In-hospital death was associated with, on admission, older age (odds ratio 1·10, 95% CI 1·03–1·17; p=0·0043), a higher Sequential Organ Failure Assessment score (5·65, 2·61–12·23; p<0·0001), and ...blood d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033), findings known to be associated with severe pneumonia.6,7 The study also presents early data on changes in clinical and laboratory findings over time, which could help clinicians to identify patients who progress to more severe disease. In-hospital mortality was high (28%), much higher than in other reports that had incomplete follow-up data,3,5,8 and was very high among the 32 patients requiring invasive mechanical ventilation, of whom 31 (97%) died. By identifying this large group of patients united by their disease and tracking them to these endpoints, the authors have provided us with insight into risk factors for in-hospital death.
With apparent declines in malaria worldwide during the last decade and more widespread use of malaria rapid diagnostic tests, healthcare workers in low-resource areas face a growing proportion of ...febrile patients without malaria. We sought to describe current knowledge and identify information gaps of the etiology severe febrile illness in low-and middle-income countries.
We conducted a systematic review of studies conducted in low-and-middle income countries 1980-2013 that prospectively assessed consecutive febrile patients admitted to hospital using rigorous laboratory-based case definitions. We found 45 eligible studies describing 54,578 patients; 9,771 (17.9%) had a positive result for ≥1 pathogen meeting diagnostic criteria. There were no eligible studies identified from Southern and Middle Africa, Eastern Asia, Oceania, Latin American and Caribbean regions, and the European region. The median (range) number of diagnostic tests meeting our confirmed laboratory case definitions was 2 (1 to 11) per study. Of diagnostic tests, 5,052 (10.3%) of 49,143 had confirmed bacterial or fungal bloodstream infection; 709 (3.8%) of 18,142 had bacterial zoonosis; 3,488 (28.5%) of 12,245 had malaria; and 1,804 (17.4%) of 10,389 had a viral infection.
We demonstrate a wide range of pathogens associated with severe febrile illness and highlight the substantial information gaps regarding the geographic distribution and role of common pathogens. High quality severe febrile illness etiology research that is comprehensive with respect to pathogens and geographically representative is needed.
Summary About 200 million cases of viral community-acquired pneumonia occur every year—100 million in children and 100 million in adults. Molecular diagnostic tests have greatly increased our ...understanding of the role of viruses in pneumonia, and findings indicate that the incidence of viral pneumonia has been underestimated. In children, respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses are the agents identified most frequently in both developed and developing countries. Dual viral infections are common, and a third of children have evidence of viral-bacterial co-infection. In adults, viruses are the putative causative agents in a third of cases of community-acquired pneumonia, in particular influenza viruses, rhinoviruses, and coronaviruses. Bacteria continue to have a predominant role in adults with pneumonia. Presence of viral epidemics in the community, patient's age, speed of onset of illness, symptoms, biomarkers, radiographic changes, and response to treatment can help differentiate viral from bacterial pneumonia. However, no clinical algorithm exists that will distinguish clearly the cause of pneumonia. No clear consensus has been reached about whether patients with obvious viral community-acquired pneumonia need to be treated with antibiotics. Apart from neuraminidase inhibitors for pneumonia caused by influenza viruses, there is no clear role for use of specific antivirals to treat viral community-acquired pneumonia. Influenza vaccines are the only available specific preventive measures. Further studies are needed to better understand the cause and pathogenesis of community-acquired pneumonia. Furthermore, regional differences in cause of pneumonia should be investigated, in particular to obtain more data from developing countries.
Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the ...potential to identify factors that may explain this heterogeneity.
To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.
MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.
Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D
or vitamin D
of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.
Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.
We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity
< 0.001. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10;
= 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D 25(OH)D concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95;
= 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20;
= 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.
Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.
Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.
This study is registered as PROSPERO CRD42014013953.
The National Institute for Health Research Health Technology Assessment programme.
In response, WHO's Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea has set targets and a framework for tackling this challenge, an important component being to ...measure progress.1 In The Lancet Infectious Diseases, the Global Burden of Disease (GBD) 2016 Lower Respiratory Infections Collaborators provide further estimates of the morbidity and mortality from lower respiratory infections, principally pneumonia and bronchiolitis.2 They also provide estimates for lower respiratory infections caused by four microorganisms—Streptococcus pneumoniae, Haemophilus influenzae type b, influenza, and respiratory syncytial virus. According to the models presented, S pneumoniae was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more than 1 million deaths, more than the other three aetiologies combined. Interventions to enhance access to health care are needed to augment preventive measures. ...a greater understanding is needed of the role of individual respiratory pathogens (more than just the four included in this study), to provide more accurate estimates of disease burden and to better target interventions.
Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and ...meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.
New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate ...649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, R
of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.
Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these ...patients.
HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.
Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.
Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.
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