Respiratory Viral Infections

Respiratory tract infections account for a huge medical and economic burden. Although the overall frequency of respiratory infections diminishes with age, from eight to 10 in the first year of life to one or two in older adults, it is generally at the extremes of life that the greatest impact occurs. Viruses are the most frequent cause of lower respiratory tract infections (LRTIs) in infants and children, accounting for ~70% of all illnesses. When carefully sought, viruses are also identified in at least 20 to 30% of LRTIs in adults and are frequently the sole pathogen identified.[1] [2] In this issue of Seminars in Respiratory and Critical Care Medicine many old and several newly identified pathogens, including two viruses with serious pandemic potential [“bird flu” and severe acute respiratory syndrome (SARS)], are reviewed by an esteemed group of investigators.

Several common themes are noted in each of the articles. They are the importance of newer molecular diagnostic tests, the nonspecific clinical illness caused by each, and the paucity of vaccines. Our current understanding of the epidemiology of these viruses has been greatly advanced, and in some cases altered substantially, by the application of highly sensitive molecular diagnostic assays. The use of reverse transcriptase polymerase chain reaction (RT-PCR) for diagnosis has provided evidence that respiratory syncytial virus is second only to influenza as a cause of serious respiratory illness among elderly and high-risk patients, groups in which standard viral diagnostic methods are inadequate.[3] As discussed by Dr. Falsey the burden of RSV disease is sufficiently large to consider development of a vaccine for this population.[4] Because the signs and symptoms associated with each of the viruses overlap considerably, diagnosis made solely on clinical grounds is always suspect. For instance, even though influenza tends to cause higher temperature and RSV more wheezing, clinical diagnosis in elderly persons is error prone. An exception might be hantavirus infection, in which hemoconcentration and thrombocytopenia should raise suspicion as discussed by Dr. Chang and colleagues from the University of New Mexico and the Lovelace Respiratory Research Institute.[5] Similarly, RT-PCR is the diagnostic method of choice for human metapneumovirus infection, a virus that mimics RSV but requires tedious culture techniques for diagnosis, as described by Deffrasnes et al.[6] Dr. Greenberg's review of the “common cold” viruses illustrates how molecular diagnostic assays can be used to identify new non-SARS coronaviruses, and have emphasized the key role that rhinovirus infection plays in reactive airway disease.[7] Finally, molecular diagnosis is critically important for proper management of hematopoietic stem cell recipients with respiratory illness, as reviewed by Kim et al from the Fred Hutchinson Cancer Institute.[8] For this particularly high risk group rapid and accurate diagnosis is needed for administration of life-saving therapy in some instances, and reinforces the need for stringent infection control measures. In addition, the accurate diagnosis of patients with seasonal influenza can be valuable because intervention with antiviral therapy may provide benefit if initiated early in the course of illness, as discussed by Dr. Lynch in detail.[9]

But what is the practical significance of identifying these common viral infections in immunocompetent patients, especially in an environment where the value of routine bacteriological studies for diagnosis of community-acquired pneumonia is questioned? Some might argue that a specific diagnosis is only of research interest, and in the absence of effective therapeutic drugs is of little clinical utility. A specific etiological diagnosis can be of value, especially in emergency room and hospital settings. Studies in children have shown that antibiotic use and diagnostic studies can be curtailed when influenza, RSV or enterovirus infection is quickly identified.[10] [11] Although less well studied, similar benefits may also be applicable to hospitalized adults with LRTI.[12]

On the other hand, few would dispute the value in identifying SARS or H5N1 influenza virus infection. Despite their severity, illness caused by SARS coronavirus and pandemic influenza strains are not clinically recognizable with great accuracy, especially early in the illness. As discussed by Drs. Muller and McGeer, control of the 2003 SARS outbreak was hampered by the absence of a reliable, sensitive, and specific diagnostic test.[13] A similar situation would certainly arise should a highly pathogenic H5N1 influenza virus develop the ability to spread from person to person as described by Drs. Rajagopal and Treanor, because use of clinical case definitions is very unlikely to be reliable.[14] This is especially true given that a case definition relying on specific travel or exposure histories, which were used in the SARS epidemic, will be lost once pandemic influenza becomes widespread. The rapid and accurate diagnosis of common respiratory viruses would also be helpful in sorting out patients when SARS or H5N1 influenza is a possibility. Together with hantavirus, these viruses highlight the importance of the sometimes forgotten animal reservoirs of serious disease that always lurk in the background.

The final common theme throughout this issue is that, despite the large medical and economic impact of respiratory viruses, effective vaccines and antiviral drugs are for the most part lacking. Prevention of infection or reduction in severity of infection, rather than treatment, is clearly optimal. This is especially valid given that patients with most viral respiratory tract infections present for medical care at a time when viral titers are falling, with the exception of SARS and hantavirus, and antiviral drugs may only provide modest benefit. Notwithstanding recent information on the epidemiology, clinical impact, and immune response to these viruses, licensed vaccines are currently available only for seasonal influenza. Even these vaccines are suboptimally efficacious in the elderly who have the greatest morbidity. In the final article, Dr. Schmidt from the National Institute of Allergy and Infectious Diseases provides an overview of the progress in vaccine development for some of these viruses and also describes general methodologies currently being applied to vaccine development.[15] With the exception of SARS coronavirus and H5N1 influenza virus in which systemic spread can occur, replication of most respiratory viruses is limited to mucosal epithelial cells. Greater understanding of mucosal immunology will be needed if we are to optimally prevent respiratory virus infections.

It is hoped that the articles in this issue will provide useful information and insight into these common, yet problematic infections.

REFERENCES

• 1 Henrickson K J, Hoover S, Kehl K S, Hua W. National disease burden of respiratory viruses detected in children by polymerase chain reaction.  Pediatr Infect Dis J. 2004;  23 S11-S18
• 2 De Roux A, Marcos M A, Garcia E et al.. Viral community-acquired pneumonia in nonimmunocompromised adults.  Chest. 2004;  125 1343-1351
• 3 Falsey A R, Hennessey P A, Formica M A, Cox C, Walsh E E. Respiratory syncytial virus infection in elderly and high-risk adults.  N Engl J Med. 2005;  352 1749-1759
• 4 Falsey A R. Respiratory syncytial virus infection in adults.  Semin Respir Crit Care Med. 2007;  28 171-181
• 5 Chang B, Crowley M, Campen M, Koster F. Hantavirus cardiopulmonary syndrome.  Semin Respir Crit Care Med. 2007;  28 193-200
• 6 Deffrasnes C, Hamelin M-E, Boivin G. Human metapneumovirus.  Semin Respir Crit Care Med. 2007;  28 213-221
• 7 Greenberg S B. Rhinovirus and coronavirus infections.  Semin Respir Crit Care Med. 2007;  28 182-192
• 8 Kim Y-J, Boeckh M, Englund J A. Community respiratory virus infections in immunocompromised patients.  Semin Respir Crit Care Med. 2007;  28 222-242
• 9 Lynch III J P, Walsh E E. Influenza: evolving strategies in treatment and prevention.  Semin Respir Crit Care Med. 2007;  28 144-158
• 10 Poehling K A, Zhu Y, Tang Y-W, Edwards K A. Accuracy and impact of a point-of-care rapid influenza test in young children with respiratory illness.  Arch Pediatr Adolesc Med. 2006;  160 713-718
• 11 Esposito S, Marchisio P, Morelli P, Crovari P, Principi N. Effect of a rapid influenza diagnosis.  Arch Dis Child. 2003;  88 525-526
• 12 Falsey A R, Murata Y, Walsh E E. Impact of rapid diagnosis on management of adults hospitalized with influenza.  Arch Intern Med. 2007;  167 354-359
• 13 Muller M P, McGeer A. Severe acute respiratory syndrome (SARS) coronavirus.  Semin Respir Crit Care Med. 2007;  28 201-212
• 14 Rajagopal S, Treanor J. Pandemic (avian) influenza.  Semin Respir Crit Care Med. 2007;  28 159-170
• 15 Schmidt A C. Progress in respiratory virus vaccine development.  Semin Respir Crit Care Med. 2007;  28 243-252