Experimental Human Pneumococcal Colonization in Older Adults Is Feasible and Safe, Not Immunogenic.

Rationale: Pneumococcal colonization is key to the pathogenesis of invasive disease but is also immunogenic in young adults, protecting against recolonization. Colonization is rarely detected in older adults, despite high rates of pneumococcal disease.Objectives: To establish experimental human pneumococcal colonization in healthy adults aged 50-84 years, to measure the immune response to pneumococcal challenge, and to assess the protective effect of prior colonization against autologous strain rechallenge.Methods: Sixty-four participants were inoculated with Streptococcus pneumoniae (serotype 6B; 80,000 cfu in each nostril). Colonization was determined by bacterial culture of nasal wash, and humoral immune responses were assessed by anticapsular and antiprotein IgG concentrations.Measurements and Main Results: Experimental colonization was established in 39% of participants (25/64) with no adverse events. Colonization occurred in 47% (9/19) of participants aged 50-59 compared with 21% (3/14) in those aged ≥70 years. Previous pneumococcal polysaccharide vaccination did not protect against colonization. Colonization did not confer serotype-specific immune boosting, with a geometric mean titer (95% confidence interval) of 2.7 µg/ml (1.9-3.8) before the challenge versus 3.0 (1.9-4.7) 4 weeks after colonization (P = 0.53). Furthermore, pneumococcal challenge without colonization led to a drop in specific antibody concentrations from 2.8 µg/ml (2.0-3.9) to 2.2 µg/ml (1.6-3.0) after the challenge (P = 0.006). Antiprotein antibody concentrations increased after successful colonization. Rechallenge with the same strain after a median of 8.5 months (interquartile range, 6.7-10.1) led to recolonization in 5/16 (31%).Conclusions: In older adults, experimental pneumococcal colonization is feasible and safe but demonstrates different immunological outcomes compared with younger adults in previous studies.

Etiology and Risk Factors for Mortality in an Adult Community-acquired Pneumonia Cohort in Malawi.

Rationale: In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa.Objectives: To describe the current etiology of CAP in Malawi and identify risk factors for mortality.Methods: We conducted a prospective observational study of adults hospitalized with CAP to a teaching hospital in Blantyre, Malawi. Etiology was defined by blood culture, Streptococcus pneumoniae urinary antigen detection, sputum mycobacterial culture and Xpert MTB/RIF, and nasopharyngeal aspirate multiplex PCR.Measurements and Main Results: In 459 patients (285 [62.1%] males; median age, 34.7 [interquartile range, 29.4-41.9] yr), 30-day mortality was 14.6% (64/439) and associated with male sex (adjusted odds ratio, 2.60 [95% confidence interval, 1.17-5.78]), symptom duration greater than 7 days (2.78 [1.40-5.54]), tachycardia (2.99 [1.48-6.06]), hypoxemia (4.40 [2.03-9.51]), and inability to stand (3.59 [1.72-7.50]). HIV was common (355/453; 78.4%), frequently newly diagnosed (124/355; 34.9%), but not associated with mortality. S. pneumoniae (98/458; 21.4%) and Mycobacterium tuberculosis (75/326; 23.0%) were the most frequently identified pathogens. Viral infection occurred in 32.6% (148/454) with influenza (40/454; 8.8%) most common. Bacterial-viral coinfection occurred in 9.1% (28/307). Detection of M. tuberculosis was associated with mortality (adjusted odds ratio, 2.44 [1.19-5.01]).Conclusions: In the antiretroviral therapy era, CAP in Malawi remains predominantly HIV associated, with a large proportion attributable to potentially vaccine-preventable pathogens. Strategies to increase early detection and treatment of tuberculosis and improve supportive care, in particular the correction of hypoxemia, should be evaluated in clinical trials to address CAP-associated mortality.

Impact of Human Immunodeficiency Virus on the Burden and Severity of Influenza Illness in Malawian Adults: A Prospective Cohort and Parallel Case-Control Study.

Background: The impact of human immunodeficiency virus (HIV) infection on influenza incidence and severity in adults in sub-Saharan Africa is unclear. Seasonal influenza vaccination is recommended for HIV-infected persons in developed settings but is rarely implemented in Africa. Methods: We conducted a prospective cohort study to compare the incidence of laboratory-confirmed influenza illness between HIV-infected and HIV-uninfected adults in Blantyre, Malawi. In a parallel case-control study, we explored risk factors for severe influenza presentation of severe (hospitalized) lower respiratory tract infection, and mild influenza (influenza-like illness [ILI]). Results: The cohort study enrolled 608 adults, of whom 360 (59%) were HIV infected. Between April 2013 and March 2015, 24 of 229 ILI episodes (10.5%) in HIV-infected and 5 of 119 (4.2%) in HIV-uninfected adults were positive for influenza by means of polymerase chain reaction (incidence rate, 46.0 vs 14.5 per 1000 person-years; incidence rate ratio, 2.75; 95% confidence interval, 1.02-7.44; P = .03; adjusted for age, sex, household crowding, and food security). In the case-control study, influenza was identified in 56 of 518 patients (10.8%) with hospitalized lower respiratory tract infection, and 88 or 642 (13.7%) with ILI. The HIV prevalence was 69.6% and 29.6%, respectively, among influenza-positive case patients and controls. HIV was a significant risk factor for severe influenza (odds ratio, 4.98; 95% confidence interval, 2.09-11.88; P < .001; population-attributable fraction, 57%; adjusted for season, sanitation facility, and food security). Conclusions: HIV is an important risk factor for influenza-associated ILI and severe presentation in this high-HIV prevalence African setting. Targeted influenza vaccination of HIV-infected African adults should be reevaluated, and the optimal mechanism for vaccine introduction in overstretched health systems needs to be determined.

Pneumonia in the developing world: Characteristic features and approach to management.

Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality in adults worldwide, but its epidemiology varies markedly by region. Whilst in high-income countries, the predominant burden of CAP is in the elderly and those with chronic cardiovascular and pulmonary co-morbidity, CAP patients in low-income settings are often of working age and, in sub-Saharan Africa, frequently HIV-positive. Although region-specific aetiological data are limited, they are sufficient to highlight major trends: in high-burden settings, tuberculosis (TB) is a common cause of acute CAP; Gram-negative pathogens such as Klebsiella pneumoniae are regionally important; and HIV-associated opportunistic infections are common but difficult to diagnose. These differences in epidemiology and aetiological profile suggest that modified approaches to diagnosis, severity assessment and empirical antimicrobial therapy of CAP are necessary, but tailored individualized management approaches are constrained by limitations in the availability of radiological and laboratory diagnostic services, as well as medical expertise. The widespread introduction of the Xpert MTB/RIF platform represents a major advance for TB diagnosis, but innovations in rapid diagnostics for other opportunistic pathogens are urgently needed. Severity assessment tools (e.g. CURB65) that are used to guide early management decisions in CAP have not been widely validated in low-income settings and locally adapted tools are required. The optimal approach to initial antimicrobial therapy choices such as the need to provide early empirical cover for atypical bacteria and TB remain poorly defined. Improvements in supportive care such as correcting hypoxaemia and intravenous fluid management represent opportunities for substantial reductions in mortality.

Community-Acquired Pneumonia in Sub-Saharan Africa.

Community-acquired pneumonia (CAP) in sub-Saharan Africa is a common cause of adult hospitalization and is associated with significant mortality. Human immunodeficiency virus (HIV) prevalence in the region leads to differences in CAP epidemiology compared with most high-income settings: patients are younger, and coinfection with tuberculosis and opportunistic infections is common and difficult to diagnose. Resource limitations affect the availability of medical expertise as well as radiological and laboratory diagnostic services. These factors impact on key aspects of health care, including pathways of investigation, severity assessment, and the selection of empirical antimicrobial therapy. This review summarizes recent data from sub-Saharan Africa describing the burden, etiology, risk factors, and outcome of CAP. We describe the rational and context-appropriate approach to CAP diagnosis and management, including supportive therapy. Priorities for future research to inform strategies for CAP prevention and initial management are suggested.

Extraordinary virtual multidisciplinary team meetings - a novel forum for the coordinated care of patients with -complex conditions within a secondary care setting.

Multidisciplinary team (MDT) meetings are increasingly regarded as best practice for the successful management of chronic disease. However, for patients with undiagnosed illnesses, multiple interacting comorbidities or other complex needs that fall outside the remit of disease-specific MDTs or the scope of expertise of individual clinicians, there is often no suitable forum at which to discuss their care to develop a coordinated plan for management. We developed and piloted a new forum for interspecialty discussion and collaboration, an extraordinary virtual MDT, to enable clinicians to arrange an urgent meeting of all involved parties in response to challenging clinical scenarios. Here, we share our experience of implementing this innovation and suggest how this novel forum for coordinated care could be further developed to improve the integration, timeliness and quality of healthcare delivery for patients with complex needs.

The role of rapid diagnostic tests in managing adults with pneumonia in low-resource settings.

In well-resourced settings the systematic use of rapid diagnostics tests (e.g. pneumococcal urinary antigen test) that define the causal pathogen to direct therapy has not resulted in significantly improved outcomes in adults with pneumonia. The management of pneumonia in many low-resource settings is complicated by a substantial burden of tuberculosis and HIV-associated opportunistic infections, in addition to the usual spectrum of pathogens seen in well-resourced settings. Clinical features alone do not reliably distinguish between these different aetiologies and physicians often have to treat empirically. Given the limitations in diagnostic laboratory capability present in most low-resource settings, rapid and point-of-care diagnostic tests could become valuable tools to guide treatment decisions. Pneumococcal and Legionella urinary antigen tests are specific and moderately sensitive, but their utility in low-resource settings is uncertain. The Cepheid Xpert MTB/RIF platform and rapid assays for urinary lipoarabinomannan can substantially speed up tuberculosis diagnosis; the current challenge is to translate this into earlier treatment and hopefully improve patient outcome. In HIV-infected patients, 1-3-ß-D-glucan is a serum marker of Pneumocystis jirovecii infection with excellent sensitivity. Further studies are needed to assess the clinical utility and cost-effectiveness of these rapid diagnostics assays when they incorporated into treatment algorithms.