Agosto 2011-‐ Enero 2012 JL Mostaza
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Predic've value of interferon-‐γ release assays for incident ac've tuberculosis: a systema'c review and meta-‐analysis
Molebogeng X Rangaka, Katalin A Wilkinson, Judith R Glynn, Daphne Ling, Dick Menzies, Judith Mwansa-‐Kambafwile, Katherine Fielding, Robert J Wilkinson, Madhukar Pai. Molebogeng X Rangaka, Katalin A Wilkinson, Judith R Glynn, Daphne Ling, Dick Menzies, Judith Mwansa-‐Kambafwile, Katherine Fielding, Robert J Wilkinson, Madhukar Pai. University of Cape Town, South Africa; London School of Hygiene and Tropical Medicine, London, UK Imperial College London, UK and McGill University and Montreal Chest InsJtute, Montreal, Canada.
Lancet Infect Dis 2012;12: 45–55
Funding Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian InsJtutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.
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Historia natural de la tuberculosis BK
PPD -‐ PPD +
5% Tb (2 primeros años)
5% Tb (resto de vida)
Letalidad 1%
Infectados Enfermos (10%) Muertes (1%)
3-‐7 semanas
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Introduc'on
• 1/3 world’s populaJon is infected with M. tuberculosis.
• IGRAs and tuberculin skin test (TST): – Surrogate marker for M. tuberculosis infecJon. – Neither can disJnguish between latent and acJve tuberculosis.
• TST + individuals: – RR tuberculosis = 2. – They benefit from isoniazid prevenJve treatment.
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To assess…
• Whether IGRAs can predict the development of acJve tuberculosis.
• Whether the predicJve ability of these tests is becer than that of the TST.
Obje've
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Methods SystemaJc review and meta-‐analysis.
• Search strategy and study selecJon – Longitudinal studies. – People who were free of acJve disease at study baseline. – Assessment of the predicJve ability of IGRAs: QuanJFERON TB® or T-‐SPOT TB®
• Data extracJon: Two reviewers. • Quality assessment: Newcastle-‐Ocawa quality assessment scale. • StaJsJcal analysis:
– Main outcome: incidence density of tuberculosis (person-‐years incidence rates). – Incidence rate raJos (IRR) for rates of disease progression in:
• IGRA+ vs IGRA-‐ individuals • TST-‐posiJve vs TST-‐negaJve individuals.
– Heterogeneity: I2 staJsJc. Se
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Incidencia acumulada
Densidad de Incidencia
Razón de tasas de incidencia (IRR) = DIa / Dib Heterogenicidad de los estudios: Parámetro I2
DI = (2/37,5 meses-‐persona) -‐-‐-‐>0,053 -‐-‐-‐>53 eventos 1000 meses-‐persona
IA = 2/6
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Results
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Results • 15 studies: 26.680 parJcipants. • Incidence of tuberculosis [median follow-‐up: 4 years]
– IGRA-‐posiJve: 4–48 cases /1000 person-‐years. – IGRA-‐negaJve: 2–24 cases / 1000 person-‐years
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• Moderate associaJon between posiJve results and subsequent tuberculosis: IRR: 2.10 (95% CI 1.42–3.08).
• IGRA-‐posiJve and TST-‐posiJve results were the same with regard to the risk of tuberculosis. • IRR: 2.11 [95% CI 1.29–3.46] for IGRA vs 1.60 [0.94–2.72] for TST (10
mm cutoff) .
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InterpretaJon
• Neither IGRAs nor the TST have high accuracy for the predicJon of acJve tuberculosis.
• IGRAs might reduce the number of people considered for prevenJve treatment.
• Tests for latent tuberculosis infecJon should be chosen: – Not on predicJve ability alone. – RelaJve specificity in different populaJons, logisJcs, cost, and paJents’ preferences.
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Lancet Infect Dis 2011;11: 907–15
Funding Merck. Servic
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Favorece a CR7 (CR7 es mejor)
Favorece a Messi (CR7 es peor)
Diferencia de goles %
0 50 100 50 100 Se
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CR7 NO es inferior
CR7 ES inferior
Favorece a CR7 (CR7 es mejor)
Favorece a Messi (CR7 es peor)
Diferencia de goles %
0 50 100 50 100
Umbral de inferioridad
10% Se
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Funding Merck.
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No es inferior Es inferior
Favorece a RAL 1*día Favorece a RAL 2*día
Diferencia %
0 50 100 50 100
Umbral de inferioridad
10%
Diferencia: –5.7% (95% CI –10.7 to –0.83; p=0.044).
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Time to loss of virological response (TLOVR) analysis
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Interpreta'on: Once-‐daily raltegravir cannot be recommended in place of twice-‐daily dosing.
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Lancet Infect Dis 2012; 12: 27–35
Funding Gilead Sciences.
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• 42-‐y man. • Recurrent ankle pain for the past 1.5 years. • Ibuprofen and corJcosteroids without success. • Methotrexate followed by an TNFα Ab.
• 8 weeks of recurrent fever, diarrhoea and malaise.
In vivo diagnosis and characterisa'on of Whipple’s disease.
Confocal laser endomicroscopy
C. Neufert, Lancet Infect Dis 2011; 11: 970.
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Lancet Infect Dis 2011; 11: 834–44
Funding None. Servic
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Background
• MulJdrug resistance among bacteria increases the need for new anJmicrobial drugs. – Tigecycline is one candidate drug.
• Previous meta-‐analysis (only published trials): – As effecJve as comparator treatments.
• Cai Y. AnQmicrob Agents Chemother 2011;55: 1162–72.
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ObjeJve
To asses if meta-‐analyses that ignore unpublished studies could reach narrow, misleading interpretaJons. Se
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Methods (Meta-‐analysis) • Search strategy and study selecJon
– PubMed, Cochrane Central Register, and Embase (up to March 30, 2011). – Clinical trial registries to idenJfy completed unpublished studies. – Eligible studies:
• Randomised trials assessing the clinical efficacy, safety, and eradicaJon efficiency of Jgecycline versus other anJmicrobial agents for any bacterial infecJon.
• Data extracJon: Two reviewers. • Quality assessment: modified Jadad score.
– Clear descripJon of sequence generaJon; allocaJon concealment; masking of parJcipants, study personnel and outcome assessors; avoidance of incomplete outcome data or selecJve outcome reporJng; and discussion of other potenJal sources of bias.
• StaJsJcal analysis: – Main outcome: Treatment success. – Meta-‐analysis: random effects models (heterogeneity across the trials). – Pooled odds raJos (ORs) and 95% CI (Mantel-‐Haenszel method).
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Findings • 14 randomised trials: 7400 paJents. • Treatment success was lower with Jgecycline.
– Odds raJo OR 0.82,95% CI 0.73–0.93. • Adverse events were more frequent in the Jgecycline group.
– OR: 1.45, 1.11–1.88 (vomiJng and nausea). • All-‐cause mortality was higher in the Jgecycline group.
– Difference was not significant (1.28, 0.97–1.69). • EradicaJon efficiency did not differ between Jgecycline and
control regimens. – Sample size for these comparisons was small.
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Interpreta'on
• Tigecycline is not becer than standard anJmicrobial agents for the treatment of serious infecJons.
• Assessment with unpublished studies is needed to make appropriate decisions about new agents.
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Lancet Infect Dis 2011;11: 760–68
Funding Health ProtecJon Agency. Servic
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Background
• The seven-‐valent pneumococcal conjugate vaccine (PCV7): – Has reduced vaccine-‐type (VT) invasive pneumococcal disease.
– Increases in non-‐vaccine-‐type (NVT) disease have varied between countries.
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ObjeJve
We assess the effect of the PCV7 vaccinaJon on VT and NVT disease in England and Wales. Se
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Methods • Study cohort:
– The populaJon of England and Wales from July, 2000, to June, 2010.
• Incidence rate raJos (IRRs) – To compare incidences of VT and NVT disease before (2000–06) and azer (2009–10) the introducJon of PCV7.
• Data: naJonal surveillance database. – Cases confirmed by culture (isolates referred for serotyping).
• We adjusted for potenJal bias: – Missing data (serotype and age of paJent). – Changes in case ascertainment rates during the study period. Se
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Trends in Invasive pneumococcal disease in England and Wales (2000–10).
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Invasive pneumococcal disease PCV7 incidence
All Reduc'on (%)
VT Reduc'on (%)
NVT Increase (%)
> 2 56 98 68 > 65 19 81 48 All 34
• 5809 cases of invasive pneumococcal disease.
• NVT serotypes increased in frequency. • Key serotypes showing replacement: 7F, 19A, and 22F.
• Increases in NVT invasive pneumococcal disease were not associated with anJmicrobial resistance.
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Interpreta'on
• Despite much serotype replacement… – SubstanJal reducJon in invasive pneumococcal disease in young children can be achieved with PCV7 vaccinaJon.
– With some indirect benefit in older age groups. • Further reducJons should be achievable by use of higher valency vaccines.
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• 24-‐y. man with no remarkable medical history.
• 2 months earlier – Influenza-‐like symptoms. – Azer a skiing weekend:
• Progressive lez bucock pain. • High-‐spiking fever. • Weight loss.
• 5 days before… – Rapidly growing and painful
lez bucock mass.
F. Lachenal. Lancet Infect Dis 2011; 11: 720
Streptococcus pneumoniae retroperitoneal and pelvic abscess
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An'science and ethical concerns associated with advocacy of Lyme disease
Paul G Auwaerter, Johan S Bakken, Raymond J DaTwyler, J Stephen Dumler, John J Halperin, Edward McSweegan, Robert B Nadelman, Susan O’Connell, Eugene D
Shapiro, Sunil K Sood, Allen C Steere, Arthur Weinstein, Gary P Wormser
The Johns Hopkins Medical InsJtuJons, BalJmore, USA; St Luke’s Hospital, Duluth, MN, USA; New York Medical College, NY, USA; AtlanJc Neuroscience InsJtute, NJ, USA ; Mount Sinai School of Medicine, New York, NY, USA; General Hospital, Southampton, UK. Yale University, New Haven, CT, USA; Cohen Children’s Medical Center, Manhasset, NY, USA; Massachusegs General Hospital, Harvard Medical School, Boston, MA, USA; Washington Hospital Center and Georgetown University Medical Center, Washington, DC, USA.
Lancet Infect Dis 2011; 11: 713–19
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“Advocacy for Lyme disease” • Lyme disease…
– Is insidious, ubiquitous, difficult to diagnose, and almost incurable. – Causes mainly non-‐specific symptoms. – Can be treated only with long-‐term anJbioJcs and other unorthodox
and unvalidated treatments.
• They used unvalidated laboratory tesJng made in Lyme specialty laboratories: – UnconvenJonal culture methods. – Immunological tests of B burgdorferi infecJon.
• T-‐cell assay and CD57 cell count. Servicio
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“…A gripping tale of microbes, medicine & money, UNDER OUR SKIN exposes the hidden story of Lyme disease, one of the most serious and controversial epidemics of our Jme. Each year, thousands go undiagnosed or misdiagnosed, ozen told that their symptoms are all in their head. Following the stories of paJents and physicians fighJng for their lives and livelihoods, the film brings into focus a haunJng picture of the health care system and a medical establishment all too willing to put profits ahead of paJents.”
Documental nominado al Oscar 2010
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N Engl J Med 2007;357:1422-‐30.
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Lyme disease
• Caused by Borrelia burgdorferi sensu lato. • InfecJon is… – Nonfatal. – Non-‐communicable from person-‐to-‐person. – Responsive to anJbioJcs. – Geographically and seasonally limited.
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Geographically limited 'ck-‐borne infec'on.
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Clinical manifestaJons
• ObjecJve – Erythema migrans. – Within weeks…
• Nervous system (meningiJs or facial nerve palsy). • Cardiac symptoms (heart block).
– Within months… • ArthriJs can develop (knee).
• SubjecJve complaints… – faJgue, arthralgia, myalgia, headache, sJff neck, and impaired concentraJon.
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G. Stanek. Lancet 2012; 379: 461–73
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DiagnósJco
• Evidencia de manifestaciones clínicas objeJvas. – Eritema migrans. – Paralisis facial, meningoencefaliJs… – Bloqueo AV. – ArtriJs rodilla. – AcrodermaJJs crónica atrófica.
• ELISA + confirmado por Inmunoblot + (“Two-‐Jer tesJng”).
• Serología posiJva en ausencia de manifestaciones clínicas caracterísJcas no soporta el diagnósJco.
• Serología negaJva descarta el diagnósJco.
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Tratamiento
• Formas tempranas: – Doxiciclina oral (10 días).
• Formas tardías (arJcular, neurológica y cardíaca). – Cezriaxona 30 días.
Responden bien al tratamiento. Excepcionalmente pueden precisar un segundo ciclo.
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A 69-‐year-‐old man with no history of Jck bites 4 year history of fibrosing skin lesions.
ELISA test results (Borrelia burgdorferi) were confirmed by western blot. Cezriaxone (2 g intravenously for 30 days). The skin lesion partly faded away azer treatment.
Acroderma''s chronica atrophicans.
J. Zajkowska. Lancet Infect Dis 2011; 11: 800 Se
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