|Abstract: ||Worldwide, severe acute respiratory infections (SARIs) cause significant morbidity and mortality. In the United States of America (USA), pneumonia and influenza ranks sixth as the cause of hospitalization among Medicare beneficiaries (available at http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/DataCompendium/2011_Data_Compendium.html, accessed September 18th 2015). In New South Wales, Australia, influenza and pneumonia was responsible for 9.1% of total deaths in 2013 (available at http://www.health.nsw.gov.au/Infectious/Influenza/Documents/2013/december-report.pdf, accessed September 18th 2015). However, these are likely underestimates of the true burden of respiratory infections as undiagnosed infection may result in respiratory or cardiovascular hospitalizations and deaths.
Respiratory viruses are commonly diagnosed using nucleic acid tests (NATs) and this is summarized in the review ‘Molecular diagnosis of respiratory viruses’ in Chapter 2. The review outlines the applications, advantages and limitations of using NATs in the diagnosis and clinical management of respiratory virus disease. Some disadvantages of the most commonly used NATs such as real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) includes the requirement of technical expertise, specialized equipment, and the relatively long turnaround times from specimen collection to results. By contrast, rapid influenza diagnostic tests (RIDTs) have the advantage of providing results in a clinically meaningful timeframe but not requiring specialized laboratory equipment or expertise to operate. This is an advantage in locations where laboratory facilities are limited. However, these assays are less sensitive compared to rRT-PCR. The two manuscripts ‘Evaluation of the Sofia Influenza A+B fluorescent immunoassay for the rapid diagnosis of influenza A and B’ and ‘Detection of influenza A and B with the Alere i Influenza A&B: a novel isothermal nucleic acid amplification assay’ addresses the issue of new assay sensitivity, and determined that these two RIDTs were less sensitive (33.3 - 77.8%) compared to rRT-PCR for the detection of influenza viruses, particularly for influenza B viruses.
Secondary bacterial pneumonia complicating influenza and other viral respiratory tract infections is a significant cause of morbidity and mortality. Rapid diagnosis of bacterial infection allows use of appropriate antimicrobials and obviates the need for further testing. Matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry has revolutionized the rapid identification of bacterial species, reviewed in ‘Current status of matrix assisted laser desorption ionization time-of-flight mass spectrometry in the clinical microbiology laboratory’. The MALDI Sepsityper™ has also allowed the rapid identification and direct antibiotic susceptibility testing of bacteria in blood cultures. Validation of this approach was examined in the manuscripts ‘Identification of bacteria in blood culture broths using matrix-assisted laser desorption-ionization Sepsityper™ and time of flight mass spectrometry’ and ‘Rapid and accurate direct antibiotic susceptibility testing of blood culture broths using MALDI Sepsityper™ combined with the BD Phoenix™ automated system’.
The recent emergence of two new respiratory viruses, A(H1N1)pdm09 virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have had significant worldwide impact. Chapter 3 explores the diagnosis and impact of these novel respiratory viruses at a population level. One manuscript, ‘Pandemic (H1N1) 2009 influenza virus seroconversion rates in HIV-infected individuals’ investigates the influenza attack rate in HIV-infected individuals through the use of hemagglutination inhibition in plasma collected prior to and after the first pandemic wave of A(H1N1)pdm09. ‘Comparisons of the impact of A(H1N1)pdm 2009 influenza in the Southern Hemisphere winter of 2009: a pooled analysis of seroepidemiological data’ examines the impact of A(H1N1)pdm09 in the Southern Hemisphere, pooling data from seroprevalence studies performed in Australia, New Zealand and Singapore. Both demonstrated high influenza attack rates in a potential at risk HIV population (14.6%), and in the general Southern Hemisphere community (17.5 – 30.8%).
The above serostudies and other publications demonstrated difficulties in direct comparison of serosurveys. This was addressed in the comment and correspondence ‘How common was pandemic (H1N1) 2009?’ and ‘The infection attack rate and severity of 2009 pandemic H1N1 influenza in Hong Kong: accuracy amidst ambiguity’. The different serological methods that have been used to perform serosurveys suggests that results between studies are not always comparable, and complicating the determination of the impact of an emerging respiratory virus.
Response to a novel or emerging virus requires clinical case definition to determine clinical and public health responses. However, there are limitations in the use of restrictive, yet non-specific definitions. The manuscript ‘Pandemic clinical case definitions are non-specific: multiple respiratory viruses circulating in the early phases on the 2009 influenza pandemic in New South Wales, Australia’ details the presence of multiple respiratory viruses co-circulating during the early phases of A(H1N1)pdm09, and that limiting testing for A(H1N1)pdm09 alone would have failed to detect other clinically relevant viruses in 44.3% of the samples tested.
The impact of a influenza B lineage not included in the Southern Hemisphere’s trivalent influenza vaccine of 2015 was assessed in ‘Increased prevalence of influenza B/Victoria lineage viruses during early stages of the 2015 influenza season in New South Wales, Australia: implications for vaccination and planning’. This manuscript details the epidemiology of influenza B viruses circulating in New South Wales during the early stages of the 2015 influenza season, the first season where the quadrivalent influenza vaccine was available in Australia. Twenty-eight percent of the influenza B viruses characterized belonged to the B/Victoria lineage.
There are concerns of MERS-CoV, influenza or other severe respiratory virus outbreaks in mass gatherings. This was discussed in the editorial ‘Mass gatherings and the implications for the spread of infectious diseases’. The study ‘Viral respiratory infections among Hajj pilgrims in 2013’ determined that human rhinoviruses (25%) were the most common respiratory virus in Australian, Qatari and Saudi Arabian pilgrims with an influenza-like illness during 2013 Hajj. Of note was that no MERS-CoV was detected in the pilgrim groups.
Specific risk factors for poor outcomes following influenza virus infection are well recognized. Although pregnancy has been previously identified as a risk factor for severe influenza infection, early data from the first wave of A(H1N1)pdm09 in Australia suggested that obesity was a novel risk factor. The manuscript ‘Viral pneumonitis is increased in obese patients infected with the pandemic A(H1N1) 2009 virus’ demonstrated that although obese patients were more likely to develop viral pneumonitis, their mortality rates were comparable to patients that were not obese. Another potential risk factor for more severe disease in influenza virus infections is the presence of bacterial and/or viral co-infections. These are explored in the manuscripts ‘The importance of bacterial and viral co-infection in severe influenza’ which examines Australian patients, and ‘Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies’, a multicentre international study. Viral co-infection was present in 3.2 – 14% and bacterial co-infection in 20.5 – 60.4% of samples tested.
This thesis highlights the use and performance of different diagnostic methods to diagnose SARIs at an individual level, estimate the attack rate and impact of novel respiratory viruses, and identify risk factors for severe disease. Further improvements in these areas will contribute to improved patient management, inform strategies to prevent and limit the impact of novel agents of SARIs, and provide future research directions in investigating the pathophysiology and pathogenesis of novel risk factors for poor outcomes.|