation alone. Of these, nine patients (27%) did not develop a skin fistula, and the lymphadenitis resolved without drainage.
Conclusions:
The novel blood test is clinically feasible method for diagnosing childhood cervicofacial NTM lymphadenitis noninvasively. Observation alone is a good alternative to surgery, without the risk of complications.
Aim:
Bacille Calmette-Guérin (BCG) vaccine (BCG) has been suggested to induce the primary immunity needed for the subsequent Kawasaki disease (KD). We studied the epidemiology of KD before and after the universal BCG vaccination ended in Finland in September 2006.
Methods:
KD cases were retrieved from national health registries from 1996-2016 for annual incidence rates. We then compared 612433 children born in the BCG vaccination era, from 1 January 1996 to 30 August 2006, to 604163 born after BCG era, from 1 September 2006 to 31 December 2016.
Results:
The annual incidence rates did not change after the BCG vaccination stopped. We found 370 first visits for KD by children born in the BCG era and 341 after universal BCG vaccination ended. The mean age at diagnosis increased from 2.6 years to 3.0 years (95% CI -0.64 to -0.012, p=0.04) and the proportion of children with Kawasaki disease under five years decreased from 87% to 81% (95% CI 1%-12%, p=0.02).
Conclusion:
Discontinuing the universal BCG vaccination programme did not change the incidence rates of KD. The increased age at diagnosis could suggest that the pathogenesis of KD may be associated with the immunological pathways primed by BCG immunisation.
Objectives
Nontuberculous mycobacterial (NTM) lymphadenitis is a rare disease of children under 5 years. Its treatment is not standardized, even a “wait-and-see” approach is shown to be effective in the literature. Here, we discuss the diagnostic and therapeutic strategies employed in our departments.
Methods
Records of pediatric patients treated for NTM cervical lymphadenitis from 2010 to 2015 in our tertiary center were retrospectively reviewed. Patients underwent cervical echotomography and/or CT scan. Every patient but one had microbiological explorations (NTM polymerase chain reaction [PCR] and culture) on fine needle aspiration of pus and/or adenitis biopsy. Differential diagnoses (tuberculosis, cat scratch disease) were excluded with serologies, chest X-Ray, and PCR on adenitis samples. Patients were classified as “proven diagnosis” (NTM detected), “highly probable” (suggestive clinical and anatomopathological aspect) or “possible” infection (suggestive adenitis alone). Treatments, follow-up and adverse events were reviewed.
Results
Thirty-one patients were treated for NTM, median age 2.40 years (Interquartile Range IQR = [1.85–3.16]). Twenty-nine patients (96.77%) had an isolated cervico-facial localization. Median follow-up was 8.00 months (IQR = [4.20–13.43]). We found 17 “proven diagnosis” (58.62%), 5 “highly probable” (17.24%) and 7 “possible” infections (24.14%). “Proven” infections were due to: Mycobacterium avium (n = 12, 66.67%) and M. intracellulare (n = 5, 27.78%). All 29 patients received antibiotics, which were effective for 10 (34.48%, group 1); 10 underwent surgical excision for a poor outcome with antibiotics (34.48%, group 2); spontaneous or surgical drainage occurred in 9 on antibiotics (31.03%, group 3). The median times to resolution for group 1, 2 and 3 were respectively 6.33 months, 6.22 months and 9.53 months. Antibiotics treatment was mostly clarithromycin (n = 27, 93.10%) and/or rifampicin (n = 19, 65.52%); 18 patients (62.07%) received both. Median antibiotics duration was 6.23 months (IQR = [5.17–7.46]), with good compliance (79.31%). The observed adverse effects were 3 (13.04%) isolated transient transaminase elevations, 1 case (4.35%) of minor creatinine elevation, and 1 case (4.35%) of transient diarrhea. Surgical drainage caused 1 transient marginal mandibular nerve palsy, resolutive after 1 month.
Conclusion
Antibiotics in NTM adenitis lead to resolution in 7 months, with good tolerance and compliance. The efficacy of “wait-and-see” attitude in the literature make excision surgery a second line treatment.
Disease caused by nontuberculous mycobacteria (NTM) is reported to increase due to an ageing population and a rise in the proportion of immunosuppressed patients. We did a retrospective cohort study of NTM-disease in the Danish population through a quarter-century to determine the disease burden and trends in annual incidence rates. 524,119 clinical specimens were cultured for mycobacteria from 1991 through 2015 at the International Reference Laboratory of Mycobacteriology in Denmark. Among these, 8,227 NTM strains were identified from 3,462 patients and distributed according to microbiological disease criteria. We observed no increase in NTM disease incidence or proportion of patients with positive NTM cultures during the study period (Quasi-Poisson regression, p = 0.275 and 0.352 respectively). Annual incidence rates were 1.20/10⁵ for definite NTM disease, 0.49/10⁵ for possible NTM disease and 0.88/10⁵ for NTM colonization. The incidence rate of NTM disease was highest in children aged 0-4 years (5.36/10⁵/year), predominantly with cervical Mycobacterium avium complex (MAC) adenitis. Surprisingly, based on more than half a million clinical specimens cultured for mycobacteria in Denmark through 25 years, the NTM disease burden and trend in incidence in the Danish population has not increased opposed to numerous internationals reports.
Since non-tuberculous mycobacteria (NTM) disease is not notifiable in most European Union (EU) and European Economic Area (EEA) countries, the epidemiological situation of the >150 NTM species is largely unknown. We aimed to collect data on the frequency of NTM detection and NTM species types in EU/EEA countries.
Officially nominated national tuberculosis reference laboratories of all EU/EEA countries were asked to provide information on: laboratory routines for detection and identification of NTM, including drug sensitivity testing (DST) methods; data on the number and type of NTM species identified; coverage and completeness of the provided data on NTM; type and number of human specimens tested for NTM; and number of specimens tested for Mycobacterium tuberculosis complex and NTM. This information was summarized and the main results are described.
In total, 99 different NTM species were identified with M. avium, M. gordonae, M. xenopi , M. intracellulare, and M. fortuitum identified most frequently. Seven percent of the NTM species could not be identified. NTM was cultured from between 0.4-2.0% of the specimens (data from four countries). The laboratories use culturing methods optimised for M. tuberculosis complex. Identification is mainly carried out by a commercial line probe assay supplemented with sequencing. Most laboratories carried out DST for rapid growers and only at the explicit clinical request for slow growers.
It is likely that the prevalence of NTM is underestimated because diagnostic procedures are not optimized specifically for NTM and isolates may not be referred to the national reference laboratory for identification. Due to the diagnostic challenges and the need to establish the clinical relevance of NTM, we recommend that countries should concentrate detection and identification in only few laboratories.
The efficacy of Bacillus Calmette-Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation for this variability is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). This study used a murine model to determine the effect that exposure to NTM after BCG vaccination had on the efficacy of BCG against aerosol Mycobacterium tuberculosis challenge. The effects of administering live M. avium (MA) by an oral route and killed MA by a systemic route on BCG-induced protection were evaluated. CD4+ and CD8+ T cell responses were profiled to define the immunological mechanisms underlying any effect on BCG efficacy. BCG efficacy was enhanced by exposure to killed MA administered by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. BCG efficacy was reduced by exposure to live MA administered by the oral route; T helper 2 cells were associated with reduced protection. These findings demonstrate that exposure to NTM can induce opposite effects on BCG efficacy depending on route of exposure and viability of NTM. A reproducible model of NTM exposure would be valuable in the evaluation of novel TB vaccine candidates.
A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity
and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine
and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call
these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against
a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated
by mechanisms including innate immune memory (also known as “trained immunity”) and cross-reacting lymphocytes. Herein we
review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen,
Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and
alter the manner and sequence in which they are given.
Nontuberculous mycobacteria (NTM) infections appear to be increasing in number and severity in developed countries worldwide. Surgical excision has been considered the standard treatment for NTM lymphadenitis, but the use of medical therapy seems to be increasing.
To determine the disease characteristics as well as the current therapeutic management of NTM infections in Canadian children.
Cases of definite or probable NTM infections were identified prospectively in children up to 18 years of age seen in 10 Canadian paediatric tertiary care centres from September 2005 to August 2006. Clinical, microbiological and pathological data were collected.
A total of 60 cases were identified. Data were complete for 45 patients, including 34 cases of lymphadenitis, four cases of skin and soft tissue infection, and seven cases of pulmonary NTM infection. Seventy-nine per cent of children (27 of 34) with lymphadenitis had an unsuccessful course of antibiotics before diagnosis. Sixty-eight per cent of purified protein derivative tests (15 of 22) were positive. NTM was detected in 76% of samples (29 of 38), of which 62% were Mycobacterium avium complex. All patients with lymphadenitis underwent surgical therapy and most patients (74%) also received antimicrobials.
Current trends indicate that the majority of the study centres are using medical therapy with variable regimen and duration as an adjunct to surgical excision in the treatment of NTM lymphadenitis. Larger numbers and longer follow-up times are needed to better evaluate the efficacy of medical therapy and outcome of disease. A randomized controlled study comparing surgical therapy alone and chemotherapy for NTM lymphadenitis is required.
Mycobacterium lentiflavum, a slow-growing nontuberculous mycobacterium, is a rare cause of human disease. It has been isolated from environmental samples worldwide. To assess the clinical significance of M. lentiflavum isolates reported to the Queensland Tuberculosis Control Centre, Australia, during 2001-2008, we explored the genotypic similarity and geographic relationship between isolates from humans and potable water in the Brisbane metropolitan area. A total of 47 isolates from 36 patients were reported; 4 patients had clinically significant disease. M. lentiflavum was cultured from 13 of 206 drinking water sites. These sites overlapped geographically with home addresses of the patients who had clinically significant disease. Automated repetitive sequence-based PCR genotyping showed a dominant environmental clone closely related to clinical strains. This finding suggests potable water as a possible source of M. lentiflavum infection in humans.
The annual numbers of cases of non-tuberculous mycobacterial lymphadenitis in south east England has increased over the period 1973 to 1993, most notably during the last few years. The most frequent cause is the Mycobacterium avium complex, followed by M malmoense. The reason for the increase is unknown but it could be due to an increased awareness in mycobacterial disease, an external factor such as pollution, or both.
Drinking water distribution systems were analyzed for viable counts of mycobacteria by sampling water from waterworks and in different parts of the systems. In addition, loose deposits collected during mechanical cleaning of the main pipelines were similarly analyzed. The study covered 16 systems at eight localities in Finland. In an experimental study, mycobacterial colonization of biofilms on polyvinyl chloride tubes in a system was studied. The isolation frequency of mycobacteria increased from 35% at the waterworks to 80% in the system, and the number of mycobacteria in the positive samples increased from 15 to 140 CFU/liter, respectively. Mycobacteria were isolated from all 11 deposits with an accumulation time of tens of years and from all 4 deposits which had accumulated during a 1-year follow-up time. The numbers of mycobacteria were high in both old and young deposits (medians, 1.8 x 10(5) and 3.9 x 10(5) CFU/g [dry weight], respectively). Both water and deposit samples yielded the highest numbers of mycobacteria in the systems using surface water and applying ozonation as an intermediate treatment or posttreatment. The number and growth of mycobacteria in system waters correlated strongly with the concentration of assimilable organic carbon in the water leaving the waterworks. The densities of mycobacteria in the developing biofilms were highest at the distal sites of the systems. Over 90% of the mycobacteria isolated from water and deposits belonged to Mycobacterium lentiflavum, M. tusciae, M. gordonae, and a previously unclassified group of mycobacteria. Our results indicate that drinking water systems may be a source for recently discovered new mycobacterial species.
We performed a prospective, 2-year nationwide study to assess incidence and disease characteristics of suspected infections
with nontuberculous mycobacteria (NTM) in children, via the Netherlands Pediatric Surveillance Unit. Data for 61 children
were reported (median age, 31 months; interquartile range, 22–50 months; female sex, 37 subjects); 2 subjects had an underlying
disease. Most children (53 [87%] of 61) had cervical lymph node enlargement, with abscess in 25 (47%) and fistula in 11 (21%).
The estimated annual incidence of NTM infection was 77 cases per 100,000 children. In 16 children, the diagnosis was based
solely on the results of skin tests with mycobacterial antigens. Cultures were performed in 36 cases and yielded mycobacteria
in 27 (75%); Mycobacterium avium was isolated from 18 cultures. Children with a culture positive for mycobacteria did not differ in presentation, complications,
or treatment from those whose cultures showed no growth. Thirty children underwent surgery, and chemotherapy was the single
treatment in 24 (39%) of the cases. The treatment of localized NTM infection in immunocompetent children by antimycobacterial
drugs should be evaluated further.
To evaluate the impact of environmental factors on the occurrence of environmental mycobacteria, viable counts of mycobacteria were measured in samples of brook water collected from 53 drainage areas located in a linear belt crossing Finland at 63 degrees north latitude. The numbers of mycobacteria were correlated with characteristics of the drainage area, climatic parameters, chemical and physical characteristics of the water, and counts of other heterotrophic bacteria in the water. The numbers of mycobacteria in the water ranged from 10 to 2,200 CFU/liter. The counts correlated positively (P < 0.001) with the presence of peatlands, precipitation data, chemical oxygen demand, water color, and concentrations of Fe, Al, Cu, Co, and Cr. The mycobacterial counts correlated negatively (P < 0.001) with water pH, whereas other heterotrophic bacterial counts lacked any correlation with pH. A linear regression model with four independent variables (i.e., peatlands in the drainage area, chemical oxygen demand, concentration of potassium, and pH) explained 83% of the variation in mycobacterial counts in brook waters. Our results suggest that acidification may enhance the growth of environmental mycobacteria.
In Finland, all newborns are currently offered BCG vaccination, and the national coverage is over 98%. The annual incidence of tuberculosis is low, at 6.6/100,000 in 2004 and has been steadily declining in recent years. Finland differs from the other Nordic countries in that the majority of cases are detected in people aged 65 and over in the indigenous population, and only a smaller proportion (12%) detected in immigrants. The high incidence of TB and MDR TB in neighbouring countries has raised concern, but no increase in TB detected in Finnish-born citizens has been seen. A decision has been made to change from mass BCG vaccination to targeting risk groups.
Recent studies suggest that the incidence of nontuberculous mycobacterial infections in children may be increasing. Nontuberculous mycobacterial lymphadenitis, skin and soft tissue infection, and pulmonary disease each present unique challenges in relation to diagnosis and treatment. In this update, we critically review the recent literature on the epidemiology, clinical features, diagnostic approaches and treatment of nontuberculous mycobacterial disease in children. In addition, we outline key areas warranting further research.
Non-tuberculous mycobacteria (NTM) are a large family of acid-fast bacteria, widespread in the environment. In children, NTM cause lymphadenitis, skin and soft tissue infections, and occasionally also lung disease and disseminated infections. These manifestations can be indistinguishable from tuberculosis on the basis of clinical and radiological findings and tuberculin skin testing. A diagnostic and therapeutic problem for respiratory physicians and other clinicians is therefore evident, particularly in settings where childhood tuberculosis is common, and bacteriological confirmation of any mycobacterial disease is difficult because of low availability of laboratory services in low-resource settings and the inherent paucibacillary nature of mycobacterial disease in childhood. The epidemiology of NTM varies by world region, and attempts to understand the burden of NTM disease and to identify risk factors in the paediatric population are hampered by inadequate mandatory NTM reporting and the overlap of clinical presentation with tuberculosis. The immune response to both NTM and Mycobacterium tuberculosis is based on cellular immunity and relies on the type-1 cytokine pathway. The disruption of this immune response by genetic or acquired mechanisms, such as mendelian susceptibility to mycobacterial disease or HIV, might result in predisposition to mycobacterial infections. Published diagnostic and management guidelines do not provide specific advice for diagnosis of NTM in children, from whom the quantity and quality of diagnostic samples are often suboptimum. Treatment of NTM infections is very different from the treatment of tuberculosis, depends on the strain and anatomical site of infection, and often involves antibiotic combinations, surgery, or both. In this Review, we summarise the epidemiological and clinical features of NTM infection in children, with a specific focus on the implications for public health in settings with a high endemic burden of childhood tuberculosis.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Cervicofacial lymphadenitis is the most common manifestation of infection with non-tuberculous mycobacteria (NTM) in immunocompetent children. Although complete excision is considered standard management, the optimal treatment remains controversial. This study reviews the evidence for different management options for NTM lymphadenitis.
A systematic literature review and meta-analysis were performed including 1951 children from sixty publications. Generalised linear mixed model regressions were used to compare treatment modalities.
The adjusted mean cure rate was 98% (95% CI 97.0-99.5%) for complete excision, 73.1% (95% CI 49.6-88.3%) for anti-mycobacterial antibiotics, and 70.4% (95% CI 49.6-88.3%) for 'no intervention'. Compared to 'no intervention', only complete excision was significantly associated with cure (OR 33.1; 95% CI 10.8-102.9; p<0.001). Complete excision was associated with a 10% risk of facial nerve palsy, 2% permanently. 'No intervention' was associated with delayed resolution.
Complete excision is associated with the highest cure rate in NTM cervicofacial lymphadenitis, but also had the highest risk of facial nerve palsy. In the absence of large, well-designed RCTs, the choice between surgical excision, anti-mycobacterial antibiotics and 'no intervention' will remain based on the extent and location of the disease, and acceptability of prolonged time to resolution.
Copyright © 2015. Published by Elsevier Ltd.
Mycobacterium lentiflavum is considered a rare pathogen causing non-tuberculous mycobacterial (NTM) lymphadenitis.
a multicenter, retrospective study was performed in immunocompetent children less than 14 years of age with microbiologically-confirmed NTM lymphadenitis treated at six hospitals in Madrid, Spain, during the period 2000-2010. We compared children with M. lentiflavum and M. avium-intracellulare complex (MAC) infection.
Forty-five microbiologically-confirmed NTM lymphadenitis patients were identified: 19 (45.2%) caused by MAC, 17 (40.5%) by M. lentiflavum, 1 by both and 5 by other mycobacteria. Fourteen out of 17 M. lentiflavum cases were diagnosed in the past five years. Regarding M. lentiflavum cases, median age was 23 months. Submandibular nodes were the most frequently involved (76.5%) with multiple locations seen in 41% of the children and spontaneous drainage in 41% of them. Drug-susceptibility tests were performed in 14 isolates and showed a complete susceptibility to clarithromycin and cycloserine, whereas 93% were resistant to rifampin, 33% to quinolones and full resistance to other tested antimycobacterial drugs was detected. All but one child required surgery and 11 were treated additionally with various drug combinations. Total resolution was achieved in 50% of children within 6 months.Compared with MAC cases, children were younger and laterocervical nodes were significantly less frequently involved. No statistically significant differences were found related to clinical characteristics, treatment and outcome.
M. lentiflavum is an emerging pathogen producing NTM lymphadenitis in Madrid.
Bacille Calmette-Guérin (BCG) is one of the most commonly administered vaccines worldwide. In addition to protection against tuberculosis (TB), evidence suggests that BCG immunisation has a number of additional beneficial non-specific immunological effects. These include a reduction in overall infant and child mortality attributable to causes other than TB in high-mortality regions. The antibody response to immunisations provides an opportunity to investigate the influence of BCG on the immune response to unrelated antigens. This study compared the antibody response to routine immunisations in BCG-immunised and non-BCG-immunised infants.
Setting: In 1986, mass BCG vaccination of newborns was discontinued in an extensive territorial sample of neonates in the Czech Republic (30 000 infants annually). The non-vaccinated children have since been tuberculin tested at two-year intervals; those with continual or repeated intensive contact with animals in households or on farms were also tested with Mycobacterium avium intracellulare complex sensitin in addition to tuberculin.Objective: Within the frame work of the surveillance programme the incidence of infection and disease caused by M. avium intracellulare complex M. avium complex) was evaluated and the protective effect of BCG vaccination analysed.Design: In 1986–1993, out of 190 874 non-vaccinated children, 36 were found to be infected by M. avium complex; 27 of them developed disease, i.e. mycobacteriosis other than tuberculosis (MOTT).Results: The annual risk of infection with M. avium complex was 4.8/100 000 children per year, of whom 3.6/ 100 000 developed mycobacteriosis. 24 patients suffered from swelling of cervical lymph nodes, 2 of mediastinal lymph nodes and one child had the disease localized both in cervical and mediastinal lymph nodes. The disease was verified bacteriologically in 9 children. Most of the diseased children had impaired immunity; a marked skin reactivity of M. avium complex sensitin was present in all infected children.Animal sources infected by M. avium complex were detected in 5 cases. Another 14 children also had close contact with animals but without proven M. avium complex infection.Conclusion: In non-BCG vaccinated children the incidence of lymphadenitis caused by M. avium complex was considerably higher than in vaccinated children. BCG cells possess antigenic determinants which confer protective immunity probably both against M. tuberculosis and against M. avium complex infections. It may thus be assumed that BCG vaccination protects both against pathogenic tubercle bacilli and M. avium complex. This should be taken into consideration before recommending discontinuation of mass BCG vaccination of newborns in areas with a high prevalence of M. avium complex infection.RésuméCadre: En 1986, la vaccination de masse des nouveaux-nés par le BCG a été supprimée dans un échantillon régional étendu de la République Tchèque (30 000 enfants par an). Depuis, les enfants non-vaccinés ont eu un test tuberculinique à des intervalles de deux ans; ceux en contact permanent ou répété avec des animaux au foyer ou dans des fermes ont également reçu un test avec la sensitine du complexe Mycobacterium avium intracellulare.Objet: Dans le cadre du programme de surveillance, l'incidence de l'infection et de la maladie causées par le complexe M. avium intracellulare (complexe M. avium) a été évaluée et l'effet protecteur de la vaccination BCG analysé.Schéma: Au cours de la période 1986 à 1993, sur 190 874 enfants non-vaccinés, 36 étaient infectés par le complexe M. avium; 27 ont développé une maladie, c'est à dire une mycobactériose autre que la tuberculose (MOTT).Résultats: Le risque annuel d'infection due au complexe M. avium était de 4.8/100 000 enfants par an, dont 3,6 100 000 ont développé une mycobactériose. 24 malades souffraient d'une intumescence des ganglions lymphatiques cervicaux, deux des ganglions lymphatiques médiastinaux, et chez un enfant l'infection était localisée dans les deux groupes. La maladie a été vérifiée par des tests bactériologiques chez 9 enfants. La plupart des enfants malades avaient une immunité altérée; une haute réactivité cutanée à la sensitine du complexe M. avium était présente chez tous les enfants infectés. Des sources animales infectées par le complexe M. avium ont été détectées dans 5 des cas. 14 autres avaient également un contact étroit avec des animaux sans que l'on puisse prouver une infection due au complexe M. avium.Conclusion: Chez des enfants non-vaccinés par le BCG l'incidence d'une lymphadénite causée par le complexe M. avium était nettement plus élevée que chez les enfants vaccinés. Les cellules BCG possèdent des déterminants antigéniques qui confèrent une immunité protectrice, probablement contre les infections dues àM. tuberculosis aussi bien que contre celles dues au complexe M. avium. On peut donc présumer que la vaccination par le BCG protège contre les bacilles tuberculeux pathogènes et contre le complexe M. avium. Ceci devrait être pris en considération avant toute recommandation de suppression de la vaccination de masse par le BCG des nouveaux-nés dans des régions ayant une haute prévalence de l'infection due au complexe M. avium.ResumenMarco de referencia: En 1986 se interrumpiö la vacunación masiva con BCG de los recién nacidos en una extensa muestra territorial de neonatos en la República Checa (30 000 niños por año). Desde entonces, los niños no vacunados fueron sometidos a tests de tuberculina a dos años de intervalo; aquéllos con contacte continue o repetido con animales en el hogar o en granjas también fueron sometidos a tests con sensitina del complejo Mycobacterium avium intracellulare, además del test de tuberculina.Objetivo: Dentro del programa de vigilancia, se evaluó la incidencia de infectión y de la morbilidad por el complejo M. avium intracellulare (complejo M. avium), al mismo tiempo que el efecto protector de la vacunación con BCG.Método: Entre 1986 y 1993, de un total de 190 874 ninos no vacunados, 36 estaban infectados con el complejo M. avium; 27 habían desarrollado la enfermedad, es decir una micobacteriosis diferente de la tuberculosis (MOTT).Resultados: El riesgo anual de infección por complejo M. avium fue de 4.8/100 000 niños y por año y de ellos 3, 6 100 000 desarrollaron una micobacteriosis. Un total de 24 pacientes presentó una tumefacción de los ganglios linfáticos cervicales, 2 de los ganglios linfáticos mediastinales y un niño presentó una enfermedad localizada tanto en los ganglios linfáticos cervicales como mediastinales. La enfermedad fue confirmada bacteriológicamente en 9 niños. La mayoría de los niños enfermes tenía una alteratión inmunitaria; en todos los niños infectados había una reactividad cutánea importante a la sensitina del complejo M. avium. En 5 casos se detectó animales infectados con complejo M. avium como fuente de infección. Otros 14 niños habían tenido contacto estrecho con animales, pero no se probó una infección con complejo M. avium.Conclusion: En los niños no vacunados con BCG, la incidencia de linfadenitis causada por el complejo M. avium fue considerablemente más elevada que en los niños vacunados. Las células BCG poseen determinantes antigénicos que confieren una protección inmunitaria, probablemente tanto contra la infección con M. tuberculosis como contra aquélla con complejo M. avium. Así, debe asumirse que la vacunación BCG protege contra ambos microorganismos patógenos. Esto debe ser tomado en consideración antes de recomendar la interrupción de la vacunación masiva con BCG de los recién nacidos en zonas con alta prevalencia de infección con complejo M. avium.
National Mycobacteria Reference Laboratory, The Netherlands.
To assess the role of factors other than laboratory improvements in the increasing frequency of isolation of non-tuberculous mycobacteria (NTM) in the Netherlands; laboratory improvements are often considered key factors in this increase.
Laboratory database study. All clinically isolated NTM referred to the national reference laboratory between January 2000 and January 2007 were retrieved from the laboratory database and categorised by species, patient age group and sample origin. Data were compared with national demographic data.
Clinical Mycobacterium avium isolates accounted for most of the increase in referred NTM. The number of respiratory M. avium samples in patients aged >40 years increased over time. This age group increased in size during the study. In this age group, the prevalence of chronic obstructive pulmonary disease (COPD) increased during the study period. M. avium isolation from lymph nodes in children remained stable, whereas extra-pulmonary M. avium isolation in the middle age group, including human immunodeficiency virus associated bloodstream isolates, decreased.
The increasing NTM notification in the Netherlands is unlikely to have been a result of laboratory improvements alone: the ageing population with an increasing prevalence of COPD is likely as important. Environmental characteristics may specifically favour M.avium.
Nontuberculous mycobacteria (NTM) are important human pathogens, yet little is known about disease prevalence in the United States. Reports suggest prevalence has increased, particularly in women, but population-based data to substantiate this are lacking. We sought to estimate NTM disease prevalence in Oregon, and describe disease by site, species, and patient demographic characteristics.
We contacted laboratories that performed mycobacterial cultures on Oregon residents in 2005-2006. For each isolate, we obtained source, collection date, species, and patient demographics. We used the microbiologic component of the American Thoracic Society/Infectious Diseases Society of America's pulmonary NTM disease criteria to define cases of pulmonary NTM, and patients with isolates from a normally sterile site were classified as having extrapulmonary disease.
We identified 933 patients with > or =1 NTM isolate. Of these, 527 (56%) met the case definition (annualized prevalence, 7.2 cases per 100,000 persons). Pulmonary cases predominated (5.6 cases per 100,000 persons), followed by skin/soft-tissue cases (0.9 cases per 100,000 persons). Mycobacterium avium complex was the most common species identified in pulmonary cases (4.7 cases per 100,000 persons). Pulmonary disease prevalence was significantly higher in women (6.4 cases per 100,000 persons) than men (4.7 cases per 100,000 persons) and was highest in persons aged >50 years (15.5 cases per 100,000 persons).
NTM are frequently isolated from Oregon residents; more than one-half of all isolates likely represent true disease. Pulmonary NTM is most common among elderly women, and M. avium causes most disease. Future efforts to monitor disease trends should be undertaken, and efforts made to validate the use of the ATS/IDSA microbiologic criteria alone to predict pulmonary NTM disease.
An increasing incidence in disease caused by nontuberculous mycobacteria is being reported. We investigated the burden of disease in immunocompetent German children in a prospective nationwide study from April 2003 to September 2005. Ninety-seven percent of children presented with lymphadenitis; median age was 2.5 years. Using the capture-recapture method, we estimated a cumulative incidence rate of 3.1/100000 children.
Mycobacterial cervical adenitis is an uncommon disease in children in Finland. During 10 years, from 1977-1986, its incidence was of the order of 0.3/year/100,000 children. Of the 12 bacteriologically verified cases, M. avium-intracellulare was isolated in nine, M. malmoense in two and M. tuberculosis in only one case. Neonatal BCG vaccination seemed to protect children against non-tuberculous mycobacterial infection, especially at 1-4 years of age. In Sweden, where neonatal BCG vaccination has been discontinued, the incidence of non-tuberculous mycobacterial adenitis is at least 30 times greater.
Specific pathogen-free mice were vaccinated subcutaneously with 10(7) CFU of BCG Pasteur or BCG Glaxo and 30 or 90 days later, the mice were challenged aerogenically with Mycobacterium tuberculosis (Erdman or South Indian strains) or with M. avium. Both vaccines induced substantial levels of resistance to tuberculosis and tuberculin hypersensitivity. There was no detectable difference in the host response to the three aerogenic challenges which could be related in any way to the immunogenicity of the BCG strain or to the mouse virulence of the challenge organism. These results do not support the hypothesis that the protective activity of BCG vaccines varies, depending upon the virulence of the infecting organism.
The effect of prior vaccination of mice with Mycobacterium bovis BCG on the subsequent course of acute aerogenic infection with various environmental mycobacteria was tested. A protective effect was recorded against infection with M. avium, and M. kansasii; by contrast no effect was noted against M. simiae or M. intracellulare. The prophylactic effects of BCG were demonstrated regardless of whether vaccination was given by the intravenous or aerogenic routes. These findings support the hypothesis that BCG vaccination, if given prior to contact, can provide some degree of protection against certain non-tuberculous mycobacterial infections.
In April 1975, the general BCG vaccination of newborns in Sweden was replaced by selective vaccination of groups at increased risk of tuberculosis.
To relate the incidence of atypical mycobacterial disease in children to BCG vaccination.
A nationwide survey in Sweden during the period 1969-90 disclosed 390 children under 15 years of age with bacteriologically confirmed atypical mycobacteria from extrapulmonary lesions.
The average, annual incidence of atypical mycobacterial disease per 100,000 children under 5 years of age increased from 0.06 during the period 1969-74 to a maximum level of 5.7 during 1981-85. Among the cohorts born in Sweden in the period 1975-85, the cumulative incidence rate before 5 years of age was estimated at 26.8 per 100,000 non-BCG-vaccinated children and at 4.6 among those BCG-vaccinated, ratio 5.9 (95% confidence limits 1.6, 48.5). Mycobacterium avium-intracellulare was found in 83%. Disseminated, fatal disease developed in 3 children. The remaining ones suffered from local infections, most often lymph-node or soft-tissue lesions. The observed incidence of bacteriologically confirmed diagnosis was estimated to represent approximately 40% of the 'true' number, if patients with diagnosis based on histological, clinical and epidemiological findings only were included.
The present study indicates that BCG vaccination plays a role in protection against localized disease caused by atypical mycobacteria in children.
Cases of nontuberculous mycobacterial lymphadenitis were analyzed in a prospective study spanning 32 years, from 1958 to 1990.
The results are based on personal observations and long-term follow-up. There were 105 cases, all of which occurred in children
aged 9 1/2 months to 12 years (median age, 2.92 years). The patients were predominantly female, and the cases occurred more
often in the winter and spring. The cervical or facial nodes were involved in 96 cases. An abrupt change in the predominant
etiologic agent (from Mycobacterium scrofulaceum to Mycobacterium avium complex) was noted in the 1970s. Positive tuberculin skin tests were the rule, and reactivity was long lasting. Complications
included a prolonged initial phase of infection (n = 6) and recurrences 3 1/2 months to 7 years later (n = 5). Resection during the early stage of infection produced the most satisfactory healing.
In 1986, mass BCG vaccination of newborns was discontinued in an extensive territorial sample of neonates in the Czech Republic (30,000 infants annually). The non-vaccinated children have since been tuberculin tested at two-year intervals; those with continual or repeated intensive contact with animals in households or on farms were also tested with Mycobacterium avium intracellulare complex sensitin in addition to tuberculin.
Within the frame work of the surveillance programme the incidence of infection and disease caused by M. avium intracellulare complex (M. avium complex) was evaluated and the protective effect of BCG vaccination analysed.
In 1986-93, out of 190,874 non-vaccinated children, 36 were found to be infected by M. avium complex; 27 of them developed disease, i.e. mycobacteriosis other than tuberculosis (MOTT).
The annual risk of infection with M. avium complex was 4.8/100,000 children per year, of whom 3.6/100,000 developed mycobacteriosis. 24 patients suffered from swelling of cervical lymph nodes, 2 of mediastinal lymph nodes and one child had the disease localized both in cervical and mediastinal lymph nodes. The disease was verified bacteriologically in 9 children. Most of the diseased children had impaired immunity; a marked skin reactivity of M. avium complex sensitin was present in all infected children. Animal sources infected by M. avium complex were detected in 5 cases. Another 14 children also had close contact with animals but without proven M. avium complex infection.
In non-BCG vaccinated children the incidence of lymphadenitis caused by M. avium complex was considerably higher than in vaccinated children. BCG cells possess antigenic determinants which confer protective immunity probably both against M. tuberculosis and against M. avium complex infections. It may thus be assumed that BCG vaccination protects both against pathogenic tubercle bacilli and M. avium complex. This should be taken into consideration before recommending discontinuation of mass BCG vaccination of newborns in areas with a high prevalence of M. avium complex infection.
Mycobacterium bovis bacille Calmette-Gueŕin (BCG) is provided to all infants born in Finland.
To analyze the cost-effectiveness of universal versus selective BCG immunization.
A Markov model was developed to simulate rates of tuberculosis (TB) and non-tuberculous mycobacterial disease (NTM), and to examine the cost-effectiveness in terms of cost per case averted of three different strategies: universal BCG, selective BCG (10% of infants at higher TB risk than other infants) or no BCG immunization.
In a cohort of 60,000 infants over 15 years, the model predicts five cases each of TB and NTM disease with universal immunization, 8-21 TB and 31 NTM cases with various strategies of selective immunization, and 25 TB and 34 NTM cases with no BCG immunization. BCG side-effects are predicted in 5, 0.5 and 0 infants, respectively. The cost per case averted for immunization strategies ranges from a cost of 38,311 US dollars to a savings of 323 dollars as selective immunization becomes more efficient at targeting infants at highest risk of TB.
In a country with a low incidence of pediatric tuberculosis, selective BCG immunization is a more cost-effective strategy than universal BCG immunization for the prevention of tuberculosis, but results in an increase in NTM cases.
Nontuberculous mycobacteria (NTM) infections seem to be increasing in numbers and in severity in developed countries worldwide.
To document the severity and to assess whether an increase in cases has occurred over the years, we described the epidemiology, clinical presentation, investigations, and treatment of NTM adenitis seen at the Montreal Children's Hospital.
Cases were identified through revision of the microbiology laboratory database for positive NTM culture from any site and through retrieval by the medical records of charts of patients with a diagnosis of adenitis and a node biopsy or excision or a diagnostic code of NTM disease, between 1990 and 2004. These charts were reviewed retrospectively.
Over the 15-year period, we identified 36 patients with a median age of 2.8 years with NTM adenitis. Of these cases, 22 (61%) occurred in the past 5 years. Only 3 children were born outside Canada. The majority (92%) presented with a cervicofacial mass, and 25% had constitutional symptoms or fever. There were 3 cases of mediastinal adenitis and 2 cases of cervical disease extending to the deep neck vessels, all of which occurred in the past 5 years. The purified protein derivative (PPD) test for tuberculosis was positive (> or = 10 mm) in 11 of 15 patients tested (73%), none of whom had ever had contact with tuberculosis. Thirty-three patients had surgery. Of the 26 patients who had excisional biopsy or functional neck dissection, 15% required a second surgery for persistence or recurrence compared with 100% of those who had incision and drainage or curettage. Cultures were positive in 72% of the 32 specimens sent, mainly for Mycobacterium avium complex. Very few complications were noted.
The number of cases of NTM disease has almost doubled between 2000-2004 compared with between 1990-1999, with more invasive cases seen in the past 4 years. The significance of this important rise in numbers is still unclear. Resolution of NTM adenitis is higher with complete surgical excision of affected lymph nodes. Moreover, given the proportion of PPD > or = 10mm among those tested, a pan-Canadian study assessing the incidence of NTM disease compared with tuberculosis is required to determine if a change in the recommendations for PPD positivity is needed.
The protective efficacy of Mycobacterium bovis-bacille Calmette Guérin (BCG) against tuberculosis (TB) is variable in both humans and cattle. Exposure to environmental mycobacteria is thought to result in inappropriate priming of host immune responses. To investigate the impact of environmental mycobacteria on BCG efficacy, cattle were infected with M. avium, vaccinated with BCG, challenged with M. bovis and skin tested prior to necropsy. Elevated levels of IFNgamma were evident in M. avium-exposed animals before and after BCG vaccination with a bias towards avian purified protein derivative (PPD-A), suggesting that M. avium primed host immune responses. Exposure to M. avium also resulted in a higher frequency of circulatory IFNgamma-producing cells in response to PPD antigens at the time of M. bovis challenge. After M. bovis inoculation, the IFNgamma response to bovine PPD (PPD-B) increased compared to pre-challenge levels, indicating that all animals had been exposed to M. bovis. Skin test responses indicated 2/6 M. avium-BCG-M. bovis animals as reactors and 2/6 as inconclusive compared with 6/6 BCG-M. bovis animals as reactors. M. avium-exposed animals also had fewer lesions and the number of tissues containing viable M. bovis at post-mortem was significantly lower (P<0.02 compared with BCG-M. bovis animals), with two of the animals described as skin test negative with no visible lesions or viable bacteria. Thus, exposure of cattle to environmental mycobacteria such as M. avium prior to BCG vaccination did not dampen BCG-specific immune responses and resulted in lower TB pathology. However, the PPD-A bias associated with M. avium exposure is likely to undermine current TB diagnostic tests and the IFNgamma test in cattle.
Finland switched from universal vaccination of all newborns to targeted risk group vaccination
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Elispot IGRA with purified protein derivative stimulation for diagnosing nontuberculous mycobacterial cervical lympadenitis
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Adverse effects of the BCG vaccine have increased since change in vaccine strain [in Finnish]
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