The nose knows: RSV and HRV

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LEARNING OBJECTIVES

Upon completion of this article, the
reader will be able to:

1. describe types of respiratory viruses;
2. describe methods of testing for RSV;
3. describe populations at risk for RSV; and
4. identify facts related to rhinovirus.

Steven Kleiboeker, DVM, PhD, joins MLO this month with insight on respiratory testing. Dr. Kleiboeker is responsible for scientific direction and oversight of the clinical diagnostic efforts as well as its pharmaceutical research services of Viracor-IBT Laboratories, where he has served as the chief scientific officer and a vice president since 2006. Prior to that, Dr. Kleiboeker was a faculty member at the University of Missouri where his duties included research, graduate teaching, and supervision of three university-based diagnostic-service laboratories (virology, serology, and molecular diagnostics). His research has focused on viral pathogenesis, phylogenetics, and diagnostics, and has included projects investigating a broad range of human and animal pathogens. Dr. Kleiboeker has served as both principal investigator and co-investigator on numerous government-funded research grants. He has published more than 40 scientific articles and monographs, and serves on editorial boards and as a reviewer for several prominent virology and microbiology journals. Dr. Kleiboeker received his PhD in Physiology from the University of Missouri and DVM from the University of Missouri.

MLO: Is respiratory syncytial virus (RSV) actually dangerous to children? What more serious illnesses can an RSV infection cause in both children and adults — other than bronchiolitis or pneumonia?

Dr. Kleiboeker: RSV is the leading cause of hospitalization and lower respiratory disease in children under five years of age. Bronchiolitis and pneumonia are the two most serious consequences of RSV infection and can be dangerous to children. While hospitalization rates are low, ranging from 0.5% to 1%, up to 9% of hospitalized infants can require serious medical intervention such as mechanical ventilation. Mortality rates are fortunately low, with recent estimates in the 0.3% range for infants hospitalized due to an RSV infection.

MLO: Most literature points to RSV being of concern if children are “at risk.” What does “at-risk” mean with RSV?

Dr. Kleiboeker: The children who are most “at risk” are often immunocompromised (i.e., have weakened immune systems) or are suffering from other serious respiratory conditions such as asthma. Others at risk include pre-term infants and children with other serious diseases such as cystic fibrosis.

MLO: We have read that RSV is identified in nasal secretions collected with a cotton swab or by suction through a bulb syringe. How many tests are available in the marketplace to test for RSV? Can you discuss the technology behind any of the newer tests? What other information should a medical laboratorian know with regard to RSV testing?

Dr. Kleiboeker: There are two main groups of assays available to detect RSV: antigen assays and molecular assays. The antigen assays detect viral protein in a sample. These tests provide clinicians with fast results and tend to be the most common form of RSV testing. These assays are technologically simple and can be performed onsite but suffer from low levels of sensitivity.

Molecular assays detect RSV genomic material. These assays are more technologically challenging, require special equipment, and are more expensive but have excellent sensitivity. Molecular tests can take several hours to run; however, most can provide results in less than 24 hours.

One newer strategy for molecular testing of RSV has incorporated detection of multiple pathogens in a single reaction. These assays, referred to as multiplex testing, allow physicians to rapidly and efficiently identify patients with multiple viral infections. Patients with two or more concurrent respiratory viral infections typically have more severe disease.

MLO: We have also read that there are many kinds of RSV so that a body never becomes immune to it. We have found information that states that there are tests for RSV, but they are not usually needed. Although that does not truly sound “contradictory,” it sounds “confusing.” If this virus recurs throughout one's life, does the treatment remain the same … are the symptoms the same over time?

Dr. Kleiboeker: Tests that identify RSV and provide a definitive diagnosis of this pathogen can play an important role in providing high-quality medical care for patients. Even though there is no specific treatment for RSV currently available, correctly diagnosing an RSV infection can prevent the unnecessary use of antibiotics — which is a key cause of increasing levels of antibiotic resistance — as well as aid in the control of hospital-based transmission of RSV to uninfected patients through careful selection of bed-placement and infection-control practices. The symptoms of RSV can be similar regardless of a patient's age; however, serious illnesses, such as pneumonia, are much more likely in very young or immunocompromised patients.

MLO: While most information we have reviewed mentions “children,” we did find a list that includes “people with immune system problems; people with heart or lung problems; and adults older than 65.” What is different about RSV for these three populations of patients? Is it more difficult to overcome? Do these patients use oxygen more often than others do?

Dr. Kleiboeker: In developed countries such as the United States, RSV is much more frequently a cause of mortality in the elderly than in infants, likely due to the increased number of other health issues confronting elderly patients as compared to infants. This is generally the same reason that people with immune-system and other health problems are more at risk for serious complications associated with RSV. That said, RSV is like many (if not most) other pathogens in that it causes more severe disease in weakened individuals. Supplementary oxygen is frequently required in patients with pneumonia due to the damage RSV can cause to lung tissue.

MLO: In many of the items we have researched, we find that treatment is “supportive care only” and that RSV bronchiolitis “remains a good example of therapeutic nihilism — nothing works except oxygen.” If this virus is “epidemic” and if it affects people throughout life, why have there not been more attempts to find satisfactory vaccine?

Dr. Kleiboeker: The lack of effective treatments beyond supportive care and oxygen largely reflects the fact that specific antiviral treatments are not yet available for RSV, as is the case for the majority of viral infections. Additionally, many RSV infections are fortunately not life threatening and will resolve on their own as the patient's immune system develops an effective response. Despite this, development of specific antiviral treatments remains an important goal for medical researchers.

The development of effective vaccines has long been a high priority and an area of extensive effort, for those working toward this goal. Lack of success in developing such a vaccine can be attributed to a number of factors, such as the variability of the virus and its ability to mutate.

Additionally, attempts to develop vaccines have demonstrated that some will paradoxically result in a condition known as immunopathology. In this condition, the vaccine induces a state within the immune system in which post-vaccination infection with RSV results in a disease more severe than that seen in unvaccinated individuals.

MLO: When we think of the common cold, we do not generally think about the fact that there are 110 distinct rhinovirus types.  When we speak of the nearly 62 million cases of the common cold annually in the United States, are we addressing all 110 types?  Are the symptoms the same for all 110?  If the rhinovirus is only one of 200 viruses that cause the common cold, are its 110 types in addition to the 200 viruses of which each could also have 110+ types?

Dr. Kleiboeker: The 110 or so rhinovirus serotypes are included in the overall estimate of 200 or more viruses causing the common cold. While rhinoviruses are the most common cause, other viruses causing the common cold include coronaviruses, adenoviruses, RSV, human metapneumovirus, and parainfluenza viruses. The various types of rhinovirus cause the common cold to vary from year to year and from location to location. Some serotypes are relatively rare, and some are relatively common. The various types of rhinoviruses are grouped into what are known as “species” A, B or C. Species A types are the most common while species C types have been more commonly associated with more serious clinical disease, including pneumonia or infection of the lungs. Notably, the severity of symptoms among people infected with rhinoviruses is highly variable, and the species or serotype of rhinovirus is only one factor contributing to the observed variability. Other key factors are the overall health of the person as well as the previous exposure of the person to either the current rhinovirus type or types that are similar enough to provide cross-protective immunity.

MLO: Up to now, what has been the “cure” for a cold, and why have there not been solutions for preventing the common cold before now?  Handwashing is suggested, but what impact does that really have on stopping the spread of the rhinovirus?

Dr. Kleiboeker: Unfortunately, there is no cure for the common cold. In uncomplicated cases, treatment is symptomatic and centered on controlling fever — if any — nasal congestion and dehydration. The reasons for a lack of effective and specific treatments are varied but primarily center on the vast number of viruses causing colds and the ability of these viruses to mutate rapidly. Handwashing — and avoiding contact between hands and one's nose/mouth area — can be effective. Since rhinoviruses, however, can be transmitted via aerosols (airborne droplets), avoiding close contact with those suffering from a cold is also important to stopping the spread of these viruses.

MLO: Because these viruses grow best at temperatures of 91^0F, supposedly they do not go into the lower respiratory tract — although bronchopneumonia can occur in children. What damage can that do to a child? What damage can rhinoviruses do, if any, in the upper respiratory tract?

Dr. Kleiboeker: Rhinoviruses do, on occasion, go into the lower respiratory tract and cause serious illness such as pneumonia. Although these viruses grow most efficiently at lower temperatures, such as those in the nose, they can at times rapidly adapt to normal body temperature or even the body temperature in a person with fever. This ability of rhinoviruses to cause illnesses such as bronchiolitis, bronchopneumonia, or pneumonia in the lower respiratory tract is a relatively new finding in medicine. Unlike infections in the upper respiratory tract, which are typically self-limiting, infections in the lower respiratory tract can require extensive medical care such as ICU-level hospitalization and mechanical ventilation. Mortality is, without question, possible due to a rhinovirus infection in the lower respiratory tract, especially in children, patients with weakened immune systems, and patients suffering from other serious diseases.

MLO: Is there a way to test for the rhinovirus? If so, what is the technology behind the test?  How many different tests are manufactured to test for rhinovirus?  If there are not lab tests to ascertain whether or not a patient has rhinovirus, is there any type of research currently going on to find a vaccine for preventing the common cold? If so, would that put an end to the 110 different types, or would one vaccine for each type be required?

Dr. Kleiboeker: Molecular tests are the only reliable methods to test for rhinoviruses. Real-time PCR methods will detect rhinoviruses with great sensitivity and specificity using methods that enzymatically amplify a short region of the viral genome until an easily detectable signal is generated. Multiplex PCR methods also have very good diagnostic utility but have the added advantage of allowing physicians to rapidly and efficiently identify patients with multiple viral infection. Unfortunately, it is not likely that we will see an end to rhinoviruses. There are simply too many types, and new ones are emerging through mutation and recombination events. The availability of good testing such as PCR-based methods, however, will greatly improve the ability to control the impact of these pathogens.

MLO: Do sufferers of rhinovirus become immune to the various types? And could one person suffer a cold for all types during a lifetime?  Is this why it is difficult to find a vaccine? How does rhinovirus affect asthmatics? 

Dr. Kleiboeker: It is possible for one person to be infected with all rhinovirus types over a lifetime but not very likely. Immunity will develop in most individuals when rhinoviruses establish an infection in the upper respiratory tract. This immunity is known as “mucosal” because it does not typically reach the bloodstream and, thus, is characteristically short-lived (e.g., a few years), in addition to being type-specific. Additionally, the serotypes can mutate and become only partially recognizable to the immune system or even unrecognizable if the person is infected a second time with the same serotype. This, coupled with the large number of rhinovirus serotypes, is the reason why a vaccine will not likely be feasible for rhinoviruses.

Rhinoviruses, like all respiratory viruses, can significantly increase the severity of asthma. There are many causes for exacerbation of asthma symptoms, however, so specific testing for viral infections may be warranted depending on the condition of individual patients.

HRV and RSV: more than just the common cold

Rhinovirus facts

References

1. Briese T, Renwick N, Venter M, et al. Global distribution of novel rhinovirus genotype. Emerg Infect Dis. 2008;14(6). http://www.cdc.gov/eid/content/14/6/944.htm. Accessed May 18, 2010.
2. Woo Kyung Kim, Korean Journal of Pediatrics. 2010;53,(2):129-135. http://synapse.koreamed.org/Synapse/Data/PDFData/0052KJP/kjp-53-129.pdf. Accessed May 18, 2010.
3. Prater A. Signs and Symptoms of Rhinovirus Infection: The Common Cold. http://common-patient-ailments.suite101.com/article.cfm/signs_and_symptoms_of_rhinovirus_infection#ixzz0oIQTbJcI. Accessed May 18, 2010.
4. McCoy L. Rhinovirus: an unstoppable cause of the common cold. August 2004. http://www.scq.ubc.ca/rhinovirus-an-unstoppable-cause-of-the-common-cold. Accessed May 18, 2010.

CDC: About RSV

• Respiratory syncytial virus (RSV) was discovered in 1956 and has since been recognized as one of the most common causes of childhood illness.
• The virus is a member of the family Paramyxoviridae and the subfamily Pneumovirinae.
• RSV is an enveloped RNA virus and two strains (subgroups A and B) are recognized, the clinical significance of which is unclear.
• Currently, there is no effective vaccine against RSV. A drug called palivizumab is available to prevent severe RSV illness in certain infants and children at high risk.
• Outbreaks of RSV occur in communities each year, usually lasting three to four months during the fall, winter, and/or spring months; however, the timing of RSV season can vary by region.
• RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia in children under 1 year of age in the United States.
• Of every 100 infants and young children with RSV infection, 25 to 40 will show signs of pneumonia or bronchiolitis.
• Each year, in the U.S. 75,000 to 125,000 children under 1 year of age are hospitalized due to RSV infection.
• Almost all children are infected with the RSV by their second birthday, but only a small percentage develop severe disease.
• RSV infection is a major cause of hospitalization in Alaska Native infants; RSV surveillance in Southwest Alaska between 1993 and1996 showed a hospitalization rate of 156 per 1,000 infants under 1 year of age.
• The National Respiratory and Enteric Virus Surveillance System lists RSV trends and current national and state surveillance reports online at www.cdc.gov/rsv/research/us-surveillance.html. Learn more about RSV at www.cdc.gov/rsv/about/index.html.