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Colonization of the upper respiratory tract by pneumococcus is important both as a determinant of disease and for transmission into the population. The immunological mechanisms that contain pneumococcus during colonization are well studied in mice but remain unclear in humans. Loss of this control of pneumococcus following infection with influenza virus is associated with secondary bacterial pneumonia. We used a human challenge model with type 6B pneumococcus to show that acquisition of pneumococcus induced early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function was associated with the clearance of pneumococcus. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate immune function and altered genome-wide nasal gene responses to the carriage of pneumococcus. Levels of the cytokine CXCL10, promoted by viral infection, at the time pneumococcus was encountered were positively associated with bacterial load.
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Coinfecção/imunologia , Influenza Humana/imunologia , Mucosa Nasal/imunologia , Infecções Pneumocócicas/imunologia , Quimiocina CXCL10/imunologia , Quimiotaxia de Leucócito/imunologia , Método Duplo-Cego , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Streptococcus pneumoniaeRESUMO
Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.
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Interferon gama/metabolismo , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Mycobacterium tuberculosis/imunologia , Receptores de Interleucina-1/metabolismo , Tuberculose Pulmonar/imunologia , Animais , Autofagia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Células HEK293 , Humanos , Imunidade Inata/genética , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/microbiologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Polimorfismo Genético , Ligação Proteica/genética , RNA Interferente Pequeno/genética , Receptores de Interferon/metabolismo , Receptores de Interleucina-1/genética , Tuberculose Pulmonar/genética , Receptor de Interferon gamaRESUMO
Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment among key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative convened international experts involved in developing both TB and bacillus Calmette-Guérin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects (eg, BCG vaccination in specific populations), and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate >1 model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways.
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Vacinas contra a Tuberculose , Tuberculose , Humanos , Tuberculose/prevenção & controle , Tuberculose/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Desenvolvimento de Vacinas , Vacina BCG/imunologia , Vacina BCG/administração & dosagem , Mycobacterium tuberculosis/imunologia , AnimaisRESUMO
BACKGROUND: In Malawi, the national pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than the USA, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any other serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy. METHODS: Healthy adults aged 18-40 were randomly assigned PCV13 (n=98) or saline (n=106), followed by intranasal SPN 6B inoculation at 20,000 (n=40), 80,000 (n=74), or 160,000 (n=90) CFU/100µl, 28 days post-vaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 post-inoculation using culture and multiplex qPCR targeting lytA/cpsA genes and compared carriage rates by vaccination status. RESULTS: Of 204 participants, 19.6% (40) exhibited experimental carriage, detected by culture and 25.5% (52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n=10/98) compared to the placebo group (28.3%, n=30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13=8% n=6/75 vs. placebo=25.9%, n=21/81) compared to those with natural carriage (PCV13=14.8%, n=4/27 vs. placebo=26.5%, n=9/34). Using a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had a lower VE of 52% compared to participants with no natural carriage (VE=69%). CONCLUSION: We have shown that PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers compared to those without natural carriage at the inoculation visit.
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Following sensory deprivation, areas and networks in the brain may adapt and reorganize to compensate for the loss of input. These adaptations are manifestations of compensatory crossmodal plasticity, which has been documented in both human and animal models of deafness-including the domestic cat. Although there are abundant examples of structural plasticity in deaf felines from retrograde tracer-based studies, there is a lack of diffusion-based knowledge involving this model compared to the current breadth of human research. The purpose of this study was to explore white matter structural adaptations in the perinatally-deafened cat via tractography, increasing the methodological overlap between species. Plasticity was examined by identifying unique group connections and assessing altered connectional strength throughout the entirety of the brain. Results revealed a largely preserved connectome containing a limited number of group-specific or altered connections focused within and between sensory networks, which is generally corroborated by deaf feline anatomical tracer literature. Furthermore, five hubs of cortical plasticity and altered communication following perinatal deafness were observed. The limited differences found in the present study suggest that deafness-induced crossmodal plasticity is largely built upon intrinsic structural connections, with limited remodeling of underlying white matter.
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Conectoma , Surdez , Humanos , Animais , Gatos , EncéfaloRESUMO
OBJECTIVE: To date the vast majority of research in the visual neurosciences have been forced to adopt a highly constrained perspective of the vision system in which stimuli are processed in an open-loop reactive fashion (i.e., abrupt stimulus presentation followed by an evoked neural response). While such constraints enable high construct validity for neuroscientific investigation, the primary outcomes have been a reductionistic approach to isolate the component processes of visual perception. In electrophysiology, of the many neural processes studied under this rubric, the most well-known is, arguably, the P300 evoked response. There is, however, relatively little known about the real-world corollary of this component in free-viewing paradigms where visual stimuli are connected to neural function in a closed-loop. While growing evidence suggests that neural activity analogous to the P300 does occur in such paradigms, it is an open question when this response occurs and what behavioral or environmental factors could be used to isolate this component. APPROACH: The current work uses convolutional networks to decode neural signals during a free-viewing visual search task in a closed-loop paradigm within an open-world virtual environment. From the decoded activity we construct fixation-locked response profiles that enable estimations of the variable latency of any P300 analogue around the moment of fixation. We then use these estimates to investigate which factors best reduce variable latency and, thus, predict the onset time of the response. We consider measurable, search-related factors encompassing top-down (i.e., goal driven) and bottom-up (i.e., stimulus driven) processes, such as fixation duration and salience. We also consider saccade size as an intermediate factor reflecting the integration of these two systems. MAIN RESULTS: The results show that of these factors only saccade size reliably determines the onset time of P300 analogous activity for this task. Specifically, we find that for large saccades the variability in response onset is small enough to enable analysis using traditional ensemble averaging methods. SIGNIFICANCE: The results show that P300 analogous activity does occur during closed-loop, free-viewing visual search while highlighting distinct differences between the open-loop version of this response and its real-world analogue. The results also further establish saccades, and saccade size, as a key factor in real-world visual processing.
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In response to sensory deprivation, the brain adapts according to contemporary demands to efficiently navigate a modified perceptual environment. This reorganization may result in improved processing of the remaining senses-a phenomenon referred to as compensatory crossmodal plasticity. One approach to explore this neuroplasticity is to consider the macrostructural changes in neural tissue that mirror this functional optimization. The current study is the first of its kind to measure MRI-derived gray matter (GM) volumes of control felines (n=30), while additionally identifying volumetric differences in response to perinatal deafness (30 ototoxically-deafened cats). To accomplish this purpose, regional and morphometric methods were performed in parallel. The regional analysis evaluated volumetric alterations of global GM, as well as the volumes of 146 regions of interest (ROIs) and 12 functional subgroupings of these ROIs. Results revealed whole-brain GM preservation; however, somatosensory and visual cortices exhibited an overall increase in volume. On a smaller scale, this analysis uncovered two auditory ROIs (second auditory cortex, A2, and ventral auditory field, VAF) that decreased in volume alongside two visual regions (anteromedial lateral suprasylvian area, AMLS and splenial visual area, SVA) that increased-all localized within the right hemisphere. Comparatively, the findings of tensor-based morphometry (TBM) generally aligned with those of the ROI-based method, as this voxel-wise approach demonstrated clusters of expansion coincident with visual- and somatosensory-related loci; although, it failed to detect any GM reductions following deafness. As distinct differences were identified in each analysis, the current study highlights the importance of employing multiple methods when exploring MRI volumetry. Overall, this study proposes that volumetric alterations within sensory loci allude to a redistribution of cortical space arising from modified perceptual demands following auditory deprivation.
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In the absence of hearing during development, the brain adapts and repurposes what was destined to become auditory cortex. As cortical thickness is commonly used as a proxy to identify cortical regions that have undergone plastic changes, the purpose of this investigation was to compare cortical thickness patterns between hearing and deaf cats. In this study, normal hearing (n = 29) and deaf (n = 26) cats were scanned to examine cortical thickness in hearing controls, as well as differential changes in thickness as a consequence of deafness. In hearing cats, a gradient in cortical thickness was identified across auditory cortex in which it is thinner in more dorsal regions and thicker in more ventral regions. Compared with hearing controls, differential thickening and thinning was observed in specific regions of deaf auditory cortex. More dorsal regions were found to be bilaterally thicker in the deaf group, while more ventral regions in the left hemisphere were thinner. The location and nature of these changes creates a gradient along the dorsoventral axis, wherein dorsal auditory cortical fields are thicker, whereas more ventral fields are thinner in deaf animals compared with hearing controls.
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Córtex Auditivo , Surdez , Animais , Córtex Auditivo/diagnóstico por imagem , Surdez/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Audição , Espessura Cortical do Cérebro , Plasticidade NeuronalRESUMO
Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).
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Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Virulência , Nariz , Infecções Pneumocócicas/prevenção & controle , Imunização , Anticorpos Antibacterianos , Imunoglobulina G , Vacinas Pneumocócicas/uso terapêuticoRESUMO
The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMÏ or bMÏ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMÏ whereas both Mbv and Mtb efficiently replicate in bMÏ. Specifically, we show that out of the four infection combinations, only the infection of bMÏ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMÏ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMÏ as mediators of this process.
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Interações Hospedeiro-Patógeno/fisiologia , Macrófagos/microbiologia , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose/microbiologia , Tropismo Viral/fisiologia , Animais , Bovinos , Células Gigantes , HumanosRESUMO
Objective: To estimate the prevalence of individual chronic conditions and multimorbidity among adults admitted to hospital in countries in sub-Saharan Africa. Methods: We systematically searched MEDLINE®, Embase®, Global Index Medicus, Global Health and SciELO for publications reporting on patient cohorts recruited between 1 January 2010 and 12 May 2023. We included articles reporting prevalence of pre-specified chronic diseases within unselected acute care services (emergency departments or medical inpatient settings). No language restrictions were applied. We generated prevalence estimates using random-effects meta-analysis alongside 95% confidence intervals, 95% prediction intervals and I2 statistics for heterogeneity. To explore associations with age, sex, country-level income status, geographical region and risk of bias, we conducted pre-specified meta-regression, sub-group and sensitivity analyses. Findings: Of 6976 identified studies, 61 met the inclusion criteria, comprising data from 20 countries and 376 676 people. None directly reported multimorbidity, but instead reported prevalence for individual conditions. Among medical admissions, the highest prevalence was human immunodeficiency virus infection (36.4%; 95% CI: 31.3-41.8); hypertension (24.4%; 95% CI: 16.7-34.2); diabetes (11.9%; 95% CI: 9.9-14.3); heart failure (8.2%; 95% CI: 5.6-11.9); chronic kidney disease (7.7%; 95% CI: 3.9-14.7); and stroke (6.8%; 95% CI: 4.7-9.6). Conclusion: Among patients seeking hospital care in sub-Saharan Africa, multimorbidity remains poorly described despite high burdens of individual chronic diseases. Prospective public health studies of multimorbidity burden are needed to generate integrated and context-specific health system interventions that act to maximize patient survival and well-being.
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Doença Crônica , Atenção à Saúde , Pacientes , Adulto , Humanos , África Subsaariana/epidemiologia , Hospitais , Estudos ProspectivosRESUMO
OBJECTIVE: To report outcomes within the Rapid Assessment for Prostate Imaging and Diagnosis (RAPID) diagnostic pathway, introduced to reduce patient and healthcare burdens and standardize delivery of pre-biopsy multiparametric magnetic resonance imaging (MRI) and transperineal biopsy. PATIENTS AND METHODS: A total of 2130 patients from three centres who completed the RAPID pathway (3 April 2017 to 31 March 2020) were consecutively entered as a prospective registry. These patients were also compared to a pre-RAPID cohort of 2435 patients. Patients on the RAPID pathway with an MRI score 4 or 5 and those with PSA density ≥0.12 and an MRI score 3 were advised to undergo a biopsy. Primary outcomes were rates of biopsy and cancer detection. Secondary outcomes included comparison of transperineal biopsy techniques, patient acceptability and changes in time to diagnosis before and after the introduction of RAPID. RESULTS: The median patient age and PSA level were 66 years and 6.6 ng/mL, respectively. Biopsy could be omitted in 43% of patients (920/2130). A further 7.9% of patients (168/2130) declined a recommendation for biopsy. The percentage of biopsies avoided among sites varied (45% vs 36% vs 51%; P < 0.001). In all, 30% (221/742) had a local anaesthetic (grid and stepper) transperineal biopsy. Clinically significant cancer detection (any Gleason score ≥3 + 4) was 26% (560/2130) and detection of Gleason score 3 + 3 alone constituted 5.8% (124/2130); detection of Gleason score 3 + 3 did not significantly vary among sites (P = 0.7). Among participants who received a transperineal targeted biopsy, there was no difference in cancer detection rates among local anaesthetic, sedation and general anaesthetic groups. In the 2435 patients from the pre-RAPID cohor, time to diagnosis was 32.1 days (95% confidence interval [CI] 29.3-34.9) compared to 15.9 days (95% CI 12.9-34.9) in the RAPID group. A total of 141 consecutive patient satisfaction surveys indicated a high satisfaction rate with the pathway; 50% indicated a preference for having all tests on a single day. CONCLUSIONS: The RAPID prostate cancer diagnostic pathway allows 43% of men to avoid a biopsy while preserving good detection of clinically significant cancers and low detection of insignificant cancers, although there were some centre-level variations.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Antígeno Prostático Específico , Anestésicos Locais , Biópsia Guiada por Imagem/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Compared to the abundance of clinical and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Our aim was to explore the relationship between viral lineage and patient outcome. METHODS: We enrolled a prospective observational cohort of adult patients hospitalised with PCR-confirmed COVID-19 disease between July 2020 and March 2022 from Blantyre, Malawi, covering four waves of SARS-CoV-2 infections. Clinical and diagnostic data were collected using an adapted ISARIC clinical characterization protocol for COVID-19. SARS-CoV-2 isolates were sequenced using the MinION™ in Blantyre. RESULTS: We enrolled 314 patients, good quality sequencing data was available for 55 patients. The sequencing data showed that 8 of 11 participants recruited in wave one had B.1 infections, 6/6 in wave two had Beta, 25/26 in wave three had Delta and 11/12 in wave four had Omicron. Patients infected during the Delta and Omicron waves reported fewer underlying chronic conditions and a shorter time to presentation. Significantly fewer patients required oxygen (22.7% [17/75] vs. 58.6% [140/239], p < 0.001) and steroids (38.7% [29/75] vs. 70.3% [167/239], p < 0.001) in the Omicron wave compared with the other waves. Multivariable logistic-regression demonstrated a trend toward increased mortality in the Delta wave (OR 4.99 [95% CI 1.0-25.0 p = 0.05) compared to the first wave of infection. CONCLUSIONS: Our data show that each wave of patients hospitalised with SARS-CoV-2 was infected with a distinct viral variant. The clinical data suggests that patients with severe COVID-19 disease were more likely to die during the Delta wave.
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COVID-19 , Adulto , Humanos , SARS-CoV-2 , Malaui , Estudos de Coortes , Confiabilidade dos DadosRESUMO
Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 µl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated (n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.
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Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , Criança , Lactente , Adulto Jovem , Adulto , Sorogrupo , Portador Sadio , Vacinas Pneumocócicas/uso terapêutico , Infecções Pneumocócicas/prevenção & controle , Nasofaringe/microbiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologiaRESUMO
Pneumococcal conjugate vaccine (PCV) efficacy is lower for noninvasive pneumonia than invasive disease. In this study, participants were immunized with 13-valent PCV (PCV13) or hepatitis A vaccine (control). Bronchoalveolar lavage samples were taken between 2 and 6 months and serum at 4 and 7 weeks postvaccination. In the lung, anti-capsular immunoglobulin G (IgG) levels were higher in the PCV13 group compared to controls for all serotypes, except 3 and 6B. Systemically, IgG levels were elevated in the PCV13 group at 4 weeks for all serotypes, except serotype 3. IgG in bronchoalveolar lavage and serum positively correlated for nearly all serotypes. PCV13 shows poor immunogenicity to serotype 3, implying lack of protective efficacy. Clinical Trials Registration. ISRCTN 45340436.
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Infecções Pneumocócicas , Anticorpos Antibacterianos , Humanos , Imunoglobulina G , Lactente , Pulmão , Vacinas Pneumocócicas , Sorogrupo , Vacinas ConjugadasRESUMO
BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi. METHODS: We conducted a household study in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%-6.1%) among adults and 0.3% (95% CI, .1%-.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%-99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy.
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Infecções por HIV , Hepatite B , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B , Humanos , Lactente , Malaui/epidemiologia , Masculino , Estudos Soroepidemiológicos , VacinaçãoRESUMO
BACKGROUND: Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. METHODS: Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. RESULTS: Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. CONCLUSIONS: Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.
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Bacillus , Tuberculose Pulmonar , Adulto , Humanos , Isoniazida/uso terapêutico , Isoniazida/farmacocinética , Rifampina/farmacocinética , Escarro/microbiologia , Antituberculosos/farmacocinética , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Pirazinamida/farmacocinética , Etambutol/uso terapêuticoRESUMO
BACKGROUND: Sepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa. METHODS: We recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression. RESULTS: There were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05-0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%. CONCLUSIONS: Sepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.
Assuntos
Infecções por HIV , Malária , Sepse , Tuberculose , Adulto , Antibacterianos , Teorema de Bayes , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Malária/complicações , Malaui/epidemiologia , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/epidemiologia , Tuberculose/complicaçõesRESUMO
BACKGROUND: Binding and neutralising anti-Spike antibodies play a key role in immune defence against SARS-CoV-2 infection. Since it is known that antibodies wane with time and new immune-evasive variants are emerging, we aimed to assess the dynamics of anti-Spike antibodies in an African adult population with prior SARS-CoV-2 infection and to determine the effect of subsequent COVID-19 vaccination. METHODS: Using a prospective cohort design, we recruited adults with prior laboratory-confirmed mild/moderate COVID-19 in Blantyre, Malawi, and followed them up for 270 days (n = 52). A subset of whom subsequently received a single dose of the AstraZeneca COVID-19 vaccine (ChAdOx nCov-19) (n = 12). We measured the serum concentrations of anti-Spike and receptor-binding domain (RBD) IgG antibodies using a Luminex-based assay. Anti-RBD antibody cross-reactivity across SARS-CoV-2 variants of concern (VOC) was measured using a haemagglutination test. A pseudovirus neutralisation assay was used to measure neutralisation titres across VOCs. Ordinary or repeated measures one-way ANOVA was used to compare log10 transformed data, with p value adjusted for multiple comparison using Sídák's or Holm-Sídák's test. RESULTS: We show that neutralising antibodies wane within 6 months post mild/moderate SARS-CoV-2 infection (30-60 days vs. 210-270 days; Log ID50 6.8 vs. 5.3, p = 0.0093). High levels of binding anti-Spike or anti-RBD antibodies in convalescent serum were associated with potent neutralisation activity against the homologous infecting strain (p < 0.0001). A single dose of the AstraZeneca COVID-19 vaccine following mild/moderate SARS-CoV-2 infection induced a 2 to 3-fold increase in anti-Spike and -RBD IgG levels 30 days post-vaccination (both, p < 0.0001). The anti-RBD IgG antibodies from these vaccinated individuals were broadly cross-reactive against multiple VOCs and had neutralisation potency against original D614G, beta, and delta variants. CONCLUSIONS: These findings show that the AstraZeneca COVID-19 vaccine is an effective booster for waning cross-variant antibody immunity after initial priming with SARS-CoV-2 infection. The potency of hybrid immunity and its potential to maximise the benefits of COVID-19 vaccines needs to be taken into consideration when formulating vaccination policies in sub-Saharan Africa, where there is still limited access to vaccine doses.
Assuntos
COVID-19 , Vacinas Virais , Formação de Anticorpos , COVID-19/prevenção & controle , COVID-19/terapia , Vacinas contra COVID-19 , Humanos , Imunização Passiva , Estudos Prospectivos , SARS-CoV-2 , Vacinas Virais/farmacologia , Soroterapia para COVID-19RESUMO
Species belonging to the Mycobacterium tuberculosis Complex (MTBC) show more than 99% genetic identity but exhibit distinct host preference and virulence. The molecular genetic changes that underly host specificity and infection phenotype within MTBC members have not been fully elucidated. Here, we analysed RD900 genomic region across MTBC members using whole genome sequences from 60 different MTBC strains so as to determine its role in the context of MTBC evolutionary history. The RD900 region comprises two homologous genes, pknH1 and pknH2, encoding a serine/threonine protein kinase PknH flanking the tbd2 gene. Our analysis revealed that RD900 has been independently lost in different MTBC lineages and different strains, resulting in the generation of a single pknH gene. Importantly, all the analysed M. bovis and M. caprae strains carry a conserved deletion within a proline rich-region of pknH, independent of the presence or absence of RD900. We hypothesized that deletion of pknH proline rich-region in M. bovis may affect PknH function, having a potential role in its virulence and evolutionary adaptation. To explore this hypothesis, we constructed two M. bovis 'knock-in' strains containing the M. tuberculosis pknH gene. Evaluation of their virulence phenotype in mice revealed a reduced virulence of both M. bovis knock-in strains compared to the wild type, suggesting that PknH plays an important role in the differential virulence phenotype of M. bovis vs M. tuberculosis.