Clinical diagnosis of influenza-like illness: the flu and beyond

Influenza virus infections are a significant global health concern presenting high morbidity and mortality, with annual epidemics in the northern and southern hemispheres as well as rare but serious pandemics. Influenza circulates through the population seasonally during the winter months and concurrently with a variety of other respiratory viral pathogens with similar and often indistinguishable clinical symptoms. Accurate identification and diagnosis of respiratory viral pathogens are essential for patient care, control of healthcare costs, and epidemiological trending.

In the United States, it has been estimated that 5% to 20% of the population is infected with influenza virus each year, causing significant financial burden estimated to be in excess of $40 billion annually.¹ Most cases of influenza infections result in mild, self-limiting illness with sudden onset of high fever, chills, headache, myalgia, and cough. Severe, potentially life-threatening complications can occur in individuals with co-morbidities such as chronic lung disease, extreme obesity (BMI > 40), immunosuppression, the extremely young (<5 years) or elderly (>60 years) as well as youth with neurologic conditions.^2,3 Influenza-like illness defines a set of clinical symptoms that can be caused by a number of viral pathogens that infect the upper and lower respiratory tract. In addition to influenza virus, other common respiratory viral pathogens include rhinovirus, adenovirus, respiratory syncytial virus, parainfluenza virus, and human metapneumovirus. Each of these has been shown to cause influenza-like illness and can be considered emerging independent health threats.^4-6 The use of clinical symptoms of influenza-like illness to define influenza infection has both low sensitivity and specificity, whereas laboratory diagnosis, described below, improves both sensitivity and specificity.⁷

Laboratory diagnosis

Several methodologies exist for diagnosis of influenza infection and other common respiratory viral pathogens, including immunofluorescent antibody stains, traditional microbiology culture, rapid antigen tests, and molecular reverse-transcription polymerase chain reaction (RT-PCR) tests. Immunofluorescent antibody staining techniques can produce results within two to four hours of sample collection, but are generally less sensitive than viral isolation from cell culture, and performance depends heavily upon laboratory expertise. Traditional culture techniques, still considered by many to be the gold standard method, exhibit reasonably good sensitivity but require long periods of time for viruses to expand, and some respiratory viruses fail to propagate in culture. Rapid antigen tests exist for influenza and respiratory syncytial virus (RSV) but have reported sensitivities as low as 20% (compared to RT-PCR with an 80% to 95% sensitivity rate); yet these tests continue to prove clinically useful due to the improved sensitivity and specificity when virus is prevalent, low cost, low skill requirements, and rapid turnaround time.⁸ The CDC Influenza Vaccination Committee recommends that a negative influenza result by rapid antigen test should not be used for treatment or infection control decisions.⁹ Molecular RT-PCR tests are the most sensitive and specific tests available and can readily differentiate between many respiratory tract infectious agents, allowing better patient management, improved healthcare cost control, and better antibiotic stewardship.¹⁰

Several expanded RT-PCR multiplex respiratory viral panels cleared by the FDA offer high sensitivity for a wide variety of respiratory viral pathogens. These tests have improved sensitivity for the detection of the respiratory viruses when compared to traditional methods in numerous peer reviewed publications.¹¹ The use of multiplex molecular tests has been shown to reduce healthcare associated costs of unnecessary diagnostic tests, improve lab operational efficiency, drive the reduction of inappropriate antibiotic use, and aid in epidemiological trending of circulating viruses.^12,13 Recent publications show the sensitivity of these multiplex tests compared to real-time PCR assays.^14-16 In recent years, increased utilization of molecular techniques has led to an abundance of studies on respiratory viral infections and the clinical impact of co-infection with one or more viruses. In one study, co-infection with respiratory syncytial virus and human metapneumovirus resulted in significant increase in pneumonia development compared to individuals infected with a single virus.¹⁷ While the clinical outcome of viral co-infection continues to be debated, there is ample evidence in the literature that the presence of multiple respiratory viruses increases disease severity and hospital length of stay.¹⁸ Similarly, the importance and risk of infection with viruses beyond influenza is now beginning to be understood.

Treatment decisions

The CDC recommends the use of influenza antivirals for confirmed or suspected influenza infection in hospitalized individuals and certain outpatient populations at risk for influenza complications, including patients with severe illness, patients with lower respiratory tract infection, and any individual with clinical deterioration.¹⁹ Currently, there are four antiviral agents approved by the FDA for treatment of influenza. The two adamantanes (amantadine and rimantadine) are active against Flu A but not Flu B viruses, but in recent years widespread adamantane resistance among circulating H3N2 has made this class of drug less useful. Two neuraminidase inhibitors, oseltamivir and zanamivir, are active against both Flu A and B, and currently circulating viruses 2009 H1N1 and H3N2 show little to no resistance. Therapeutic antiviral compounds are occasionally used for respiratory syncytial virus infection, particularly in the very young and elderly.

Clinical decisions surrounding the accurate diagnosis of respiratory viral pathogens beyond influenza and RSV are likely to emerge in the future. For example, it is now clear that rhinovirus plays a role in the development of wheezing and asthma in children, in exacerbations of asthma and cystic fibrosis, and in lower respiratory tract infections in elderly.⁵ A phase IIb study for the use of BTA-798 to limit severity and duration of rhinovirus episodes in children with asthma has recently been completed.²⁰ Human metapneumovirus has been shown to have the possibility of severe outbreak potential in adult settings, and adenovirus similarly has caused devastating outbreaks in assisted living facilities, military recruit housing, and inpatient immunocompromised populations.⁵

Nearly 50% of all respiratory infections caused by viruses are inappropriately prescribed antibiotics.²¹ Inappropriate use of antibiotics has significant complications including increased bacterial resistance to antibiotics, Clostridium difficile outbreaks, and antibiotic-induced gastroenteritis.²¹ Poor differentiation of the clinical etiologies of influenza-like illness, and failure to rapidly and accurately diagnose the broad variety of respiratory viral pathogens prevalent during typical respiratory “flu season,” drive inappropriate antibiotic use. Antibiotics should only be considered to reduce severity when bacterial co-infection is suspected (most commonly Streptococcus pneumonia and with lower frequency Staphlococcus aureus and Haemophilus influenza).²² Today the diagnosis of respiratory pathogens influences clinical decisions, supportive care of the patient, and cohorting decisions, and can help reduce unnecessary medical tests and inappropriate antibiotic use. However, it is not difficult to imagine a future when each of these pathogens results in a specific clinical course of treatment.

Influenza A update

It has long been understood that zoonotic hosts (swine, birds, horses) are a reservoir for influenza viruses and are the predominant source of co-infection induced re-assortment leading to new and potentially pathogenic influenza viruses.²³ Viral recombinations in animal hosts typically show low virulence and communicability in humans. However, outbreaks in 1997 of highly pathogenic H5N1 avian influenza in Hong Kong, swine influenza in 1976, and the recent H1N1 swine flu of 2009 continue to highlight the importance of monitoring influenza subtype and novel variants for vaccination, epidemiology, and pandemic potential.

In 2011, an H3N2 variant virus (H3N2v) was described in swine which can transmit to human hosts with seasonal influenza-like symptoms. In summer 2012 this virus infected hundreds of people, many after exposure to swine in the Midwest (www.cdc.gov/flu/swineflu/h3n2v-case-count.htm). The virus isolated from humans was found to contain the M gene of the 2009 pandemic H1N1 virus, and this has led to increased concern about potential development of communicability and risk to human health. The Centers for Disease Control and Prevention (CDC) keeps an active surveillance program monitoring circulating and emerging strains as well as anti-viral resistance (www.cdc.gov/flu/weekly/index.htm#whomap). Molecular methodologies deliver the best opportunity to detect this influenza variant by nucleic acid sequence detection, whereas the CDC has shown that several rapid antigen tests fail to detect this variant influenza virus.¹⁹

The view from here

Acute upper and lower respiratory viral infections commonly occur worldwide with significant morbidities and mortalities. Influenza A is most widely studied as a result of seasonal epidemics, occasional pandemics, and overall risk of severe infection and associated mortality. However, accurate diagnosis of all respiratory viral pathogens will improve patient outcomes and may reduce healthcare costs while promoting antibiotic stewardship. Recent studies have shown significant clinical episodes associated with respiratory viral pathogens previously thought to be inconsequential and to cause only transient influenza-like illness. The broader use of multiplex molecular detection increases the likelihood of discovering anti-viral drugs and specific clinical treatment for many respiratory pathogens in the coming years.

Peter M. Krein, PhD, is Senior Manager, Scientific Affairs, for California-based GenMark Diagnostics.

References

1. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalization in the United States. JAMA. 2004;292(11):1333-1340.
2. Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2008;57(RR-7):1-60.
3. Blanton L, Peacock G, Cox C, Jhung M, Finelli L, Moore C. Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. Pediatrics. 2012;130(3):390-396.
4. Proud D. Role of rhinovirus infections in asthma. Asian Pac J Allergy Immunol. 201;29(3):201-208.
5. Grey GC, McCarthy T, Lebeck MG, et al. Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006. Clin Infect Dis. 2007;45(9):1120-1131.
6. Williams JV, Crowe JE Jr, Enriquez R, et al. Human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in adults. J Infectious Dis. 2005;192(7):1149-1153.
7. Babcock HM, Merz, LR, Dubberke ER, Fraser VJ. Case-control study of clinical features of influenza in hospitalized patients. Infect Control Hosp Epidemiol. 2008;29(10):921-926.
8. Uyeki TM, Prasad R, Vukotich C, et al. Low sensitivity of rapid diagnostic test for influenza. Clin Infect Dis. 2009;48(9):e89-92.
9. Fiore AE, Uyeki TM, Broder K, et al. Prevention and control of influenza with vaccines: recommendation of the advisory committee on immunization practices (ACIP). MMWR. 2010;59(RR-8):1-62.
10. Weinberg GA, Erdman DD, Edwards KM, et al. Superiority of reverse-transcription polymerase chain reaction to conventional viral culture in the diagnosis of acute respiratory tract infections in children. J Infect Disease. 2004;189(4):706-710.
11. Garbino J, Gerbase MW, Wunderli W, et al. Lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact. Am J Respir Crit Care Med. 2004;170(11):1197-1203.
12. Dundas NE, Ziadie MS, Revell PA, et al. A lean laboratory: operational simplicity and cost effectiveness of the Luminex xTAG respiratory viral panel. J Mol Diagn. 2011;13(2):175-179.
13. Schnepf N, Resche-Rigon M, Chaillon A, et al. High burden of non-influenza viruses in influenza-like illness in the early weeks of H1N1v epidemic in France. PLoS One. 2011;6(8):e23514.
14. Pabbaraju K, Tokaryk KL, Wong S, Fox JD. Comparison of the Luminex xTAG respiratory viral panel with in house nucleic acid amplification tests for diagnosis of respiratory virus infections. J Clin Microbiol. 2008:46(9):3056-3062.
15. Pierce VM, Elkan M, Leet M, McGowan KL, Hodinka RL. Comparison of the Idaho Technology Filmarray system to real-time PCR for detection of respiratory pathogens in children. J Clin Microbiol. 2012:50(2):364-371.
16. Pierce VM, Hodinka RL. Comparison of the GenMark Diagnostics eSensor respiratory viral panel to real-time RCP for detection of respiratory viruses in children. J Clin Microbiol. 2012:Aug 8. [Epub ahead of print] doi10.1128/JCM.01384-12.
17. Caracciolo S, Minini C, Colombrita D. Human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features. Pediatr Infect Dis J. 2008:27(5):406-412.
18. Mansbach JM, Piedra PA, Teach SJ, et al. Prospective Multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med. 2012:166(8):700-706.
19. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM. Antiviral agents for the treatment and chemoprophylaxis of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR. 2011;60(RR-1):1-24.
20. Clinicaltrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT01175226?term=BTA-798&rank=1. Accessed September 28, 2012.
21. Chan PA. Mermel LA, Andrea SB, et al. Distinguishing characteristics between pandemic 2009-2010 influenza A (H1N1) and other viruses in patients hospitalized with respiratory illness. PLoS One. 2011;6(9)e24734.
22. Pasman L. The complication of coinfection. Yale J Biol and Med. 2012;85(1):127-132.
23. Hillman MR. Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine. 2002;20(25-26):3068-3087.