The socioeconomic impact of tuberculosis on children and adolescents: a scoping review and conceptual framework.

BACKGROUND: Tuberculosis (TB) has been repeatedly shown to have socioeconomic impacts in both individual-level and ecological studies; however, much less is known about this effect among children and adolescents and the extent to which being affected by TB during childhood and adolescence can have life-course implications. This paper describes the results of the development of a conceptual framework and scoping review to review the evidence on the short- and long-term socioeconomic impact of tuberculosis on children and adolescents. OBJECTIVES: To increase knowledge of the socioeconomic impact of TB on children and adolescents. METHODS: We developed a conceptual framework of the socioeconomic impact of TB on children and adolescents, and used scoping review methods to search for evidence supporting or disproving it. We searched four academic databases from 1 January 1990 to 6 April 2021 and conducted targeted searches of grey literature. We extracted data using a standard form and analysed data thematically. RESULTS: Thirty-six studies (29 qualitative, five quantitative and two mixed methods studies) were included in the review. Overall, the evidence supported the conceptual framework, suggesting a severe socioeconomic impact of TB on children and adolescents through all the postulated pathways. Effects ranged from impoverishment, stigma, and family separation, to effects on nutrition and missed education opportunities. TB did not seem to exert a different socioeconomic impact when directly or indirectly affecting children/adolescents, suggesting that TB can affect this group even when they are not affected by the disease. No study provided sufficient follow-up to observe the long-term socioeconomic effect of TB in this age group. CONCLUSION: The evidence gathered in this review reinforces our understanding of the impact of TB on children and adolescents and highlights the importance of considering effects during the entire life course. Both ad-hoc and sustainable social protection measures and strategies are essential to mitigate the socioeconomic consequences of TB among children and adolescents.

Detecting tuberculosis: rapid tools but slow progress.

The World Health Organization (WHO) currently recommends Xpert® MTB/RIF as the initial test for all people with presumptive tuberculosis (TB). A number of challenges have been reported, however, in using this technology, particularly in low-resource settings. Here we examine these challenges, and provide our perspective of the barriers to Xpert scale-up as assessed through a survey in 16 TB burden countries in which the Médecins Sans Frontières is present. We observed that the key barriers to scale-up include a lack of policy adoption and implementation of WHO recommendations for the use of Xpert, resulting from high costs, poor sensitisation of clinical staff and a high turnover of trained laboratory staff; insufficient service and maintenance provision provided by the manufacturer; and inadequate resources for sustainability and expansion. Funding is a critical issue as countries begin to transition out of support from the Global Fund. While it is clear that there is still an urgent need for research into and development of a rapid, affordable point-of-care test for TB that is truly adapted for use in low-resource settings, countries in the meantime need to develop functional and sustainable Xpert networks in order to close the existing diagnostic gap.

L'Organisation Mondiale de la Santé (OMS) recommande actuellement l'Xpert® MTB/RIF comme test initial pour toutes les personnes suspectes de tuberculose (TB). Le recours à cette technique s'est cependant heurté à un certain nombre de défis, particulièrement dans les contextes de faibles ressources. Nous examinons ici ces défis et proposons notre vision des contraintes à l'expansion comme l'a montré une enquête dans 16 pays très frappés par la TB où Médecins Sans Frontières est présent. Nous affirmons que les entraves majeures à l'expansion incluent un manque d'adoption politique et de mise en œuvre des recommandations de l'OMS relatives à l'utilisation de l'Xpert, résultant des coûts élevés, d'une sensibilisation insuffisante du personnel clinique et d'un taux élevé de renouvellement du personnel de laboratoire formé ; une offre insuffisante de service et de maintenance de la part du fabricant ; et des ressources insuffisantes pour la pérennité et l'expansion. Le financement est un problème crucial à mesure que les pays commencent leur transition vers l'arrêt du soutien du Fonds Mondial. Il est clair qu'il y a toujours un besoin urgent de recherche et de développement d'un test de TB rapide, abordable, réalisable sur place et réellement adapté à une utilisation dans des contextes de faibles ressources. Dans l'intervalle, les pays ont cependant besoin d'élaborer des réseaux d'Xpert fonctionnels et pérennisables de manière à combler le fossé existant en matière de diagnostic.

En la actualidad, la Organización Mundial de la Salud (OMS) recomienda como primer método diagnóstico la prueba Xpert® MTB/RIF en todas las personas con presunción clínica de tuberculosis (TB). Se ha comunicado, no obstante, una serie de dificultades con la utilización de esta técnica sobre todo en entornos con recursos limitados. En el presente estudio se examinan estas dificultades y se ofrece una perspectiva de los obstáculos a la ampliación de escala de la recomendación, a partir de una encuesta realizada en 16 países con carga de morbilidad por TB donde está presente Médicos Sin Fronteras. Los autores afirman que los principales obstáculos a la ampliación de escala son los siguientes: la falta de adopción de políticas en favor de las recomendaciones de la OMS sobre la utilización de la prueba Xpert y el refuerzo de su cumplimiento, debido a los costos altos, la escasa sensibilización del personal médico y una alta rotación del personal de laboratorio capacitado; la insuficiencia de la prestación de servicios y mantenimiento por parte del fabricante; y los recursos insuficientes para la sostenibilidad y la ampliación. El financiamiento constituye un elemento primordial a medida que los países dejan de percibir el apoyo del Fondo Mundial. Es evidente que existe una necesidad urgente de investigación y desarrollo de una prueba en el lugar de la consulta que sea asequible y efectivamente adaptada a los entornos con recursos escasos, pero mientras tanto, los países deben crear redes funcionales y sostenibles de la prueba Xpert a fin de subsanar las deficiencias actuales en el diagnóstico.

Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS.

The enzyme DXS catalyzes the first, rate-limiting step of the 2-C-methyl-d-erythritol-4-phosphate (MEP, 1) pathway using thiamine diphosphate (ThDP) as cofactor; the DXS-catalyzed reaction constitutes also the first step in vitamin B1 and B6 metabolism in bacteria. DXS is the least studied among the enzymes of this pathway in terms of crystallographic information, with only one complete crystal structure deposited in the Protein Data Bank (Deinococcus radiodurans DXS, PDB: ). We synthesized a series of thiamine and ThDP derivatives and tested them for their biochemical activity against two DXS orthologues, namely D. radiodurans DXS and Mycobacterium tuberculosis DXS. These experimental results, combined with advanced docking studies, led to the development and validation of a homology model of M. tuberculosis DXS, which, in turn, will guide medicinal chemists in rationally designing potential inhibitors for M. tuberculosis DXS.

Prevention of mother-to-child transmission of HIV in a refugee camp setting in Tanzania.

The objective of this article is to describe the results of a 2-year pilot programme implementing prevention of mother to child HIV transmission (PMTCT) in a refugee camp setting. Interventions used were: community sensitization, trainings of healthcare workers, voluntary counselling and HIV testing (VCT), infant feeding, counselling, and administration of Nevirapine. Main outcome measures include: HIV testing acceptance rates, percentage of women receiving post test counselling, Nevirapine uptake, and HIV prevalence among pregnant women and their infants. Ninety-two percent of women (n=9,346) attending antenatal clinics accepted VCT. All women who were tested for HIV received their results and posttest counselling. The HIV prevalence rate among the population was 3.2%. The overall Nevirapine uptake in the camp was 97%. Over a third of women were repatriated before receiving Nevirapine. Only 14% of male counterparts accepted VCT. Due to repatriation, parent's refusal, and deaths, HIV results were available for only 15% of infants born to HIV-infected mothers. The PMTCT programme was successfully integrated into existing antenatal care services and was acceptable to the majority of pregnant women. The major challenges encountered during the implementation of this programme were repatriation of refugees before administration of Nevirapine, which made it difficult to measure the impact of the PMTCT programme.

[Ectopic neuroglial tissue associated with intrapulmonary congenital cystic adenomatoid malformation]. / Ectopia neurogliale associata a malformazione adenomatoide cistica polmonare.

BACKGROUND: Few cases of ectopic neurological tissue have been reported in the lung. The aim of the present study was to give a brief overview of these cases and to examine an additional case of intrapulmonary neuroglial heterotopia. We have identified only sixteen similar cases in the literature. CASE DESCRIPTION: The object of our study was a male fetus of Asian parents at the 23rd week of gestation, in which ultrasound tests revealed the presence of anterior encephalocele. Routine postmortem examination of lung samples showed neuroglial tissue and a congenital adenomatoid cystic malformation of type II. The lesion was made up of multiple small cysts lined with columnar or ciliated cuboidal epithelium. A possible link between adenomatoid malformation and intrapulmonary neurological tissue has not so far been reported in the literature. Immunohistochemical analysis showed the presence in the pulmonary parenchyma of neuronal cells (neuron-specific enolase positive), astrocytes (glial fibrillary acidic protein positive) and intra-alveolar squamous cells (citokeratines positive), indicative of fetal aspiration of amniotic fluid. CONCLUSIONS: There are several possible explanations for the presence of intrapulmonary neuroglial heterotopia: fetal aspiration, neural crest migration defects or vascular embolization with implantation. However, in the view of the microscopic findings and at the same time recognizing the intrapulmonary aspiration of amniotic fluid, the authors maintain that the most likely explanation for the heterotopia is that of consequential multiple malformations. Moreover neuroglial ectopy and cystic adenomatoid congenital malformation of the lung could have appeared simultaneously, due to embryologic insult between the 4th and the 20th week of gestation.

Primary malignant rhabdoid tumours of the central nervous system: an immunohistochemical and ultrastructural study.

Three cases of primary rhabdoid tumour of the CNS (RT-CNS) are presented. In case 1 a hemispheric tumour developed in a 10.5 months old girl, who survived for 6 months after incomplete resection, radio- and polychemotherapy. Case 2 was a 4 years and 8 months old boy with a large IIIrd ventricle tumour, who died of leptomeningeal tumour dissemination 7 months after diagnosis despite radiotherapy. In case 3 a pineal mass occurring in a 14 month old female was radioresistant and totally exstirpated. The child died due to tumour recurrence two months later. Autopsy examination revealed widespread leptomeningeal dissemination. All three cases fulfilled light and electron microscopic criteria of RT-CNS including abundant eosinophilic cytoplasm, vesicular nuclei with large nucleoli and conspicuous anti-vimentin positive filaments. Extensive immunohistochemical studies showed expression of epithelial (EMA, KL1), macrophage (alpha-1 antichymotrypsin), neuro-ectodermal (GFAP, NSE, beta-tubulin III) and myogenic markers (desmin, actin). Different stress proteins (alpha-B crystallin, HSP70) were also expressed. Tumour cells showed a proliferation (MIB1) index of 28.4% (case 1) and 33.4% (case 2). From our study it can be concluded that RT-CNS reveals significant immuno-morphological heterogeneity thus supporting the view that it is not a specific pathological entity but merely a phenotypic appearance of different neoplasms, some of which are linked to primitive neuro-ectodermal tumours.

Clinical and pathological features in hydrocarbon-induced parkinsonism.

A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n-hexane and halogenated compounds. The patient developed a rapid-course disease that progressed even after withdrawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.

Primary multiple epithelioid leiomyosarcoma of the liver.

Sarcomas represent only 1-2% of primary malignant tumors of the liver. We report the twenty first case of primary hepatic leiomyosarcoma in the literature. Metastases from gastrointestinal tract, female genital system and lung have to be excluded before confirming diagnosis of a primary neoplasm. Extensive involvement of the liver parenchyma contraindicated surgery, the treatment of choice when the tumor is solitary or multiple but located in one lobe. Chemotherapy, as employed in our patient, is the alternative therapeutic option in inoperable cases, but its role has to be clarified.

Autoptic findings in HIV-1 positive children.

The growing incidence of AIDS in children and newborns has been related to increasing incidence of AIDS in women. Case records were composed by 14 children with death occurring at different ages--from 1 hour to 12 years--and 1 female fetus, all with serological confirmation of AIDS. Brain and internal organs samples were collected at autopsy for morphological, immunohistochemical and "in situ" hybridization's technical examination. The prevailing extracerebral pathology observed at autopsy consisted of opportunistic infections. The cerebral findings were HIV-encephalopathy; cytomegalovirus encephalitis; vascular alterations such as necrosis and hemorrhage; calcifications and edema. Neurologic symptoms were reported in 3 children of intravenous drug-abuser mothers as drug withdrawal syndrome. HIV positivity in one or both the intravenous drug-abuser parents is the main risk factor of congenital AIDS. This factor means lack of care during the gestational stage and may determine relevant differences in the course of disease. The cerebral changes due to opportunistic infection must be differentiated from HIV-specific lesions; it has to be stressed that "diffuse" leukoencephalopathy is not AIDS-specific but can be found in every chronic encephalitis/encephalopathy especially in newborns and children. Chronologically, HIV encephalopathy appears as late manifestation of the disease, due to an infiltration of CNS of HIV-infected macrophages and not to an impairment of neuronal or glial cells infected by HIV in the early stages of the disease.

Progressive multifocal leukoencephalopathy (PML) in the acquired immunodeficiency syndrome (AIDS). A neuropathological autopsy study of 21 cases.

In a neuropathological autopsy study of 21 cases of AIDS-associated PML no fundamental morphological differences to non-AIDS PML were found. PML in AIDS often showed very large foci as well as necrotizing lesions. Partial involvement of cerebral cortex and deep gray matter were common findings; infratentorial lesions could be observed in more than three quarters of cases. Perivascular mononuclear infiltrates within PML foci were frequent and obviously not associated with a more benign clinical course. Possible reasons for these peculiarities of PML in AIDS are discussed. In 7 cases evidence of concomitant HIV encephalopathy was found; this may be one relevant factor contributing to severity of PML in AIDS. PML has to be regarded as a common complication of HIV infection, which may show atypical morphological and neuroradiological features.

Evidence of clonal progression in a case of Richter syndrome.

BACKGROUND: The debate continues as to whether Richter syndrome should be defined as non-Hodgkin lymphoma (NHL) because of a more malignant clone of neoplastic cells superimposed on preexisting chronic lymphocytic leukemia (CLL) or as the chance occurrence of two unrelated tumors. The cellular characteristics of the neoplastic clone involved in the CLL phase and the subsequent NHL were investigated in a patient in whom Richter syndrome developed. METHODS: Cell analysis was performed with immunofluorescence, histologic analysis, DNA extraction, and Southern blot analysis. RESULTS: The separated CLL and NHL B-cells from blood and bone marrow, as well as the neoplastic cells in autopsy specimens of the organs affected by NHL, particularly the brain, were found to express the same light chain of surface immunoglobulin (SIg). The change MD-->M in the SIg heavy-chain expression and the appearance of cytoplasmic IgMk suggested isotype switching simulating that observed on the final phases of primary B-cell differentiation. This hypothesis was confirmed by Southern blot analysis of DNA from blood cells in the CLL phase and in Richter transformation, which showed that the two cell populations had identical Ig gene rearrangement. CONCLUSIONS: The NHL in the patient in this study represented a malignant progression of CLL, not a second lymphoid malignancy.

AIDS-myelopathy. A neuropathological study.

Vacuolar myelopathy belongs to the AIDS-associated diseases. It is characterized by vacuolation and infiltration of the long tracts of the spinal cord by macrophages. The clinical and morphological findings of 8 AIDS-patients with vacuolar myelopathy are reported here. The syndrome developed during the final stages of AIDS and was associated with HIV-encephalopathy in 5 cases. The vacuoles were mainly due to intramyelinic swelling and vacuolation. Vacuolated macrophages and axons contributed only to a minor degree. In one case only, HIV-antigens were detected immunohistochemically. The results are discussed in the light of modern pathogenetical concepts of HIV-related diseases.

Progressive multifocal leukoencephalopathy and gliomas in a HIV-negative patient.

A case of progressive multifocal leukoencephalopathy (PML) is reported, detected at autopsy of a 30-year-old patient. The clinical picture was characterized by a progressive course of mental deterioration and ingravescent neurological symptoms. The patient was HIV-negative. He died of bronchopneumonia, after a clinical course of 13 months. Autopsy disclosed pulmonary tuberculosis with involvement of regional lymph nodes. In the brain, besides numerous PML-foci of varying age and structure, a pleomorphic astrocytoma was found in the white matter of the right parietal lobe. In the brain stem glial proliferation resembling diffuse gliomatosis was also present. In situ hybridization revealed Papova-virus (JCV) in oligoglial nuclei, but not in neoplastic astrocytes. This is the third report on the concomitant occurrence of PML and glioma in man.

[The CNS in AIDS and in asymptomatic HIV positive patients]. / Das ZNS bei AIDS und bei asymptomatischen HIV-Trägern.

Neuropathological investigations were carried out on 166 autopsies of HIV-seropositive patients, with and without AIDS. Opportunistic infections and lymphomas were present in about 50% of cases; 65 patients were bearers of HIV-encephalopathy. HIV core protein p24 was detected in few mono- and multinucleated macrophages (HIV-cells), only in cases with HIV-encephalopathy. In the CNS of HIV-positive, asymptomatic patients no histological or immunohistochemical abnormalities were seen. These findings let suppose that AIDS-Dementia is a result of a late infiltration of HIV-infected macrophages from the bloodstream into the brain and not due to an impairment of neuronal or glial cells infected by HIV in the early stages of the disease.

[Progressive multifocal leukoencephalopathy (PML) in AIDS: morphological and topographical characteristics]. / Die progressive multifokale Leukoenzephalopathie (PML) bei AIDS: Morphologische und topographische Besonderheiten.

15 autopsy cases of PML in AIDS are presented. Frequent findings were: Very large, confluent PML-lesions (7 cases), lesions with prominent necrotic features (10 cases) and with marked perivascular mononuclear infiltrates (6 cases). In 9 cases additional PML-foci were seen in the cerebellum and/or the brain stem, and in 1 case there was even an exclusive involvement of those structures. Such characteristics regarding severity and topography of PML in AIDS, may be due to additional toxic factors. In 7 cases HIV-encephalopathy with multinucleated macrophages was present.

[Pathology of the internal organs and central nervous system in acquired immunodeficiency syndrome (with special reference to opportunistic infections)]. / La patologia degli organi interni e del sistema nervoso centrale nella sindrome da immunodeficienza acquisita (con particolare riferimento alle infezioni opportunistiche).

Extracerebral and cerebral pathology in AIDS (with particular emphasis on the opportunistic infections). The Authors present the extracerebral pathology of 27 cases of AIDS observed at the Department of Pathology of Milan and the cerebral pathology of 80 cases of AIDS collected by three Institutes (Department of Pathology of Milan, Department of Pathology of Rimini and Department of Neuropathology of Münster) with particular emphasis on the pathology of the opportunistic infections. In the adults' group, the most frequent infections are the protozoan ones (T. gondii) followed with equal incidence by the viral and fungal diseases. In the pediatric group the viral diseases are the most frequently seen. Almost all of the adults show multiple infections in the same organ or in different organs. Diffuse lesions with heavy pathologic fields were observed also without tissue reaction. As to cerebral pathology AIDS' patients with opportunistic infections show focal symptoms, whereas the so called "subacute microglial encephalitis" generally appears as a demential syndrome. In cases with progressive multifocal leukoencephalopathy JC virus was always found and in one case also SV 40 - and BK virus. The diffuse demyelinization in some cases of HIV-Encephalopathy is aspecific. In HIV-positive newborns with cerebral signs, the lesions are characterized by oedema, spongiosis and microcalcifications of the basal ganglia; these are aspecific lesions which can be found in toxic and infectious encephalopathies.

Cerebral listeriosis in adults. Three cases report.

The Authors describe three autoptic cases of meningoencephalitis in adults due to an emerging pathogen, the Gram-positive bacillus Listeria monocytogenes. Only one of these was an immunosuppressed patient (recurrent carcinoma of the larynx and bladder papillomas), while no severe cause of debilitation was detected in the other two cases, excluding colonic diverticulosis in both. The post-mortem examination revealed leptomeningitis and encephalitis. Lympho-monocytic tissue reaction with perivascular cuffing was present in all the cases. The etiologic agent, L. monocytogenes, was identified by cultures from clinical or autoptic specimens.