[Dengue vaccines, a time for cautious optimism?] / Vaccins contre la dengue, le temps de l'optimisme prudent ?

Vaccine could take a central role in the strategy to reduce the burden of dengue. The development of an effective and safe vaccine must address various immunological challenges. Several vaccines are currently in development. To date, two live-attenuated vaccines have been deployed. Both have an effectiveness that varies depending on the serotypes. The deployment of the Dengvaxia vaccine, which began in 2015, was marked by a major safety alert leading to its use being restricted to previously dengue-seropositive people over 9 years old. The Qdenga vaccine is currently being deployed. There is for now insufficient data to ensure its safety in seronegative people. Some travelers, who have previously been infected with dengue, are a group for whom a vaccination recommendation applies.

Les vaccins pourraient occuper une place centrale dans la stratégie de réduction du fardeau de la dengue. Le développement d'un vaccin efficace et sûr est complexe car il doit relever plusieurs défis immunologiques. Différents vaccins sont en développement. À ce jour, deux vaccins vivants atténués ont été déployés. Tous deux ont une efficacité qui varie selon les sérotypes. Le déploiement du vaccin Dengvaxia, débuté en 2015, a été marqué par une alerte de sécurité majeure conduisant à restreindre son usage aux personnes de plus de 9 ans, préalablement séropositives pour la dengue. Le vaccin Qdenga est en cours de déploiement. Le recul est insuffisant pour assurer son innocuité chez les séronégatifs. Certains voyageurs, ayant déjà été infectés par la dengue, constituent un groupe pour lequel une recommandation vaccinale s'applique.

[Malaria vaccines: a new tool for elimination?] / Vaccins contre le paludisme : un nouvel outil pour l'élimination ?

A malaria vaccine represents an essential complementary tool to curb the stagnation, or even increase, in malaria cases observed over the last decade due to the emergence of resistance to insecticides impregnated on mosquito nets, wars and internal conflicts, as well as global warming. In October 2021, WHO recommended the use of the RTS,S/ASO1 vaccine for children aged 5-17 months in areas of moderate to high transmission. In October 2023, a second vaccine received WHO approval for deployment in the same population, following demonstration of around 70 % efficacy in protecting young children against malaria for one year. Given their partial efficacy, however, these vaccines are not generally recommended for travelers to endemic countries.

Un vaccin contre le paludisme représente une mesure complémentaire essentielle pour juguler la stagnation, voire l'augmentation des cas de paludisme observée durant cette dernière décade en raison de l'émergence de la résistance aux insecticides imprégnés sur les moustiquaires, des guerres et conflits internes ainsi que du réchauffement climatique. En octobre 2021, l'OMS a recommandé l'emploi du vaccin RTS,S/ASO1 pour les enfants de 5 à 17 mois dans les zones de transmission modérée à forte. En octobre 2023, un second vaccin a reçu l'aval de l'OMS pour son déploiement dans la même population, suite à la démonstration d'une efficacité d'environ 70 % pour protéger les jeunes enfants contre le paludisme pendant une année. Vu leur efficacité partielle, ces vaccins ne sont cependant généralement pas recommandés pour les voyageurs se rendant dans les pays d'endémie.

[Is mortality an objective indicator for measuring the impact of an epidemic?: The example of Covid-19 in Switzerland]. / La mortalité est-elle un indicateur objectif pour mesurer l'impact d'une épidémie ?. L'exemple du Covid-19 en Suisse.

Measuring the health impact of an epidemic using appropriate indicators is necessarily complex. Mortality does not sum up all the issues, but at least it seems to be an objective indicator. There are, however, a number of different mortality indicators, which do not all convey the same message. During the Covid-19 epidemic in Switzerland, the mortality rate rose by 10.2% in 2020, while life expectancy fell by "only" 0.8%, or 8.3 months, a decline described as "modest" or "complete freefall" depending on when it was published. In reality, the population living in Switzerland in 2020 lost an average of "only" 2.4 days, as the epidemic did not last their entire lives. The use of such an indicator, in comparison with losses due to other factors, would enable us to better estimate the real impact of an epidemic.

Mesurer l'impact sanitaire d'une épidémie à l'aide d'indicateurs appropriés est forcément complexe. La mortalité ne résume pas tous les enjeux mais semble au moins être un indicateur objectif. Il existe cependant différents indicateurs de mortalité ne donnant pas tous le même message. Lors de l'épidémie de Covid-19 en Suisse, le taux de mortalité a augmenté de 10,2 % en 2020, alors que l'espérance de vie n'a diminué « que ¼ de 0,8 %, ou 8,3 mois, recul par ailleurs qualifié de « modeste ¼ ou de « chute libre ¼ selon quand il a été publié. En réalité, la population vivant en Suisse en 2020 n'a perdu en moyenne « que ¼ 2,4 jours car l'épidémie n'a pas duré toute sa vie. L'utilisation d'un tel indicateur, en comparaison avec les pertes dues à d'autres facteurs, permettrait une meilleure estimation de l'impact réel d'une épidémie.

Seroprevalence trends of anti-SARS-CoV-2 antibodies and associated risk factors: a population-based study.

PURPOSE: We aimed to assess the seroprevalence trends of SARS-CoV-2 antibodies in several Swiss cantons between May 2020 and September 2021 and investigate risk factors for seropositivity and their changes over time. METHODS: We conducted repeated population-based serological studies in different Swiss regions using a common methodology. We defined three study periods: May-October 2020 (period 1, prior to vaccination), November 2020-mid-May 2021 (period 2, first months of the vaccination campaign), and mid-May-September 2021 (period 3, a large share of the population vaccinated). We measured anti-spike IgG. Participants provided information on sociodemographic and socioeconomic characteristics, health status, and adherence to preventive measures. We estimated seroprevalence with a Bayesian logistic regression model and the association between risk factors and seropositivity with Poisson models. RESULTS: We included 13,291 participants aged 20 and older from 11 Swiss cantons. Seroprevalence was 3.7% (95% CI 2.1-4.9) in period 1, 16.2% (95% CI 14.4-17.5) in period 2, and 72.0% (95% CI 70.3-73.8) in period 3, with regional variations. In period 1, younger age (20-64) was the only factor associated with higher seropositivity. In period 3, being aged ≥ 65 years, with a high income, retired, overweight or obese or with other comorbidities, was associated with higher seropositivity. These associations disappeared after adjusting for vaccination status. Seropositivity was lower in participants with lower adherence to preventive measures, due to a lower vaccination uptake. CONCLUSIONS: Seroprevalence sharply increased over time, also thanks to vaccination, with some regional variations. After the vaccination campaign, no differences between subgroups were observed.

[Dengue fever is knocking on the doors of Europe]. / La dengue frappe aux portes de l'Europe.

Dengue is a subject of major concern in global health because its incidence is increasing, and its geographical area continues to expand. On a global scale, the projections available point in the direction of an extension of the geographical areas of the Aedes vectors, partly in connection with the increase in temperatures and the modification of precipitation cycles in the context of the climate change. This expansion is expected at the borders of the areas of current spread with, however, a possible contraction in certain areas that are now endemic. In Europe, the threat of a dengue epidemic outbreak now exists. It is on this continent that the number of new exposures in immunologically naïve people is likely to be the greatest in the near future.

La dengue est un sujet de préoccupation majeure en santé globale car son incidence augmente et son aire géographique ne cesse de s'étendre. À l'échelle globale, les projections dont on dispose vont dans le sens d'une extension des zones géographiques des vecteurs Aedes, en lien en partie avec l'augmentation des températures et la modification des cycles de précipitation dans le contexte du changement climatique. Cette expansion est attendue aux frontières des zones de diffusion actuelle avec toutefois une contraction possible dans certaines zones aujourd'hui endémiques. En Europe, la menace d'une flambée épidémique de dengue existe désormais. C'est sur ce continent que le nombre de nouvelles expositions chez des personnes immunologiquement naïves risque d'être le plus important dans un avenir proche.

Changes in SARS-CoV-2 Spike versus Nucleoprotein Antibody Responses Impact the Estimates of Infections in Population-Based Seroprevalence Studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses to the spike (S) protein monomer, S protein native trimeric form, or the nucleocapsid (N) proteins were evaluated in cohorts of individuals with acute infection (n = 93) and in individuals enrolled in a postinfection seroprevalence population study (n = 578) in Switzerland. Commercial assays specific for the S1 monomer, for the N protein, or within a newly developed Luminex assay using the S protein trimer were found to be equally sensitive in antibody detection in the acute-infection-phase samples. Interestingly, compared to anti-S antibody responses, those against the N protein appear to wane in the postinfection cohort. Seroprevalence in a "positive patient contacts" group (n = 177) was underestimated by N protein assays by 10.9 to 32.2%, while the "randomly selected" general population group (n = 311) was reduced by up to 45% relative to the S protein assays. The overall reduction in seroprevalence targeting only anti-N antibodies for the total cohort ranged from 9.4 to 31%. Of note, the use of the S protein in its native trimer form was significantly more sensitive compared to monomeric S proteins. These results indicate that the assessment of anti-S IgG antibody responses against the native trimeric S protein should be implemented to estimate SARS-CoV-2 infections in population-based seroprevalence studies.IMPORTANCE In the present study, we have determined SARS-CoV-2-specific antibody responses in sera of acute and postinfection phase subjects. Our results indicate that antibody responses against viral S and N proteins were equally sensitive in the acute phase of infection, but that responses against N appear to wane in the postinfection phase where those against the S protein persist over time. The most sensitive serological assay in both acute and postinfection phases used the native S protein trimer as the binding antigen, which has significantly greater conformational epitopes for antibody binding compared to the S1 monomer protein used in other assays. We believe these results are extremely important in order to generate correct estimates of SARS-CoV-2 infections in the general population. Furthermore, the assessment of antibody responses against the trimeric S protein will be critical to evaluate the durability of the antibody response and for the characterization of a vaccine-induced antibody response.

Clinical sign and biomarker-based algorithm to identify bacterial pneumonia among outpatients with lower respiratory tract infection in Tanzania.

BACKGROUND: Inappropriate antibiotics use in lower respiratory tract infections (LRTI) is a major contributor to resistance. We aimed to design an algorithm based on clinical signs and host biomarkers to identify bacterial community-acquired pneumonia (CAP) among patients with LRTI. METHODS: Participants with LRTI were selected in a prospective cohort of febrile (≥ 38 °C) adults presenting to outpatient clinics in Dar es Salaam. Participants underwent chest X-ray, multiplex PCR for respiratory pathogens, and measurements of 13 biomarkers. We evaluated the predictive accuracy of clinical signs and biomarkers using logistic regression and classification and regression tree analysis. RESULTS: Of 110 patients with LRTI, 17 had bacterial CAP. Procalcitonin (PCT), interleukin-6 (IL-6) and soluble triggering receptor expressed by myeloid cells-1 (sTREM-1) showed an excellent predictive accuracy to identify bacterial CAP (AUROC 0.88, 95%CI 0.78-0.98; 0.84, 0.72-0.99; 0.83, 0.74-0.92, respectively). Combining respiratory rate with PCT or IL-6 significantly improved the model compared to respiratory rate alone (p = 0.006, p = 0.033, respectively). An algorithm with respiratory rate (≥ 32/min) and PCT (≥ 0.25 µg/L) had 94% sensitivity and 82% specificity. CONCLUSIONS: PCT, IL-6 and sTREM-1 had an excellent predictive accuracy in differentiating bacterial CAP from other LRTIs. An algorithm combining respiratory rate and PCT displayed even better performance in this sub-Sahara African setting.

[Covid-19 crisis: testing and vaccination in the light of diminishing returns]. / Crise du Covid-19 : le testing et la vaccination à l'aune des rendements décroissants.

At the time of the assessment of the sanitary measures taken to fight the crisis, we have analysed the testing and vaccination following the grid well known in health economics: the law of diminishing returns. In the first phase, the returns are positive and increasing, the increase in benefits being faster than the increase in costs. In the second phase, returns are still positive but decreasing, with costs increasing faster than benefits. In the third and last phase, the returns become negative, with benefits decreasing despite an increase in costs. Both testing and vaccination, which were very beneficial at the beginning of the crisis, progressively followed a trajectory of diminishing returns with the extension of the measures to wider populations (asymptomatic or young persons), or for example with the emergence of the Omicron variant.

À l'heure du bilan des mesures sanitaires prises pour juguler la crise, nous avons soumis le testing et la vaccination à la grille d'analyse connue en économie de la santé : la loi des rendements décroissants. Dans une première phase, les rendements sont positifs et croissants, l'augmentation des bénéfices étant plus rapide que celle des coûts. Dans une deuxième phase, les rendements sont toujours positifs mais décroissants, l'augmentation des coûts étant plus rapide que celle des bénéfices. Dans une troisième et dernière phase, les rendements deviennent négatifs, les bénéfices diminuant malgré une augmentation des coûts. Tant le testing que la vaccination, très bénéfiques au début de la crise, ont progressivement suivi une trajectoire de rendements décroissants avec l'extension des mesures à des populations plus larges (asymptomatiques ou jeunes), ou par exemple avec l'apparition du variant Omicron.

[Eco-tourism: what recommendations?] / Voyager écolo : quelles recommandations ?

Which recommendations family doctors and travel health practitioners can provide to their patients, to reduce their environmental footprint when travelling? Avoiding flying is the biggest action a traveler can take to reduce their greenhouse gas emissions. Staying at eco-lodges, or carbon offsetting, may help, but one must be aware of false or exaggerated claims on their impact. Using UV light, filters, halogens or boiling water, are effective ways to disinfect water and reduce the waste created from plastic water bottles. Given the large carbon footprint of medications and laboratory exams, limiting prescription of antibiotics or antimalarials in pre-travel consultations, or limiting unnecessary laboratory exams in returning travelers by following the latest recommendations, could reduce greenhouse emissions of the medical practice.

Quelles recommandations les généralistes et médecins du voyage peuvent-ils fournir à leur patientèle pour réduire les impacts environnementaux de leurs voyages ? Éviter les trajets en avion est l'action la plus efficace pour réduire ses émissions de gaz à effet de serre. Séjourner dans des éco-lodges ou la compensation carbone financière peuvent être positifs mais leur bénéfice est souvent surestimé. Filtres, UV, halogènes ou cuisson permettent la désinfection efficace de l'eau et la réduction des déchets dus aux bouteilles en plastique. Au vu de l'empreinte carbone des traitements et examens de laboratoire, limiter la prescription d'antibiotiques et d'antimalariques en consultation prévoyage ainsi que les examens inutiles au retour selon les recommandations actuelles réduisent aussi les impacts de la pratique médicale.

[COVID-19 Diagnosis]. / Diagnostic du Covid-19 en milieu ambulatoire.

The need to curb the circulation of SARS-CoV-2 virus in the community and to diagnose those at risk of developing complications implies that an appropriate test should be chosen according to the epidemiological and clinical context. Rapid antigen tests, either nasopharyngeal or nasal, have the advantage of reflecting contagiousness better than PCR and giving an immediate result, reason why they are used as first-line for community diagnosis and screening. A rapid test allows immediate management of outpatients and does not falsely attribute the current acute episode to a previous SARS-CoV-2 infection. PCR, whether nasopharyngeal or buccosalivary, is useful for epidemiological surveillance, including that of new variants, as well as identification of severe COVID in the post-infectious phase.

La nécessité de freiner la circulation du virus SARS-CoV-2 dans la communauté et diagnostiquer les personnes à risque de développer des complications implique de choisir le test approprié selon le contexte épidémiologique et clinique. Les tests antigéniques rapides, soit nasopharyngés, soit nasaux, ont l'avantage de mieux refléter la contagiosité que la PCR et de donner un résultat immédiat, raison pour laquelle ils sont utilisés en première intention pour le diagnostic et le dépistage communautaire. Un test rapide permet d'orienter tout de suite la prise en charge ambulatoire d'un·e patient·e et ne pas attribuer faussement un épisode aigu à une ancienne infection à SARS-CoV-2. La PCR, qu'elle soit nasopharyngée ou buccosalivaire, est utile pour la surveillance épidémiologique, notamment des nouveaux variants, ainsi que pour l'identification d'un Covid sévère dans la phase postinfectieuse.

[Mass testing for Covid-19 : what can we learn from real-world implementation ?] / Dépistage de masse du Covid-19 : quelles leçons tirer des récentes expériences ?

While several modelling studies suggest mass testing for SARS-CoV-2 could be effective, real-world attempts at implementation have not been sufficient to evaluate its contribution to controlling the pandemic. To slow the spread of the virus, a mass-testing campaign would need frequent testing over a prolonged period with high rates of participation, all while maintaining public health measures. Screening seems more useful for targeted populations or high-risk events (businesses, teaching facilities, public or private institutions, sporting or cultural events). With their low cost and rapid results, rapid tests should be favored for these interventions.

Bien que des modélisations de dépistage de masse pour le SARS-CoV-2 suggèrent une certaine efficacité, leur réalisation en pratique n'a, à ce jour, pas été confirmée et leur potentiel impact en termes de contrôle sur la pandémie reste à démontrer. Pour espérer endiguer la propagation du virus, il faut réaliser un dépistage fréquent, sur une période prolongée, et atteindre un taux de participation très élevé, cela tout en maintenant les mesures sanitaires. Le dépistage semble toutefois envisageable s'il est ciblé sur une population ou un événement à risque (entreprises, lieux de formation, établissements publics ou privés, manifestations sportives ou culturelles). De par leur faible coût et leur rendu rapide du résultat, les tests rapides sont à favoriser pour de telles stratégies interventionnelles de dépistage.

[SARS-CoV-2 screening in travelers: what approach to assess transmission risk ?] / Dépistage de l'infection à SARS-CoV-2 chez les voyageurs - Quelle approche pour évaluer le risque de transmis.

Before a trip, a screening for SARS-CoV-2 infection by RT-PCR is often required and raises the problem of detection of residual viral RNA at distance from the acute infection (post-Covid). At the University Hospital of Geneva, we developed an expertise to distinguish acute from post-Covid infections. Between October and December 2020, 30% of the people tested positive were able to travel because the result corresponded to post-Covid and 65% were put in isolation because of an acute infection with a risk of transmission. To overcome the detection of residual viral RNA by RT-PCR, a rapid antigenic test would be an interesting and less expensive alternative. It could also be performed a few hours before departure.

Avant un voyage, un dépistage de l'infection à SARS-CoV-2 par RT-PCR est souvent exigé et soulève le problème de la détection d'ARN viral résiduel chez une personne à distance de l'infection aiguë (post-Covid). Aux HUG, nous avons développé une expertise permettant de distinguer les infections aiguës des post-Covid. Entre octobre et décembre 2020, 30 % des personnes dépistées positives ont pu voyager car le résultat correspondait à des post-Covid et 65 % ont été mises en isolement en raison d'une infection aiguë avec risque de transmission. Pour pallier la détection de l'ARN viral résiduel par la RT-PCR, un test rapide antigénique serait une alternative intéressante et moins chère. Il pourrait également être effectué juste avant le départ.

Prognostic Accuracy of Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1)-based Algorithms in Febrile Adults Presenting to Tanzanian Outpatient Clinics.

BACKGROUND: The inability to identify individuals with acute fever at risk of death is a barrier to effective triage and management of severe infections, especially in low-resource settings. Since endothelial and immune activation contribute to the pathogenesis of various distinct life-threatening infections, we hypothesized that measuring mediators of these pathways at clinical presentation would identify febrile adults at risk of death. METHODS: Plasma concentrations of markers of endothelial (angiopoetin-1/2, soluble fms-like tyrosine kinase-1, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1) and immune (soluble triggering receptor expressed on myeloid cells [sTREM-1], interleukin-6, interleukin-8, chitinase-3-like protein-1, soluble tumor necrosis factor receptor-1, procalcitonin [PCT], C-reactive protein [CRP]) activation pathways were determined in consecutive adults with acute fever (≥38°C) at presentation to outpatient clinics in Dar es Salaam, Tanzania. We evaluated the accuracy of these mediators in predicting all-cause mortality and examined whether markers could improve the prognostic accuracy of clinical scoring systems, including the quick sequential organ failure assessment (qSOFA) and Glasgow coma scale (GCS). RESULTS: Of 507 febrile adults, 32 died (6.3%) within 28 days of presentation. We found that sTREM-1 was the best prognostic marker for 28-day mortality (area under the receiver operating characteristic [AUROC] 0.87, 95% confidence interval [CI] 0.81-0.92) and was significantly better than CRP (P < .0001) and PCT (P = .0001). The prognostic accuracy of qSOFA and the GCS were significantly enhanced when sTREM-1 was added (0.80 [95% CI 0.76-0.83] to 0.91 [95% CI 0.88-0.94; P < .05] and 0.72 [95% CI 0.63-0.80] to 0.94 [95% CI 0.91-0.97; P < .05], respectively). CONCLUSIONS: Measuring sTREM-1 at clinical presentation can identify febrile individuals at risk of all-cause febrile mortality. Adding severity markers such as sTREM-1 to simple clinical scores could improve the recognition and triage of patients with life-threatening infections in resource-limited settings.

Clinical relevance of low-density Plasmodium falciparum parasitemia in untreated febrile children: A cohort study.

BACKGROUND: Low-density (LD) Plasmodium infections are missed by standard malaria rapid diagnostic tests (standard mRDT) when the blood antigen concentration is below the detection threshold. The clinical impact of these LD infections is unknown. This study investigates the clinical presentation and outcome of untreated febrile children with LD infections attending primary care facilities in a moderately endemic area of Tanzania. METHODS/FINDINGS: This cohort study includes 2,801 febrile pediatric outpatients (median age 13.5 months [range 2-59], female:male ratio 0.8:1.0) recruited in Dar es Salaam, Tanzania between 01 December 2014 and 28 February 2016. Treatment decisions were guided by a clinical decision support algorithm run on a mobile app, which also collected clinical data. Only standard mRDT+ cases received antimalarials. Outcomes (clinical failure, secondary hospitalization, and death) were collected in follow-up visits or interviews on days 3, 7, and 28. After patient recruitment had ended, frozen blood from all 2,801 patients was tested for Plasmodium falciparum (Pf) by ultrasensitive-quantitative polymerase chain reaction (qPCR), standard mRDT, and "ultrasensitive" mRDT. As the latter did not improve sensitivity beyond standard mRDT, it is hereafter excluded. Clinical features and outcomes in LD patients (standard mRDT-/ultrasensitive-qPCR+, not given antimalarials) were compared with those with no detectable (ND) parasitemia (standard mRDT-/ultrasensitive-qPCR-) or high-density (HD) infections (standard mRDT+/ultrasensitive-qPCR+, antimalarial-treated). Pf positivity rate was 7.1% (n = 199/2,801) and 9.8% (n = 274/2,801) by standard mRDT and ultrasensitive qPCR, respectively. Thus, 28.0% (n = 76/274) of ultrasensitive qPCR+ cases were not detected by standard mRDT and labeled "LD". LD patients were, on average, 10.6 months younger than those with HD infections (95% CI 7.0-14.3 months, p < 0.001). Compared with ND, LD patients more frequently had the diagnosis of undifferentiated fever of presumed viral origin (risk ratio [RR] = 2.0, 95% CI 1.3-3.1, p = 0.003) and were more often suffering from severe malnutrition (RR = 3.2, 95% CI 1.1-7.5, p = 0.03). Despite not receiving antimalarials, outcomes for the LD group did not differ from ND regarding clinical failures (2.6% [n = 2/76] versus 4.0% [n = 101/2,527], RR = 0.7, 95% CI 0.2-3.5, p = 0.7) or secondary hospitalizations (2.6% [n = 2/76] versus 2.8% [n = 72/2,527], RR = 0.7,95% CI 0.2-3.2, p = 0.9), and no deaths were reported in any Pf-positive groups. HD patients experienced more secondary hospitalizations (10.1% [n = 20/198], RR = 0.3, 95% CI 0.1-1.0, p = 0.005) than LD patients. All the patients in this cohort were febrile children; thus, the association between parasitemia and fever cannot be investigated, nor can the conclusions be extrapolated to neonates and adults. CONCLUSIONS: During a 28-day follow-up period, we did not find evidence of a difference in negative outcomes between febrile children with untreated LD Pf parasitemia and those without Pf parasitemia. These findings suggest LD parasitemia may either be a self-resolving fever or an incidental finding in children with other infections, including those of viral origin. These findings do not support a clinical benefit nor additional risk (e.g. because of missed bacterial infections) to using ultrasensitive malaria diagnostics at a primary care level.

Diagnostic Performance of Conventional and Ultrasensitive Rapid Diagnostic Tests for Malaria in Febrile Outpatients in Tanzania.

BACKGROUND: A novel ultrasensitive malaria rapid diagnostic test (us-RDT) has been developed for improved active Plasmodium falciparum infection detection. The usefulness of this us-RDT in clinical diagnosis and fever management has not been evaluated. METHODS: Diagnostic performance of us-RDT was compared retrospectively to that of conventional RDT (co-RDT) in 3000 children and 515 adults presenting with fever to Tanzanian outpatient clinics. The parasite density was measured by an ultrasensitive qPCR (us-qPCR), and the HRP2 concentration was measured by an enzyme-linked immunosorbent assay. RESULTS: us-RDT identified few additional P. falciparum-positive patients as compared to co-RDT (276 vs 265 parasite-positive patients detected), with only a marginally greater sensitivity (75% vs 73%), using us-qPCR as the gold standard (357 parasite-positive patients detected). The specificity of both RDTs was >99%. Five of 11 additional patients testing positive by us-RDT had negative results by us-qPCR. The HRP2 concentration was above the limit of detection for co-RDT (>3653 pg of HRP2 per mL of blood) in almost all infections (99% [236 of 239]) with a parasite density >100 parasites per µL of blood. At parasite densities <100 parasites/µL, the HRP2 concentration was above the limits of detection of us-RDT (>793 pg/mL) and co-RDT in 29 (25%) and 24 (20%) of 118 patients, respectively. CONCLUSION: There is neither an advantage nor a risk of using us-RDT, rather than co-RDT, for clinical malaria diagnosis. In febrile patients, only a small proportion of infections are characterized by a parasite density or an HRP2 concentration in the range where use of us-RDT would confer a meaningful advantage over co-RDT.

Safety and Efficacy of C-reactive Protein-guided Antibiotic Use to Treat Acute Respiratory Infections in Tanzanian Children: A Planned Subgroup Analysis of a Randomized Controlled Noninferiority Trial Evaluating a Novel Electronic Clinical Decision Algorithm (ePOCT).

BACKGROUND: The safety and efficacy of using C-reactive protein (CRP) to decide on antibiotic prescription among febrile children at risk of pneumonia has not been tested. METHODS: This was a randomized (1:1) controlled noninferiority trial in 9 primary care centers in Tanzania (substudy of the ePOCT trial evaluating a novel electronic decision algorithm). Children aged 2-59 months with fever and cough and without life-threatening conditions received an antibiotic based on a CRP-informed strategy (combination of CRP ≥80 mg/L plus age/temperature-corrected tachypnea and/or chest indrawing) or current World Health Organization standard (respiratory rate ≥50 breaths/minute). The primary outcome was clinical failure by day (D) 7; the secondary outcomes were antibiotic prescription at D0, secondary hospitalization, or death by D30. RESULTS: A total of 1726 children were included (intervention: 868, control: 858; 0.7% lost to follow-up). The proportion of clinical failure by D7 was 2.9% (25/865) in the intervention arm vs 4.8% (41/854) in the control arm (risk difference, -1.9% [95% confidence interval {CI}, -3.7% to -.1%]; risk ratio [RR], 0.60 [95% CI, .37-.98]). Twenty of 865 (2.3%) children in the intervention arm vs 345 of 854 (40.4%) in the control arm received antibiotics at D0 (RR, 0.06 [95% CI, .04-.09]). There were fewer secondary hospitalizations and deaths in the CRP arm: 0.5% (4/865) vs 1.5% (13/854) (RR, 0.30 [95% CI, .10-.93]). CONCLUSIONS: CRP testing using a cutoff of ≥80 mg/L, integrated into an electronic decision algorithm, was able to improve clinical outcome in children with respiratory infections while substantially reducing antibiotic prescription. CLINICAL TRIALS REGISTRATION: NCT02225769.

Performance of prediction rules and guidelines in detecting serious bacterial infections among Tanzanian febrile children.

BACKGROUND: Health-workers in developing countries rely on clinical algorithms, such as the Integrated Management of Childhood Illnesses (IMCI), for the management of patients, including diagnosis of serious bacterial infections (SBI). The diagnostic accuracy of IMCI in detecting children with SBI is unknown. Prediction rules and guidelines for SBI from well-resourced countries at outpatient level may help to improve current guidelines; however, their diagnostic performance has not been evaluated in resource-limited countries, where clinical conditions, access to care, and diagnostic capacity differ. The aim of this study was to estimate the diagnostic accuracy of existing prediction rules and clinical guidelines in identifying children with SBI in a cohort of febrile children attending outpatient health facilities in Tanzania. METHODS: Structured literature review to identify available prediction rules and guidelines aimed at detecting SBI and retrospective, external validation on a dataset containing 1005 febrile Tanzanian children with acute infections. The reference standard, SBI, was established based on rigorous clinical and microbiological criteria. RESULTS: Four prediction rules and five guidelines, including IMCI, could be validated. All examined rules and guidelines had insufficient diagnostic accuracy for ruling-in or ruling-out SBI with positive and negative likelihood ratios ranging from 1.04-1.87 to 0.47-0.92, respectively. IMCI had a sensitivity of 36.7% (95% CI 29.4-44.6%) at a specificity of 70.3% (67.1-73.4%). Rules that use a combination of clinical and laboratory testing had better performance compared to rules and guidelines using only clinical and or laboratory elements. CONCLUSIONS: Currently applied guidelines for managing children with febrile illness have insufficient diagnostic accuracy in detecting children with SBI. Revised clinical algorithms including simple point-of-care tests with improved accuracy for detecting SBI targeting in tropical resource-poor settings are needed. They should undergo careful external validation against clinical outcome before implementation, given the inherent limitations of gold standards for SBI.

Large-scale implementation of electronic Integrated Management of Childhood Illness (eIMCI) at the primary care level in Burkina Faso: a qualitative study on health worker perception of its medical content, usability and impact on antibiotic prescription and resistance.

BACKGROUND: Electronic clinical decision algorithms (eCDAs) that guide clinicians during patient management are being deployed in resource-limited settings to improve the quality of care and rational use of medicines (especially antimicrobials). Little is known on how local clinicians perceive the use and impact of these tools in their daily practice. This study investigates clinician insights on an eIMCI tool. Specifically, we report their views on its medical content, assess their knowledge on microbes, antimicrobials and the development of resistance. METHODS: This qualitative study was conducted in the frame of a large-scale implementation in Burkina Faso of an eIMCI tool developed by the Swiss NGO Terre des hommes. Twelve in-depth interviews and 2 focus-group discussions were conducted including 21 health workers from 10 primary care facilities. Emerging themes were identified using qualitative data analysis software. RESULTS: eIMCI users expressed a high level of satisfaction, slowness of the tablet was perceived as the major inconvenience limiting uptake. Several frequent illnesses were identified as missing in the algorithm along with guidance for fever without focus. When asked about existing types of microbes, 9 and 4 out of 21 participants could mention bacteria and virus respectively; only 5 correctly answered that antibiotics had no action on viral disease and 6 mentioned the risk of antibiotic resistance. Level of knowledge was higher in nurses than in less trained health workers. The tool was perceived as improving patient management and the rational use of antibiotics. Positive changes in health facility organisation were reported, such as task shifting and improved triage. eIMCI was also perceived as a learning tool, and users expressed a strong desire to expand the geographic and temporal scope of the intervention. CONCLUSION: The use of eICMI was widely accepted and perceived as a powerful tool guiding daily practice. Findings suggest that it has positive effects on the health care system beyond the quality of consultation. To support large uptake and sustainability, better training of health workers in infectiology is essential and the medical content of eIMCI should be optimized to include frequent diseases and, for each of them, the appropriate management plan.

Procalcitonin and lung ultrasonography point-of-care testing to decide on antibiotic prescription in patients with lower respiratory tract infection in primary care: protocol of a pragmatic cluster randomized trial.

BACKGROUND: A minority of patients presenting with lower respiratory tract infection (LRTI) to their general practitioner (GP) have community-acquired pneumonia (CAP) and require antibiotic therapy. Identifying them is challenging, because of overlapping symptomatology and low diagnostic performance of chest X-ray. Procalcitonin (PCT) can be safely used to decide on antibiotic prescription in patients with LRTI. Lung ultrasound (LUS) is effective in detecting lung consolidation in pneumonia and might compensate for the lack of specificity of PCT. We hypothesize that combining PCT and LUS, available as point-of care tests (POCT), might reduce antibiotic prescription in LRTIs without impacting patient safety in the primary care setting. METHODS: This is a three-arm pragmatic cluster randomized controlled clinical trial. GPs are randomized either to PCT and LUS-guided antibiotic therapy or to PCT only-guided therapy or to usual care. Consecutive adult patients with an acute cough due to a respiratory infection will be screened and included if they present a clinical pneumonia as defined by European guidelines. Exclusion criteria are previous antibiotics for the current episode, working diagnosis of sinusitis, severe underlying lung disease, severe immunosuppression, hospital admission, pregnancy, inability to provide informed consent and unavailability of the GP. Patients will fill in a 28 day-symptom diary and will be contacted by phone on days 7 and 28. The primary outcome is the proportion of patients prescribed any antibiotic up to day 28. Secondary outcomes include clinical failure by day 7 (death, admission to hospital, absence of amelioration or worsening of relevant symptoms) and by day 28, duration of restricted daily activities, episode duration as defined by symptom score, number of medical visits, number of days with side effects due to antibiotics and a composite outcome combining death, admission to hospital and complications due to LRTI by day 28. An evaluation of the cost-effectiveness and of processes in the clinic using a mixed qualitative and quantitative approach will also be conducted. DISCUSSION: Our intervention targets only patients with clinically suspected CAP who have a higher pretest probability of definite pneumonia. The intervention will not substitute clinical assessment but completes it by introducing new easy-to-perform tests. TRIAL REGISTRATION: The study was registered on the 19th of June 2017 on the clinicaltrials.gov registry using reference number; NCT03191071 .

Dengue fever in Dar es Salaam, Tanzania: clinical features and outcome in populations of black and non-black racial category.

BACKGROUND: Although the incidence of dengue across Africa is high, severe dengue is reported infrequently. We describe the clinical features and the outcome of dengue according to raceduring an outbreak in Dar es Salaam, Tanzania that occurred in both native and expatriate populations. METHODS: Adults with confirmed dengue (NS1 and/or IgM on rapid diagnostic test and/or PCR positive) were included between December 2013 and July 2014 in outpatient clinics. Seven-day outcome was assessed by a visit or a call. Association between black race and clinical presentation, including warning signs, was assessed by logistic regression adjusted for age, malaria coinfection, secondary dengue and duration of symptoms at inclusion. The independent association between demographic and comorbidities characteristics of the patients and severe dengue was evaluated by multivariate logistic regression that included potential confounders. RESULTS: After exclusion of 3 patients of mixed race, 431 patients with dengue (serotype 2, genotype Cosmopolitan) were included: 241 of black and 190 of non-black race. Black patients were younger (median age 30 versus 41 years; p < 0.001) and attended care after a slightly longer duration of symptoms (median of 2.9 versus 2.7 days; p = 0.01). Malaria coinfection was not significantly different between black (5%) and non-black (1.6%) patients (p = 0.06). The same proportion of patients in both group had secondary dengue (13 and 14%; p = 0.78). Among warning signs, only mucosal bleed was associated with race, black race being protective (adjusted OR 0.44; 95% CI 0.21-0.92). Overall, 20 patients (4.7%) presented with severe dengue. Non-black race (adjusted OR 3.9; 95% CI 1.3-12) and previously known diabetes (adjusted OR 43; 95% CI 5.2-361) were independently associated with severe dengue. CONCLUSIONS: Although all patients were infected with the same dengue virus genotype, black race was independently protective against a severe course of dengue, suggesting the presence of protective genetic or environmental host factors among people of African ancestry. The milder clinical presentation of dengue in black patients might partly explain why dengue outbreaks are under-reported in Africa and often mistaken for malaria. These results highlight the need to introduce point-of-care tests, beside the one for malaria, to detect outbreaks and orientate diagnosis. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01947075 , retrospectively registered on the 13 of September 2014.