Rapid diagnostics urgently needed for killer infections
Authors: Alimuddin Zumla, Vanya Gant, Matthew Bates, Peter Mwaba, Markus Maeurer, Ziad A Memish
Journal: The Lancet Respiratory Medicine (2013)

Respiratory tract infections (RTIs) cause millions of deaths worldwide. They are caused by disparate bacteria, viruses, fungi, and parasites that have similar presentations and thus cannot be easily distinguished clinically. There is presently no standardised, rapid, accurate, sensitive, and specific point-of-care diagnostic test available that can identify causative pathogens within a few hours of consultation. Therefore, patients presenting with RTIs at all points of health care are empirically treated with broad-spectrum antibiotics designed to cover many possible pathogens. The management of patients with RTIs is further complicated by the growing global threat posed by the emergence and spread of antibiotic-resistant bacteria1Beceiro A Tomás M Bou G Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world?.Clin Microbiol Rev. 2013; 26: 185-230Crossref PubMed Scopus (708) Google Scholar (including multidrug-resistant strains of Mycobacterium tuberculosis2Zignol M van Gemert W Falzon D et al.Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010.Bull World Health Organ. 2012; 90 (19D.): 111Crossref PubMed Google Scholar) and azole-resistant fungi.3Hayes GE Denning DW Frequency, diagnosis and management of fungal respiratory infections.Curr Opin Pulm Med. 2013; 19: 259-265Crossref PubMed Scopus (33) Google Scholar Clinicians are often unaware of the presence of more than one pathogen, although co-infections of bacteria4Chertow DS Memoli MJ Bacterial coinfection in influenza: a grand rounds review.JAMA. 2013; 309: 275-282Crossref PubMed Scopus (314) Google Scholar or other respiratory viruses5Stefanska I Romanowska M Donevski S Gawryluk D Brydak LB Co-infections with influenza and other respiratory viruses.Adv Exp Med Biol. 2013; 756: 291-301Crossref PubMed Scopus (42) Google Scholar and influenza are well described, as are bacterial, viral, or parasitic infections with pulmonary tuberculosis.6Marais BJ Lönnroth K Lawn SD et al.Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.Lancet Infect Dis. 2013; 13: 436-448Summary Full Text Full Text PDF PubMed Scopus (230) Google Scholar Autopsy studies of patients who die because of RTIs suggest that, in many cases, the empirical antibiotic treatment prescribed was inappropriate for the causative pathogens, and that co-infections were not suspected before death.7Bates M Mudenda V Mwaba P Zumla A Deaths due to respiratory tract infections in Africa: a review of autopsy studies.Curr Opin Pulm Med. 2013; 19: 229-237Crossref PubMed Scopus (62) Google Scholar New and emerging pathogens with epidemic potential also pose diagnostic challenges. Global scientific and political attention is currently focused on two new viruses associated with severe RTIs and high mortality: the avian influenza A H7N9 virus from China and novel coronavirus from the Arabian Peninsula. Both were rapidly reported by the Program for Monitoring Emerging Diseases (ProMED). On March 31, 2013, the China Health and Planning Commission reported three cases of avian influenza A H7N9—a virus originating from poultry and wild birds.8Zhang W Wang L Hu W et al.Epidemiological characteristics of cases for influenza A (H7N9) virus infections in China.Clin Infect Dis. 2013; (published online April 30.)https://doi.org/10.1093/cid/cit277Crossref Scopus (22) Google Scholar As of May 14, a total of 132 confirmed cases of avian influenza A H7N9 (with 35 deaths; 27% case fatality) had been recorded by ProMED. The first case of novel coronavirus was reported in September, 2012, from Saudi Arabia. As of May 15, 2013, a total of 40 cases (with 20 deaths; 50% case fatality) have been reported to WHO according to ProMED: 30 in Saudi Arabia (15 deaths); two in Jordan (two deaths); four in the UK (two deaths); two in Germany (one death), and two in France (no deaths). Most cases were linked with the Middle East. The source of the novel coronavirus remains unknown. Person-to-person transmission has been recorded, but only in individuals with comorbidities, according to ProMED. Transmission of RTIs—particularly imported influenza viruses—at mass gatherings is well documented,9Al-Tawfiq JA Zumla A Memish ZA Respiratory tract infections during the annual Hajj: potential risks and mitigation strategies.Curr Opin Pulm Med. 2013; 19: 192-197Crossref PubMed Scopus (64) Google Scholar and poses a threat to global health security. About 10 million pilgrims from 183 countries are expected to visit Mecca and Medina in Saudi Arabia for the Umrah and Hajj pilgrimages in 2013, and will be in close proximity to each other, thus posing a major public health concern. Rapid serological diagnostic tests for the novel coronavirus are in development and will be useful for surveillance and cross-sectional and longitudinal cohort studies. Advances in molecular diagnostics have been applied to simultaneous detection of pathogens and their antibiotic resistance from one sputum sample. The absence of rapid accurate diagnostic tests for pulmonary tuberculosis was further compounded by the widespread inability to screen for drug-resistant bacteria. The introduction of the GeneXpert MTB/RIF Assay, which detects Mycobacterium tuberculosis DNA and rifampicin resistance from sputum samples in 2 h, could revolutionise tuberculosis diagnostics.10Lawn SD Mwaba P Bates M et al.Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test.Lancet Infect Dis. 2013; 13: 349-361Summary Full Text Full Text PDF PubMed Scopus (360) Google Scholar A lateral flow immunoassay for detection of meticillin-resistant Staphylococcus aureus in sputum is also now available.11Wiriyachaiporn S Howarth PH Bruce KD Dailey LA Evaluation of a rapid lateral flow immunoassay for Staphylococcus aureus detection in respiratory samples.Diagn Microbiol Infect Dis. 2013; 75: 28-36Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar Although several new rapid molecular diagnostic platforms capable of simultaneously identifying both pathogens and the genetic determinants of antimicrobial resistance are emerging,12Endimiani A Hujer KM Hujer AM et al.Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia?.Clin Infect Dis. 2011; 52: S373-S383Crossref PubMed Scopus (71) Google Scholar they do not seem to be well suited to clinical presentations or downstream management strategies for patients with RTIs. Furthermore, none can identify new emerging organisms for which genetic sequences are unavailable. However, rapid sequencing technologies linked to bioinformatics have provided proof of diagnostic principle in a short time.13Greninger AL Chen EC Sittler T et al.A metagenomic analysis of pandemic influenza A (2009 H1N1) infection in patients from North America.PLoS One. 2010; 5: e13381Crossref PubMed Scopus (143) Google Scholar Until new diagnostics are developed to serve clinical need, the mainstay of clinical management for any RTI will remain dependent on imperfect diagnostics and linked to empirical broad-spectrum antibiotics. Thus, clinicians have to maintain clinical awareness of other possible causes of RTIs, whether they are opportunistic or not. An ideal diagnostic test for RTIs should be rapid (a result within 1 h of consultation), cheap, easy to use, sensitive, and specific, and should screen for many microorganisms and their antibiotic resistance. Furthermore, the diagnostics platform should be transportable, robust, and ideally run on solar power for use in the remote health-care settings in developing countries. Whether or not an ideal diagnostic platform for RTIs can be delivered, advances in biotechnology give hope. Such a device would improve the health and lives of patients with RTIs worldwide, and would also contribute to global health surveillance and security. To achieve this ideal, physicians, scientists, biotechnology companies, funding agencies, and governments need to work together to drive the development of improved diagnostic tests for both developed and developing countries. We declare that we have no conflicts of interest. China's H7N9 outbreak slows but experts remain waryThe novel strain of H7N9 avian influenza that appeared in China in February, 2013, is waning nearly as rapidly as it had emerged. The upward march of new cases—which climbed by more than 120 during April—slowed to a crawl in May, with just five reported as of May 14. After 3 weeks with no new cases in Shanghai, officials declared an end to the emergency response they activated on April 2, although hospitals will continue to monitor influenza-like illnesses and live poultry markets remain shuttered. Full-Text PDF