RESUMO
Rationale: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was defined as TB with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]), any fluoroquinolone (FQ), and any second-line injectable drug (SLID). In 2019, the World Health Organization issued new recommendations for treating patients with drug-resistant TB, substantially limiting the role of SLIDs in MDR-TB treatment and thus putting the definition of XDR-TB into question. Objectives: To propose an up-to-date definition for XDR-TB. Methods: We used a large data set to assess treatment outcomes for patients with MDR-TB exposed to any type of longer regimen. We included patients with bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We performed logistic regression to estimate the adjusted odds ratios (aORs) for an unfavorable treatment outcome (failure, relapse, death, loss to follow-up), and estimates were stratified by the resistance pattern (FQ and/or SLID) and group A drug use (moxifloxacin/levofloxacin, linezolid, and/or bedaquiline). Measurements and Main Results: We included 11,666 patients with MDR-TB; 4,653 (39.9%) had an unfavorable treatment outcome. Resistance to FQs increased the odds of an unfavorable treatment outcome (aOR, 1.91; 95% confidence interval [CI], 1.63-2.23). Administration of bedaquiline and/or linezolid improved treatment outcomes regardless of resistance to FQs and/or SLIDs. Among patients with XDR-TB, compared with persons receiving no group A drug, aORs for an unfavorable outcome were 0.37 (95% CI, 0.20-0.69) with linezolid only, 0.40 (95% CI, 0.21-0.77) with bedaquiline only, and 0.21 (95% CI, 0.12-0.38) with both. Conclusions: Our study supports a new definition of XDR-TB as MDR-TB and additional resistance to FQ plus bedaquiline and/or linezolid and helps assess the adequacy of this definition for surveillance and treatment choice.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adulto , Idoso , Bases de Dados Factuais , Diarilquinolinas/uso terapêutico , Esquema de Medicação , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Fluoroquinolonas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Linezolida/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Rifampina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis. METHODS: We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection. FINDINGS: We included 11â920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0-2·9) for all patients with HIV-infection, 1·8 (1·5-2·2) for HIV-positive patients on ART, and 4·2 (3·0-5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death. INTERPRETATION: Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Adulto , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Fatores de Risco , Tuberculose Resistente a Múltiplos Medicamentos/complicaçõesRESUMO
BackgroundHealthcare workers (HCW) have been identified as index cases in disease outbreaks of vaccine-preventable diseases (VPD) in hospitals.AimWe investigated whether Danish paediatric HCW were protected against selected serious VPD.MethodsWe included 90% of staff members from two paediatric departments. All 555 HCW (496 women) supplied a blood sample for serology and filled in a questionnaire. Antibodies were measured with enzyme immunoassay against measles, mumps, rubella (MMR), varicella zoster, pertussis toxin and diphtheria toxin.ResultsProtective levels of IgG were found for measles (90.3%), mumps (86.5%), rubella (92.3%), varicella (98.6%) and diphtheria (80.5%). We found seropositivity for all three MMR components in 421 (75.9%) HCW, lowest in those younger than 36 years (63.3%). Only 28 (5%) HCW had measurable IgG to pertussis. HCW with self-reported immunity defined as previous infection or vaccination, had protective levels of IgG against measles, mumps, rubella and varicella in 87.4-98.8% of cases, not significantly higher than in those not reporting immunity. Previous history of disease had a high positive predictive value (PPV) of 96.8-98.8%. The PPV for previous vaccination ranged from 82.5% to 90.3%. In contrast, negative predictive values of self-reported history of disease and vaccination were remarkably low for all diseases.ConclusionThe immunity gaps found primarily in young HCW indicate a need for a screening and vaccination strategy for this group. Considering the poor correlation between self-reported immunity and seropositivity, efforts should be made to check HCW's immune status in order to identify those who would benefit from vaccination.
Assuntos
Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Doenças Preveníveis por Vacina , Anticorpos Antivirais , Criança , Dinamarca/epidemiologia , Feminino , Pessoal de Saúde , Humanos , Sarampo/epidemiologia , Sarampo/prevenção & controle , Vacina contra Sarampo-Caxumba-Rubéola , Caxumba/epidemiologia , Caxumba/prevenção & controle , Rubéola (Sarampo Alemão)/prevenção & controle , Estudos Soroepidemiológicos , VacinaçãoRESUMO
BackgroundIn Denmark, influenza surveillance is ensured by data capturing from existing population-based registers. Since 2017, point-of-care (POC) testing has been implemented outside the regional clinical microbiology departments (CMD).AimWe aimed to assess influenza laboratory results in view of the introduction of POC testing.MethodsWe retrospectively observed routine surveillance data on national influenza tests before and after the introduction of POC testing as available in the Danish Microbiological Database. Also, we conducted a questionnaire study among Danish CMD about influenza diagnostics.ResultsBetween the seasons 2014/15 and 2018/19, 199,744 influenza tests were performed in Denmark of which 44,161 were positive (22%). After the introduction of POC testing, the overall percentage of positive influenza tests per season did not decrease. The seasonal influenza test incidence was higher in all observed age groups. The number of operating testing platforms placed outside a CMD and with an instrument analytical time ≤ 3â¯h increased after 2017. Regionally, the number of tests registered as POC in the Danish Microbiological Database and the number of tests performed with an instrument analytical time ≤ 3â¯h or outside a CMD partially differed. Where comparable (71% of tests), the relative proportion of POC tests out of all tests increased from season 2017/18 to 2018/19. In both seasons, the percentage of positive POC tests resulted slightly lower than for non-POC tests.ConclusionPOC testing integrated seamlessly into national influenza surveillance. We propose the use of POC results in the routine surveillance of seasonal influenza.
Assuntos
Influenza Humana , Dinamarca/epidemiologia , Humanos , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Testes Imediatos , Estudos Retrospectivos , Estações do AnoRESUMO
We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12â months (the "shorter regimen") and individualised regimens of ≥20â months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12â months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13â104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17-â-0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Rifampina , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BackgroundPoint-of-care tests (POCT) for influenza A and B viruses and respiratory syncytial virus (RSV) were implemented in emergency departments of all hospitals in the Capital Region of Denmark in 2018.AimTo establish whether POC testing for influenza viruses or RSV is based on a valid respiratory symptom indication, whether changes in patient management based on a positive result are safe and whether syndromic POC testing may benefit patients with influenza or RSV.MethodsSamples from 180 children (< 18 years) and 375 adults tested using POCT between February and July 2018 were retested for 26 respiratory pathogens. Diagnosis, indication for POC testing, hospitalisation time, antimicrobial therapy and readmission or death within one month of testing were obtained from patient records.ResultsA valid indication for POC testing was established in 168 (93.3%) of children and 334 (89.1%) of adults. A positive POCT result significantly reduced antibiotic prescription and median hospitalisation time by 44.3 hours for adults and 14.2 hours for children, and significantly increased antiviral treatment in adults. Risk of readmission or death was not significantly altered by a positive result. Testing for 26 respiratory pathogens established that risk of coinfection is lower with increasing age and that POCT for adults should be restricted to the influenza and RSV season.ConclusionPositive POCT resulted in changed patient management for both children and adults, and was deemed safe. POCT for additional pathogens may be beneficial in children below 5 years of age and outside the influenza and RSV season.
Assuntos
Serviço Hospitalar de Emergência , Vírus da Influenza A , Vírus da Influenza B , Influenza Humana , Testes Imediatos , Infecções por Vírus Respiratório Sincicial , Vírus Sinciciais Respiratórios , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Vírus da Influenza A/isolamento & purificação , Vírus da Influenza B/isolamento & purificação , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Influenza Humana/terapia , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/terapia , Vírus Sinciciais Respiratórios/isolamento & purificação , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12â030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/mortalidade , Amicacina/uso terapêutico , Antituberculosos/administração & dosagem , Capreomicina/uso terapêutico , Carbapenêmicos/uso terapêutico , Clofazimina/uso terapêutico , Diarilquinolinas/uso terapêutico , Quimioterapia Combinada , Fluoroquinolonas/uso terapêutico , Humanos , Canamicina/uso terapêutico , Levofloxacino/uso terapêutico , Linezolida/uso terapêutico , Moxifloxacina , Recidiva , Falha de TratamentoRESUMO
BACKGROUND: Nontuberculous mycobacteria belonging to the Mycobacterium avium complex are recognized as opportunistic pathogens to humans. Mycobacterium arosiense is one of the novel members of the Mycobacterium avium complex. The organism has only rarely been reported in human clinical cases and may be routinely misidentified. CASE PRESENTATION: An adult male with a history of a discus prolapse and sarcoidosis presented with high fever and a strong back pain with projection to the extremities. A Magnetic Resonance Imaging scan of columna revealed a tumor suspect process at thoracic vertebrae 11/12 with changes at the second lumbar vertebra, which was partly removed by laminectomy. Biopsy smears revealed acid-fast bacilli and turned out to be Mycobacterium tuberculosis complex PCR negative. The routine line probe assay INNO-LiPa v2 (INNOGENETICS NV, Gent), which differentiates 16 mycobacterial species indicated the presence of a not readily identifiable NTM species. Whereas, the GenoType Mycobacterium CM v2.0 (HAIN Lifescience GmbH) that routinely differentiates 14 clinically relevant mycobacteria revealed a Mycobacterium intracellulare species. However, additional diagnostic sequencing of the 16S rRNA gene confirmed the presence of a Mycobacterium arosiense species. CONCLUSIONS: This is the second unusual case of osteomyelitis with clinical significance ever to be reported, caused by Mycobacterium arosiense and complicated by an underlying sarcoidosis. Mycobacterium arosiense has rarely been reported clinically and the first description of the species was identified as the cause of osteomyelitis in a child with a hereditary partial interferon gamma deficiency. Symptoms attributed to sarcoidosis waned on Mycobacterium arosiense treatment and it is inconclusive whether the patient ever suffered from sarcoidosis. Mycobacterium arosiense was misidentified by the GenoType as Mycobacterium intracellulare and implicates that the diagnosis requires supplemental sequencing of the 16S rRNA gene.
Assuntos
Infecções por Mycobacterium/etiologia , Mycobacterium/patogenicidade , Osteomielite/microbiologia , Sarcoidose/etiologia , Adulto , Humanos , Masculino , Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/terapia , Osteomielite/terapia , Reação em Cadeia da Polimerase , RNA Ribossômico 16S/genéticaRESUMO
RATIONALE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. OBJECTIVES: To document the management and treatment outcome in patients with MDR-TB in Europe. METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). MEASUREMENTS AND MAIN RESULTS: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%). CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Estudos de Coortes , Europa (Continente)/epidemiologia , Humanos , Incidência , Estudos Prospectivos , Resultado do TratamentoRESUMO
Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto , Antituberculosos/farmacologia , Comorbidade , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , História do Século XXI , Humanos , Incidência , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Vigilância da População , Fatores de Risco , Tuberculose Resistente a Múltiplos Medicamentos/história , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaAssuntos
Avaliação de Resultados em Cuidados de Saúde/métodos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Organização Mundial da SaúdeRESUMO
Patients may harbor both drug-susceptible and -resistant bacteria, representing heteroresistance. We studied mixtures of isoniazid-resistant and -susceptible Mycobacterium tuberculosis strains. Conventional drug susceptibility testing was the most sensitive method of detection, whereas the line probe assay and sequencing were not able to detect the clinically relevant 1% proportion of resistant bacteria.
Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/uso terapêutico , Proteínas de Bactérias/genética , Sequência de Bases , Catalase/genética , Genótipo , Humanos , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Oxirredutases/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Tuberculosis patients may harbor both drug-susceptible and -resistant bacteria, i.e., heteroresistance. We used mixtures of rifampin-resistant and -susceptible Mycobacterium tuberculosis strains to simulate heteroresistance in patient samples. Molecular tests can be used for earlier discovery of multidrug resistance (MDR), but the sensitivity to detect heteroresistance is unknown. Conventional phenotypic drug susceptibility testing was the most sensitive, whereas two line probe assays and sequencing were unable to detect the clinically important 1% resistant bacteria.
Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/genética , Fenótipo , Sensibilidade e EspecificidadeAssuntos
Antituberculosos/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Avaliação de Resultados da Assistência ao Paciente , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Coinfecção/tratamento farmacológico , Coinfecção/microbiologia , Coinfecção/virologia , Controle de Doenças Transmissíveis/normas , Coleta de Dados , Intervalo Livre de Doença , Europa (Continente) , Alemanha , Infecções por HIV/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Prevalência , Modelos de Riscos Proporcionais , Análise de Regressão , Risco , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologiaRESUMO
BACKGROUND: Human immunodeficiency virus-1-associated neurocognitive disorder is a known complication in individuals treated with antiretroviral therapy. Cerebrospinal fluid escape, which is defined as discordant higher cerebrospinal fluid viremia than plasma, may occur in antiretroviral therapy-experienced individuals. Different cerebrospinal fluid versus plasma mutation patterns have been observed in individuals with cerebrospinal fluid escape. CASE PRESENTATION: A 46-year-old adult African male with human immunodeficiency virus-1 infection and acquired immunodeficiency syndrome based on cerebral toxoplasmosis and a chronic hepatitis B virus infection developed cerebrospinal fluid escape. A different human immunodeficiency virus-1 genotypic drug resistance profile was observed in plasma compared with cerebrospinal fluid. Brain biopsy and cerebral magnetic resonance imaging indicated the development of human immunodeficiency virus encephalopathy. A discordant protease inhibitor mutation/wild-type T74PT in plasma but not in cerebrospinal fluid indicated poor central nervous system penetration due to the selective pressure of drug therapy. An intensified antiretroviral therapy regimen including dolutegravir with good central nervous system penetration improved conditions. CONCLUSIONS: This case shows the importance of measuring human immunodeficiency virus drug resistance in cerebrospinal fluid, which might differ from resistance detected in plasma samples and target effective antiretroviral therapy treatment accordingly.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Hepatite B Crônica , Adulto , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Plasma , Carga ViralRESUMO
BACKGROUND: Acute flaccid myelitis is a serious condition of the spinal cord. More than 80% of patients experience a mild respiratory illness or fever consistent with a viral infection prior to acute flaccid myelitis development. Enterovirus A71 is known to circulate in Denmark, and has previously been associated with severe neurological symptoms. In this case report we describe acute flaccid rhombencephalomyelitis with radiculitis in an infant with an enterovirus infection. CASE PRESENTATION: The 8-month-old male of Asian origin presented with fever and gastrointestinal symptoms, followed by severe neurological deficits such as flaccid paralysis of the neck and upper extremities. An initial magnetic resonance imaging scan of the brain was normal, and the boy was treated for encephalitis. A follow-up magnetic resonance imaging scan of the brain and spinal cord 1 week later showed the development of pathological symmetrical gray matter hyperintensity lesions on T2-weighted images in the brainstem and upper medulla spinalis, and nerve enhancement in the terminal thread of the spinal cord and the cervical roots; findings consistent with rhombencephalomyelitis with radiculitis causing flaccid paralysis. Enterovirus A71 was detected in both nasopharyngeal and fecal specimens. Other differential diagnostic etiologies of viral and bacterial encephalitis, including poliovirus, were excluded. CONCLUSIONS: This is the first case in Denmark of a patient diagnosed with acute flaccid rhombencephalomyelitis strongly linked to an enterovirus A71 infection. This case emphasizes the diagnostic importance of combining a history of respiratory and/or gastrointestinal illness, fever, and delayed onset of varying degrees of paralysis with progressive characteristic spinal and brain lesions. Analysis of respiratory, fecal, and cerebrospinal samples for the presence of enterovirus, and eliminating other differential pathogens, is essential to confirm the diagnosis.
Assuntos
Infecções por Enterovirus , Enterovirus , Mielite , Radiculopatia , Criança , Dinamarca , Infecções por Enterovirus/complicações , Infecções por Enterovirus/diagnóstico , Humanos , Lactente , Masculino , Mielite/diagnósticoRESUMO
Point-of-care (POC) quantification of antibody responses against SARS-CoV-2 spike protein can enable decentralized monitoring of immune responses after infection or vaccination. We evaluated a novel POC microfluidic cartridge-based device (ViroTrack Sero COVID-19 Total Ab) for quantitative detection of total antibodies against SARS-CoV-2 spike trimeric spike protein compared to standard laboratory chemiluminescence (CLIA)-based tests. Antibody responses of 101 individuals were measured on capillary blood, venous whole blood, plasma, and diluted plasma samples directly on the POC. Results were available within 7 min. As the reference, plasma samples were analyzed on DiaSorin LIAISON XL CLIA analyzer using LIAISON SARS-CoV-2 IgM, LIAISON SARS-CoV-2 S1/S2 IgG, and LIAISON SARS-CoV-2 TrimericS IgG assays. The Spearman rank's correlation coefficient between ViroTrack Sero COVID-19 Total Ab and LIAISON SARS-CoV-2 S1/S2 IgG and LIAISON SARS-CoV-2 TrimericS IgG assays was found to be 0.83 and 0.89, respectively. ViroTrack Sero COVID-19 Total Ab showed high correlation between the different matrixes. Agreement for determination of samples of >230 binding antibody units (BAU)/mL on POC and CLIA methods is estimated to be around 90%. ViroTrack Sero Covid Total Ab is a rapid and simple-to-use POC test with high sensitivity and correlation of numerical results expressed in BAU/mL compared to those of a commercial CLIA assay. IMPORTANCE Serological testing is an important diagnostic support tool in the fight against COVID-19. So far, serological testing has been performed on either lateral flow assays, which perform only qualitatively and can be difficult for the individual to read, or standard laboratory assays, which are time- and resource-consuming. The purpose of the study was to evaluate the performance of a new POC microfluidic cartridge-based device based on immunomagnetic agglutination assay that can provide an accurate numerical quantification of the total antibodies within only 7 min from a single drop of capillary blood. We demonstrated a high level of correlation between the POC and the two CLIA laboratory-based immunoassays from Diasorin, thus allowing a potentially wider use of quantitative serology tests in the COVID-19 pandemic.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , COVID-19/diagnóstico , Vacinas contra COVID-19 , Humanos , Imunoensaio/métodos , Imunoglobulina G , Pandemias , Testes Imediatos , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus , VacinaçãoRESUMO
OBJECTIVE: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes. METHODS: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available. RESULTS: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies. CONCLUSION: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.
Assuntos
Anticorpos Antivirais/sangue , Teste para COVID-19/estatística & dados numéricos , COVID-19/epidemiologia , Recém-Nascido/sangue , Parceiros Sexuais , Adulto , COVID-19/sangue , Dinamarca/epidemiologia , Feminino , Hospitalização , Hospitais Universitários , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Masculino , Complicações do Trabalho de Parto/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Análise de Regressão , Fatores de Risco , SARS-CoV-2/imunologiaRESUMO
A retrospective nationwide study including all culture-verified multidrug-resistant (MDR) tuberculosis (TB) cases was performed in Denmark. The aim was to examine the long-term treatment outcome of MDR-TB, to assess if MDR-TB transmission occurs, and to evaluate a rapid mutation analysis detecting rifampin and isoniazid resistance in this cohort. Clinical data were obtained from patient records. A restriction fragment length polymorphism genotype database of all TB cases was compared for identical strains indicating active transmission. Twenty-nine cases of MDR-TB were identified and the incidence was low at 0.5%. Acquired MDR-TB and active transmission was rare. Mutations in rifampin (rpoB) and isoniazid (katG, inhA) genes correctly determined resistance in 100% and 82% of all isolates tested, respectively. Initial treatment success was 89% for 27 MDR-TB patients with available outcome data. Initially 3 patients defaulted; no deaths were reported. Including successfully re-treated default patients and censoring patients who spent <2 y in the cohort, long-term treatment success was achieved for all 26 patients (mean follow-up 8.9 y). MDR-TB has a good prognosis in the high-income, low TB burden country of Denmark. Continued surveillance and rapid detection of resistance mutations directly in smear-positive patients may improve the standard of MDR-TB care.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adolescente , Adulto , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , Catalase/genética , Criança , Pré-Escolar , Impressões Digitais de DNA , Análise Mutacional de DNA , DNA Bacteriano/genética , RNA Polimerases Dirigidas por DNA/genética , Dinamarca/epidemiologia , Feminino , Humanos , Incidência , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Masculino , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Oxirredutases/genética , Polimorfismo de Fragmento de Restrição , Estudos Retrospectivos , Rifampina/farmacologia , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/transmissão , Adulto JovemRESUMO
This PhD thesis is based on 5 studies conducted in the period 2006-2010 during my employment at the International Reference Laboratory of Mycobacteriology, Statens Serum Institut. The overall aim was to assess tuberculosis (TB) treatment in Denmark with specific focus on the risk of relapse of TB disease, and to analyse treatment outcome of patients with multidrug-resistant (MDR) or isoniazid-resistant TB. The project established the need for rapid methods to detect resistance and follow-up of treatment. A rapid method to detect drug resistance was optimised and evaluated for use directly in clinical specimens. The studies were based on data from the Mycobacterial registry in the period 1992-2007, which included the results from microscopy, culture, drug-susceptibility and restriction fragment length polymorphism (RFLP). Information on dates of death/emigration were taken from the CPR-registry and treatment from surveillance data and patient records. The rate of recurrent TB was found to be low in Denmark, during 13.5 years of follow-up. Relapse accounted for 1.3% of the recurrent cases and reinfection was rare, only in 0.5% cases. The relapse hazard increased up to four years after diagnosis. Cavitary disease was associated with relapse as opposed to reinfection and may need prolonged treatment and closer monitoring. The incidence of MDR-TB and isoniazid resistance was confirmed to be low. Successful short- and long-term treatment outcome of MDR-TB and isoniazid-resistant TB was high. High- and low-level isoniazid resistance did not affect treatment outcome. A multiplex PCR hybridization mutation analysis, that simultaneously detects the most frequent rpoB and katG gene mutations conferring rifampin and high-level isoniazid resistance, was optimized for direct use and evaluated in smear-positive specimens as opposed to slow conventional drug-susceptibility testing (DST). The second-generation rifampin and isoniazid resistance mutation assay additionally included detection of mutations within the inhA gene conferring low-level isoniazid resistance. This assay was found to be rapid (< 48 h) and easy to perform in isolates and clinical specimens. A high concordance between mutation and conventional DST results was found for rifampin, while results varied for isoniazid . The mutation analysis identified all MDR-TB cases and the majority of isoniazid-resistant cases in Denmark. Standard 6-month multiple anti-TB drug therapy is necessary to treat drug-susceptible TB. Drug-resistant TB often requires therapy adjustments and extended treatment. MDR-TB particularly poses therapeutic challenges. Rapid detection of resistance mutations directly in smear-positive patient specimens may improve MDR-TB patient treatment, although the impact on isoniazid-resistant TB treatment outcome remains to be determined. The mutation assay is a rapid supplement to the gold standard conventional DST in high-income countries such as Denmark, while in low-income countries it can be used for preliminary DST. The assay may be applied to smear-positive samples from patients suspected of treatment failure, recurrent TB, drug-resistant TB exposure or originating from countries with high levels of DR. The new extended mutation assay has proved to be a useful tool, which has now been included in the World Health Organization's policy to combat and prevent new cases of MDR and extensively drug-resistant TB.