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What You Need to Know About Testing for the New Pandemic Virus

A White Paper

Jay M. Lieberman, M.D., Medical Director
Focus Diagnostics, the infectious disease diagnostics business of Quest Diagnostics

September 2009

Introduction

". . . the United States Government has reported 20 laboratory confirmed human cases of swine influenza A/H1N1 … the virus is being described as a new subtype of A/H1N1 not previously detected in swine or humans."  — World Health Organization (WHO) April 26, 2009¹

"Pandemic." It's a word that elicits our worst fears about the power infectious diseases hold over human health. Pandemics, such as HIV/AIDS, smallpox, the plague and influenza, have caused much suffering and many deaths over the course of human history. For example, the 1918/1919 influenza pandemic is estimated to have resulted in more than 40 million deaths around the world.²

The current influenza pandemic raises several questions. How is this influenza virus different from other influenza viruses? What is its potential impact on human health? And, for the clinician, how do I deliver the best care — including testing — to patients who may be infected?

In this brief paper, we sort through the confusion in order to provide answers to these and other questions now being asked about the 2009 H1N1 influenza virus, the source of the first influenza pandemic in more than 40 years.

A New Influenza Virus

"A defining characteristic of a pandemic is the almost universal vulnerability of the world’s population to infection. Not all people become infected, but nearly all people are at risk."  — Dr. Margaret Chan, Director-General of the WHO³

Influenza viruses are ribonucleic acid (RNA) viruses categorized as A, B or C. Influenza A viruses cause disease not only among humans, but also in birds, pigs and horses. They tend to cause more severe disease and be more common in humans than influenza B and C viruses.

Influenza A viruses are subtyped according to two proteins expressed on their surface: hemagglutinin (H) and neuraminidase (N). Hemagglutinin facilitates binding of the virus to respiratory epithelial cells — a type of tissue found lining the respiratory tract — while neuraminidase breaks bonds with the host cell to promote infection. Two influenza A virus subtypes, H1N1 or H3N2, have been responsible for annual outbreaks of so-called "seasonal flu" of varying severity for the past several decades. A major cause of these yearly epidemics is the fact that influenza A viruses undergo frequent minor genetic mutations ("antigenic drift") that result in people having only partial protection against the virus.

Classically, influenza pandemics have been thought to result from antigenic shift resulting in a new influenza virus A subtype. In the spring of 2009, a novel influenza A virus — also subtyped as H1N1 — was identified in North America. The virus contains genetic elements of human, avian and swine influenza A viruses and had not been known to previously circulate among humans or pigs.

Within weeks of its discovery, the 2009 H1N1 influenza virus — initially referred to as "swine flu" — had spread to dozens of countries. On June 11, 2009, the World Health Organization (WHO) declared a phase 6 pandemic — the highest phase — in recognition of the 2009 H1N1 influenza virus' novel genetic make-up and rapid global spread.

While both seasonal and the pandemic influenza viruses are type A, notable differences exist:

Limited Immunity. When a pandemic influenza virus emerges, the population lacks immunity against the novel virus. Although some information suggests that older adults may be less susceptible to infection, possibly as a response to infection with a mild H1N1 variant decades ago, most individuals have no immunity to the new strain.

Spread Continues in Warm Weather. Seasonal flu viruses, as the name implies, generally cause disease during specific times of the year and generally do not circulate when the weather is warmer. Influenza viruses spread less easily in hot and humid conditions. The 2009 pandemic influenza A (H1N1) virus has demonstrated remarkable persistence by continuing to spread during the Northern Hemisphere's summer season.

Infects Younger Patients. Unlike seasonal flu, which tends to primarily cause severe illness and death among adults 65 years of age or older, pandemic viruses cause disproportionately high rates of illness in young patients. With seasonal influenza, more than 90% of deaths occur in individuals 65 years of age and older. In contrast, during the first few months after the emergence of the 2009 pandemic virus, the largest percentage of deaths — 41% — has occurred in adults between the ages of 25 and 49.⁴

Seasonal and pandemic influenza viruses also share certain features. Among these is their ability to sometimes cause serious disease in otherwise healthy individuals and, more frequently, among individuals with underlying health conditions. Generally, disease with the pandemic virus has been mild. However, certain high-risk patients, such as pregnant women and people with lung, heart, or kidney disease are at increased risk of serious illness and death. In addition, obesity has been noted as an underlying medical condition in some hospitalized 2009 H1N1 influenza patients.⁵

Testing Options

A number of testing options are available to detect the presence of influenza A viruses, typically from nasal or nasopharyngeal swab specimens. These tests include direct antigen detection tests, such as direct immunofluorescence (DFA) and enzyme immunoassay (EIA); viral culture; and reverse transcriptasepolymerase chain reaction (RT-PCR), which amplifies viral RNA to make it detectable in a specimen.

Each testing technique has its pros and cons. Rapid antigen tests can produce results at the point of care, enabling the physician to make treatment decisions on the spot. However, they are also the least sensitive of the tests, meaning that they are more likely to falsely report a negative result in an infected patient. In one study, two rapid antigen tests were found to have sensitivities of 18% and 48%, compared to 89% for viral culture and 98% for PCR.⁶ A survey of rapid tests from the Centers for Disease Control and Prevention (CDC) found that "compared to RT-PCR, the sensitivity of RIDTs (rapid influenza diagnostic tests) for detecting novel influenza A (H1N1) virus infections ranged from 10-70%."⁷

While real-time RT-PCR lab tests require more time for results reporting than rapid tests, their improved accuracy makes them the "recommended test for confirmation of cases with the pandemic virus," according to the CDC.

In considering the available testing options, physicians should bear in mind that most tests that detect the presence of an influenza A virus do not identify specific subtypes, such as the pandemic virus. As a result, most tests offer little help to a physician who wants to distinguish infection with seasonal influenza from pandemic influenza. At the present time, the FDA has only authorized two tests — one from the CDC and one from a commercial laboratory company — for use in specifically detecting the 2009 H1N1 influenza virus during the pandemic emergency. Both tests are based on RT-PCR.

To Test or Not to Test for the Pandemic Strain?

Considering that few tests reliably identify the 2009 H1N1 influenza virus subtype, physicians may wonder if diagnosing infection with the virus is important to clinical care.

The CDC recommends that physicians test patients who have "an acute febrile respiratory illness or sepsis-like syndrome," with priority given to patients who are seriously ill and require hospitalization or are at "high-risk for severe disease." It also notes that certain groups may have "atypical presentations." The CDC further explains that "not everyone with suspected influenza virus infection will require confirmatory diagnosis. . . ." Ultimately, physicians should be mindful of  "local guidance on testing" and "use their clinical judgment" when deciding to test a patient.

While guidelines help, decision making ultimately lies with the physician evaluating the individual patient. Testing for the 2009 H1N1 influenza virus has several potential benefits:

Selection of Antiviral Therapy. The 2009 pandemic influenza A (H1N1) virus is susceptible (sensitive) to two FDA approved antiviral drugs — oseltamivir (brand name Tamiflu®) and zanamivir (brand name Relenza®) — but resistant to amantadine (brand name Symadine or Symmetrel®) and rimantadine (brand name Flumadine®). In fact, the CDC's interim recommendations on antiviral therapy dated September 8, 2009, states “for antiviral treatment of 2009 H1N1 virus infection, either oseltamivir or zanamivir are recommended."⁸ However, one of the two seasonal influenza A subtypes (H1N1) that has circulated the past two influenza seasons has followed a different pattern, showing resistance to oseltamivir, and susceptibility to amantadine and rimantadine in addition to zanamivir.⁹ Therefore, if a seasonal influenza A virus is circulating, identifying which influenza virus A subtype — pandemic or seasonal — is causing illness may help guide selection of the most potentially effective antiviral therapy.

Avoid Unnecessary Antiviral Therapy. In some cases, a physician may commence therapy with an antiviral before knowing if the patient is infected with the pandemic virus. For high-risk or severely ill patients, this empiric therapy is certainly warranted and is recommended. However, continuing to provide an antiviral to a patient who is not infected is potentially harmful to the patient and wasteful to the health care system. Indiscriminate use of antivirals may result in a shortage of therapies for patients who might truly benefit from them. Furthermore, widespread and inappropriate use of antivirals may promote the development of treatment-resistant strains and thereby reduce our therapeutic options. A limited number of oseltamivir-resistant pandemic H1N1 virus isolates have been identified and, as the CDC emphasizes, these reports "underscore the importance of careful and limited use of antiviral medications for chemoprophylaxis . . ."¹⁰

Guide Decision Making for Vulnerable Patients. Knowing that an otherwise healthy child or adult is infected with pandemic influenza could help a physician promptly assess and provide antiviral treatment to high-risk family members who become ill or prompt antiviral prophylaxis of high-risk close contacts.

Implement Appropriate Isolation Measures. Diagnosing the virus causing illness enables clinicians to appropriately isolate infected patients, if hospitalized, and alert those they come into contact with of their potential for infection.

Promote Epidemiological Assessments. From a public health perspective, accurate diagnoses may assist in helping public health authorities track and manage the pandemic.

Relieve Patient Anxiety. Testing for the 2009 H1N1 influenza virus may be a source of relief for patients who may worry, perhaps without cause, that they are infected with the pandemic strain.

Looking to the Future

"The virus can come back in a second wave. . . . When you're over the first wave, start preparing for the future." — Dr. Margaret Chan, Director-General of the WHO¹

Absent a crystal ball, experience with prior pandemics and growing understanding of the characteristics of the current pandemic virus points to certain predictions.

"Second Wave" Likely. The 2009 H1N1 influenza virus is not behaving like seasonal flu viruses – specifically, it didn't fade away during the warm months of summer. Given its persistence, the virus appears poised to "re-emerge" as the weather cools and children and young adults head back to school, possibly becoming the predominant influenza virus circulating this fall and winter. Indeed, in a report of influenza activity for the week ending September 4, 2009, the American College Health Association found that approximately 73% of 204 participating schools had reported new cases of influenza like illnesses.¹²

Increased Morbidity and Mortality. Even if disease caused by the 2009 pandemic H1N1 virus is no more severe than that caused by seasonal influenza, rates of morbidity and mortality could be much higher than usual, given that almost all of us are susceptible. Influenza is, after all, a serious illness that claims approximately 36,000 lives each year in the U.S. A recent report from a Presidential Advisory Panel concluded that the pandemic H1N1 virus could result in 30,000 to 90,000 deaths and as many as 1.8 million hospitalizations in a "plausible scenario."¹³ While this may not be the most likely scenario, it is reasonable to surmise that the 2009 H1N1 influenza virus will be a significant source of illness this year and place major strains on the health care system.

Immunization Essential. Widespread immunization with an effective vaccine may offer the best hope of reducing the potential impact of pandemic H1N1 influenza. As of the beginning of September, the best case estimate is that the first doses of vaccine will be available in the U.S in mid-October. Yet, the second wave of pandemic virus could begin much sooner than that.

Clinicians on the Front Line. Physicians will have their hands full treating patients this fall and winter season. While the path of the new influenza virus remains unknown, the quality of health outcomes will depend largely on the decisions physicians make using the most reliable tests, therapies and scientific knowledge available.

Helpful Information

For more information on caring for patients affected by the 2009 H1N1 influenza virus, we recommend you refer to these online sources:

CDC H1N1 Web Site. Provides comprehensive information on the 2009 H1N1 influenza virus, including guidelines for testing and identifying at-risk patients.
www.cdc.gov/h1n1flu

The Infectious Disease Society of America. In 2009, the IDSA published guidelines for testing for seasonal influenza titled "Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America."
www.idsociety.org/content.aspx?id=9202#flu

WHO Antiviral Therapy Guidelines. The WHO's "Guidelines for Pharmacological Management of Pandemic (H1N1) 2009 Influenza and other Influenza Viruses" provides information on antiviral treatment for patients suspected of infection with seasonal or pandemic influenza viruses.
www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf

References

¹ "Swine flu illness in the United States and Mexico - update 2," WHO Global Alert and Response, April 26, 2009

² Emerging Infectious Diseases, Vol. 9, No. 10, October 2003

³ "Concern over flu pandemic justified," Speech to the Sixty-second World Health Assembly, Geneva, Switzerland, May 18, 2009

⁴ Source: CDC web site at www.cdc.gov/h1n1flu/surveillanceqa.htm

⁵ Source: CDC web site at www.cdc.gov/h1n1flu/identi fyingpatients/htm

⁶ Ginocchio et al. J Clin Virol 2009;45:191

⁷ Source: CDC web site at www.cdc.gov/h1n1flu/guidance/rapid_testing.htm

⁸ Source: CDC web site at www.cdc.gov/h1n1flu/recommendations.htm

⁹ Source: CDC web site at www.cdc.gov/h1n1flu/guidance/rapid_testing.htm

¹⁰ Source: CDC web site at www.cdc.gov/h1n1flu/recommendations.htm

¹¹ "To Flu Experts, 'Pandemic' Confirms the Obvious," The New York Times, June 11, 2009

¹² Source: American College Health Association web site at www.acha.org/H1N1.cfm

¹³ President’s Council of Advisors on Science and Technology (PCAST); refer to
www.ostp.gov/cs/pcast