Influenza and the Role of Laboratory Testing

Seasonal influenza is a respiratory illness caused by the influenza A or B virus that occurs annually in the winter months. In the United States, an average of 31 million people contract influenza each year, 11 million seek outpatient health care, 226,000 require hospitalization, and 36,000 die of influenza-associated complications.1 Additionally, influenza costs billions in direct health care expenses, along with substantial indirect economic loss associated with missed workdays and loss of productivity.

Diagnosing influenza can be difficult because clinical signs and symptoms often overlap with other respiratory illnesses including the common cold (Table 1) and other more serious infections, such as avian influenza (bird flu) or severe acute respiratory syndrome (SARS). Early and accurate influenza diagnosis provides opportunities for medical treatment that can reduce the severity and duration of the illness and allow implementation of containment strategies, especially in vulnerable populations.

Photo 1. Transmission electron micrograph (TEM) of influenza virus particles.

 

Scientists at Mayo Clinic have been studying influenza since the early 1900s when Dr. Edward C. Rosenow began working to develop an influenza vaccine. His efforts contributed to the body of knowledge that led to the development of successful influenza vaccines that remain the primary method of prevention (Sidebar, page 8). Recent technological advances have provided the means to develop rapid detection tests such as Mayo Medical Laboratories’ #88544 Influenza Virus Type A and B RNA by Rapid PCR. This sensitive and specific assay can provide clinicians with timely laboratory results that, along with the clinical symptoms, can accurately establish a diagnosis of influenza infection.

Influenza Infection

Influenza is a contagious viral infection of the respiratory system. People of all ages contract influenza, but young children have a higher infection rate.Common symptoms of influenza

infection include whole body aches, weakness, chills, sweats, and fever over 101° F that resolve in 2 to 4 days; sore throat, headache, runny nose, and sneezing that resolve in 4 to 7days; and dry cough and malaise that can linger for more than 2 weeks.1 Children present with nausea and vomiting more often than adults.

The incubation period after exposure is 1 to 4 days.1 People infected with influenza typically can spread the disease from 1 day before to 5 days after symptoms begin; little or no virus is detectable in normal adults 5 days after onset of symptoms. Alternatively, children and immunocompromised people may be able to spread influenza for weeks or even months.

Symptoms	Flu	Cold
Fever	Common	Rare
Fatigue	Common	Rare
Headache	Common	Rare
Muscle Aches	Often severe	Mild
Nasal Congestion	Rare	Common
Sneezing	Rare	Common
Sore Throat	Rare	Common
Cough	Dry, Often Svere	Usually mild to moderate

Table 1. Comparison of influenza versus cold symptoms.

Complications Associated With Influenza

While influenza can be acutely debilitating, most people have no lasting effects after an influenza infection. Older adults (≥65 years old), people with weakened immune systems, and people with chronic illnesses have increased rates of serious complications and death. Complications can include:

• Ear infections
• Acute sinusitis
• Bronchitis
• Secondary bacterial pneumonia
• Acute respiratory distresslike syndrome
• Primary viral pneumonia
• Myositis and rhabdomyolysis
• Central nervous system involvement such as encephalitis or transverse myelitis

In addition, influenza infections may also result in exacerbation of other serious chronic diseases such as diabetes mellitus, renal disease, or congestive heart failure.

Influenza Viruses

Types of Influenza and Their Origin

Influenza viruses belong to the family Orthomyxoviridae and are divided into 3 types: type A, type B, and type C (Table 2).

Influenza types A and B typically circulate in the winter months. Influenza type A typically produces the most severe disease and can be found in humans and other mammals. Influenza type B is more common than type A, and is commonly found in humans, but is not typically found in other mammals. Influenza B usually causes milder disease than influenza A, although it can cause severe disease in older adults and those who have serious chronic illness. Influenza type C is rarely recognized as a cause of human infection and disease.

The Viral Particle

All 3 types of influenza share similar morphology, and can be round, elongated, or irregularly shaped (Photos 1, 2a, and 2b). Each type of influenza particle is made up of different numbers of RNA segments and viral proteins (Table 2). Matrix proteins line the inside of the viral envelope. In the center of the envelope, the viral particle carries its genome on segments of single-strand RNA. The outside of the virus particle is studded with 2 different glycoproteins: hemagglutinin and neuraminidase. Hemagglutinin helps the virus attach to a cell and initiate infection, and neuraminidase helps newly formed viral particles leave the host cell to infect other cells. To date, 16 different subtypes of hemagglutinin and 9 different subtypes of neuraminidase have been identified in animal influenza viruses. Only hemagglutinin (H) subtypes H1, H2, and H3 and neuraminidase (N) subtypes N1 and N2 have been found in human influenza virus causing seasonal epidemics.

Table 2. Influenza virus type characteristics

How Influenza Strains Are Named

Each strain of influenza is named using standard nomenclature that includes the virus type, the location where the strain was first found, a laboratory identification number (strain number), and the year the strain was discovered. Influenza A strains are further categorized by the different subtypes of hemagglutinin and neuraminidase they possess.For example, A/Solomon Islands/3/2006 (H1N1) is a strain of influenza A that was first isolated in the Solomon Islands, the strain number is 311, it was first identified in 2006, and the hemagglutinin/ neuraminidase subtype is H1N1 (see Figure). The most common subtypes of influenza A that are circulating globally are H1N1, H3N2, and H1N2.

Figure. Influenza nomenclature

 

Influenza Virus Is Always Mutating

The surface glycoproteins of the influenza virus are always changing due to 2 processes called antigenic drift and antigenic shift. Antigenic drift happens when point mutations occur in the genetic sequences that code for hemagglutinin and neuraminidase as the virus makes copies of its genome during viral replication. Small changes in the antigenic sites of these proteins are often enough to make the surface proteins of the new strain of virus unrecognizable to the human immune system. Influenza A and B frequently undergo antigenic drift. Thus, each year a new influenza vaccine is developed that is targeted to the strains that are anticipated to be prevalent. For example, the World Health Organization (WHO) has recommended that the influenza vaccine for the 2007 to 2008 season include A/Solomon Islands/3/2006-like (H1N1), A/Wisconsin/76/2005-like (H3N2), and B/Malaysia/2506/2004-like viruses. Determining the emerging strains of influenza virus requires the cooperation of the global community. Often the new viruses are first isolated in developing countries that often do not benefit from the resulting vaccine or expensive medical treatments.

Photos 2a and 2b . TEM of influenza virus particles

 

Infrequently, influenza type A can undergo a sudden dramatic change, called antigenic shift. In this process, 2 different influenza strains infect the same cell and exchange genetic material. The new combination of hemagglutinin and neuraminidase can create a new influenza A subtype. Because humans have not been exposed to the subtype before, they have little or no immunity to the new subtype, and this can lead to severe influenza epidemics (disease outbreaks that tend to affect many individuals at the same time in one geographical location) or pandemics (disease outbreaks that affect a high proportion of individuals in different regions of the globe simultaneously). Pandemic influenza tends to infect larger numbers of people and can cause more deaths than seasonal influenza.

Testing and Diagnosing Influenza

During periods of low influenza activity in a community, sporadic influenza cases cannot easily be differentiated from infections caused by other respiratory viruses using clinical signs and symptoms. Clinical findings alone often overlap with other pathogens and diseases, including the rhinoviruses, coronaviruses, adenovirus, parainfluenza virus, respiratory syncytial virus, pharyngitis, tracheobronchitis, bronchiolitis, and croup. While clinical findings are helpful, they do not confirm or exclude diagnosis.

A study showed that during a known influenza outbreak, the presence of a fever and a cough within 48 hours of the onset of symptoms had a 79% positive predictive value (63%–78% sensitivity, 55%–71% specificity as compared to viral culture).2 However, the sensitivity and predictive value of clinical definitions vary depending on the level of influenza activity. Subsequent studies in older patients demonstrated a range of predictive values from 30% to 78%. These disparate results highlight the challenges of identifying influenza illness in the absence of laboratory confirmation.

During periods of low influenza activity, laboratory testing should be used to support an influenza diagnosis. During peak outbreaks, it is cost-effective to make a diagnosis based on clinical symptoms. For up-to-date surveillance information about influenza outbreaks, the Centers for Disease Control and Prevention (CDC) provides online weekly updates from October through May at http://www.cdc.gov/flu/weekly/fluactivity.htm.

Influenza Testing Methods

Methods of diagnostic testing for influenza include serology, viral culture, immunofluorescence, pointof-care (POC) antigen testing, and polymerase chain reaction (PCR). Table 3 compares different types of influenza tests. Of note, it is difficult to make direct comparisons of sensitivity and specificity among the different test types because of variables such as specimen type, prevalence of circulating influenza in the population, and timing of sample collection.

Serology

Serological testing detects antibodies that begin to appear approximately 2 weeks after infection and peak 4 to 7 weeks after infection. This testing requires paired acute and convalescent samples. Thus, while serological testing approaches 100% sensitivity, it is not useful for patient management. Serological testing is recommended only for surveillance and retrospective diagnosis of emerging influenza strains and subtypes in public health and research laboratories.

Viral Cell Culture

Viral culture has been considered the “gold standard.” It remains the method of choice for epidemiological purposes such as tracking circulating viruses and identifying subtypes, because it can provide active virus for subsequent testing and also can be used with a wide variety of specimen types. Conventional viral culture involves inoculating cultured cells with a patient specimen and monitoring the cells for cytopathic effects, hemadsorption after the addition of erythrocytes, or specific antibody staining. The turnaround time for viral culture is longer than other tests, despite modifications to the conventional culture method such as the shell vial assay, which uses centrifugation to enhance detection of viral activity. Viral culture also is labor intensive, poses more risk for laboratory personnel, and is less sensitive than PCR testing.

Immunofluorescence Microscopy

Immunofluorescence microscopy involves analyzing respiratory epithelial cells that are stained with influenza-specific antibodies. This is an attractive method because it can be used to simultaneously detect other respiratory viruses and can be used with a wide variety of specimen types. However, the method is manual and very labor intensive. Additionally, results are dependent on the specificity of the monoclonal antibodies to the circulating subtypes and analysis can be subjective.

Point-of-Care Antigen Testing

POC antigen testing has many advantages such as ease of use and, most notably, a very rapid turnaround time. However, the WHO does not recommend using POC antigen testing because of sensitivity issues.4 Specimen type and the timing of specimen collection (viral shedding peaks 48 hours after onset of symptoms) can affect sensitivity. If POC antigen tests are used, both the WHO and the US Food and Drug Administration (FDA) recommend confirming negative test results with another method such as RTPCR, viral culture, or immunofluorescence, especially during peak influenza season.4,5 Likewise, positive tests during low periods of influenza activity should be confirmed with another method.

Rapid PCR

PCR testing is the most sensitive method for detecting human influenza virus. In a series of 557 respiratory tract specimens, Mayo Medical Laboratories’ #88544 Influenza Virus Type A and B RNA by Rapid PCR assay was able to detect influenza virus in 16.5% of respiratory samples, as compared to 8.8% for viral cell culture and 4.3% for a POC antigen test.3 The negative predictive value for the PCR assay is 99.9% and it has a shorter turnaround time than viral culture methods.

Table 3. Influenza virus and Test characteristics

Additionally, Mayo’s PCR assay can more readily identify influenza viruses in patients who have had symptoms for more than 3 days, immunosuppressed patients, and those with chronic lung diseases (for whom frequent lower respiratory tract infections are often associated with low viral levels). The PCR assay also is useful for confirming test results obtained by other, less sensitive, testing methods.

Methodology

The specimen types for #88544 Influenza Virus Type A and B RNA by Rapid PCR include nasopharyngeal aspirate or wash, nasopharyngeal swab (rayon minitip), or throat swab. While nasopharyngeal aspirates or washes require more time to collect and cause more discomfort to the patient, they typically provide a better yield of viral particles.

Automated instrumentation is used to extract viral nucleic acids from respiratory specimens. The viral RNA contained in the specimen extract is reverse transcribed into cDNA. The cDNA serves as a template for amplification that is directed by primers that pair with sequences of the viral matrix protein gene. This gene is highly conserved in both influenza A and influenza B type viruses. Target nucleic acid amplification is monitored in real time using fluorescence resonance energy transfer technology (FRET). The assay instrumentation has a built-in thermocycler to amplify the nucleic acids, and a builtin fluorometer to detect the fluorescence emitted from the nucleic acid probes that annealed to the amplified target DNA at the end of each PCR cycle. Real-time PCR offers enhanced sensitivity and speed, making it an appealing alternative to conventional culture-based methods.

Limitations of Rapid PCR

Positive test results can be considered diagnostic, and the test has a very high (99.9%) negative predictive value. The sensitivity of PCR testing can be affected by patient age, specimen type, or use of an inadequate specimen. Additionally, inappropriate specimen collection, storage, or transport can contribute to falsenegative test results. When interpreting results from any test, a physician must assess the clinical picture and use his or her clinical experience to determine if further laboratory testing is needed.

PCR test results may not correlate with cell culture, the previous gold standard. This is because PCR testing is more sensitive and specific, and may detect low-titer viral infection that cannot be detected by viral culture methods.

When to Use PCR Testing

The following guidelines can be used to determine when PCR testing may be cost-effective:6

• PCR testing can provide a prompt diagnosis, which can reduce the inappropriate use of antibiotics for viral infections and provide an opportunity to receive antiviral medical treatment. In addition, prompt accurate diagnosis can eliminate unnecessary testing costs, such as chest X-rays or additional laboratory tests.
• PCR testing is useful for hospitalized patients throughout the influenza season to confirm the diagnosis of influenza in febrile patients, especially for immunocompromised patients. Early identification of influenza in symptomatic individuals gives health care workers important information that allows them to take steps to reduce the risk of nosocomial infection (infections contracted while in a health care facility).
• PCR testing is useful for determining if an outbreak of illness in a closed setting such as a school, nursing home, cruise ship, or military base is due to influenza.
• PCR testing of vaccinated adults with influenza-like symptoms and who are at low risk of developing complications may be useful to establish an accurate diagnosis, especially when local influenza activity is low.
• Once it is established that influenza is present in the community, PCR testing should only be performed if it will affect diagnostic or treatment decisions. During peak season, it is typically more cost-effective to treat patients who have clinical symptoms of influenza rather than perform diagnostic testing.

Influenza Treatment

Nothing can cure influenza, but antiviral drugs (eg, oseltamivir [Tamiflu] or zanamivir [Relenza]) can relieve the severity and shorten the length of illness by 1 to 2 days. These drugs act by inhibiting neuraminidase activity and preventing replicated viral particles from leaving the infected host cell. However, treatment must occur within 48 hours of the onset of symptoms. The drug also may be given to at-risk patient populations in the absence of demonstrated symptoms:

• When influenza virus is known to be circulating in the community, chemoprophylactic antiviral treatment is recommended for individuals ≥1 year old who are at high risk of developing complications and have not been vaccinated1
• If an outbreak is detected in an inpatient care setting (hospital, nursing home) or in other isolated groups (cruise ships, military bases, boarding schools), the vaccination of eligible people combined with the early administration of prophylactic antiviral drugs may prevent infection or lessen the severity of disease

Summary

Mayo Medical Laboratories’ #88544 Influenza Virus Type A and B RNA by Rapid PCR assay offers a costeffective diagnostic test for influenza that combines superior sensitivity with competitive turnaround times. Positive test results are considered diagnostic for influenza and can provide needed confirmation of the presence of influenza A or B in the community early in the flu season. This information can guide both treatment and containment measures to prevent the spread of influenza.

References

1. Centers for Disease Control and Prevention: Prevention and Control of Influenza Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007 Early Release. 2007;56:1–40

2. Monto AS, Gravenstein S, Elliott M, et al: Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000;160(21):3243–3247

3. Zitterkopf NL, Surbhi S, Espy MJ, et al: Relevance of influenza A virus detection by PCR, shell vial assay, and tube cell culture to rapid reporting procedures. J Clin Micro 2006;44(9):3366–3367

4. World Health Organization: WHO recommendations on the use of rapid testing for influenza diagnosis http://www.who. int/csr/disease/avian_influenza/guidelines/ RapidTestInfluenza_web.pdf

5. US Food and Drug Administration’s Office of In Vitro Diagnostic Device Evaluation and Safety: Cautions in using rapid tests for detection of influenza A viruses. http://www.fda.gov/cdrh/ oivd/tips/rapidflu.html

6. Centers for Disease Control and Prevention (CDC): The interim guidance for influenza
diagnostic testing during the 2006–07 Influenza season. http://www.cdc.gov/flu/professionals/labdiagnosis.htm

Ask Us

Question:

I have heard a lot about avian flu infecting humans. Is avian influenza related to human influenza A that circulates during the winter season?

Answer:

The avian or so-called “bird flu” virus (H5N1), an influenza A subtype, can be directly transmitted from domestic birds to humans. Thus far, this viral strain has not been easily transmitted between people, and so, a pandemic of avian influenza has not occurred. However, because humans have virtually no immunity to this influenza strain, H5N1 can cause severe morbidity and mortality in humans.

Question:

How should you handle a specimen suspected of containing the avian flu subtype (H5N1) or other potentially pandemic emerging infectious diseases?

Answer:

Do not send these specimens to Mayo Medical Laboratories. Mayo does not provide a test for avian flu (H5N1) or for the coronavirus that causes severe acute respiratory syndrome (SARS).

If you suspect a case of avian flu or another emerging pandemic threat, you should contact your State Department of Health immediately. All state public health laboratories are part of the Laboratory Response Network (LRN), established by the Centers for Disease Control and Prevention (CDC) as part of an integrated national and international laboratory network that can respond quickly to emerging infectious diseases.

The CDC recommends that when avian flu is suspected (for example, if a patient has traveled to a country with a confirmed avian flu outbreak in humans or poultry and had direct contact with infected birds) oropharyngeal swabs or lower respiratory tract specimens should be collected because evidence has demonstrated they contain the highest quantity of H5N1 virus. If bronchoalveolar lavage (a procedure that can generate aerosolization of the viral particles) is performed, infection control procedures should be used, including wearing a gown, gloves, goggles or face shield, and a respirator. For further guidance on specimen collection go to the CDC’s “Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Avian Influenza A (H5N1) Virus in the United States” at http://www2a.cdc.gov/ han/ArchiveSys/ViewMsgV.asp?AlertNum=00246. Package and ship these specimens according to your state public health laboratory’s instructions.

Local laboratories are discouraged from handling suspect specimens except to package and ship them to the state public health laboratory, because of the threat to laboratory personnel, as well as the US poultry industry in the case of avian flu. The submitting laboratory should not set up cultures, since specimens from a patient suspected of harboring avian flu virus should only be cultured under enhanced Biosafety Level 3 conditions. For more information about requirements for different Biosafety Levels (BSL) go to the CDC online presentation: The 1, 2, 3’s of Biosafety Levels at http://www.cdc.gov/OD/ohs/symp5/ jyrtext.htm.

Hospitals and clinical laboratories are encouraged to have a pandemic influenza plan in place to protect staff and transport suspect specimens to state public health laboratories.

For additional information about preparing your laboratory for an influenza pandemic, see the following online sources:

The CDC “Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Avian Influenza A (H5N1) Virus in the United States” at http://www2a.cdc.gov/han/ ArchiveSys/ViewMsgV.asp?AlertNum=00246

The Department of Health and Human Services provides information for clinical laboratory surveillance at http://www.pandemicflu.gov/ plan/pdf/Checklist.pdf

The Association of Public Health Laboratories features links to state laboratories at http://www.aphl.org/about_aphl/about_phl/ member_laboratory_listing/Pages/default.aspx

Abstracts of Interest

Using Smudge Cells on Routine Blood Smears to Predict Clinical Outcome in Chronic Lymphocytic Leukemia: A Universally Available Prognostic Test

Grzegorz S. Nowakowski, Md; James d. Hoyer, Md; Tait d. Shanafelt, Md;
Susan M. Geyer, Phd; Betsy R. LaPlant, MS; Timothy G. Call, Md;
diane F. Jelinek, Phd; Clive S. Zent, Md; and Neil E. Kay, Md

Recently developed prognostic tests in early Rai and Binet stage chronic lymphocytic leukemia (CLL) require considerable technologic expertise and are not available worldwide. Smudge cells are CLL cells ruptured during smear preparation. We hypothesized that smudge cell formation is inversely correlated with expression of vimentin, a cytoskeletal protein and prognostic marker, and that the percentage of smudge cells would predict prognosis in CLL. We reviewed the blood smears of 75 patients with previously untreated early- and intermediate-stage CLL (Rai stage 0-II) who were seen at the Mayo Clinic in Rochester, Minn, between September 1989 and December 2000. A total of 200 lymphocytes and smudge cells were counted on each slide and the results expressed as a percentage of the total lymphocytes (intact and smudged). The median percentage of smudge cells was 27% (range, 4%–72%). The percentage of smudge cells inversely correlated with vimentin expression (r=–0.57; P=.007). The median percentage of smudge cells was higher in patients with the mutated immunoglobulin heavy chain gene than in those with the unmutated immunoglobulin heavy chain gene (31% vs 13%; P=.02). Patients with less than 30% smudge cells had a median time from diagnosis to initial treatment of 72.7 months, whereas the median time from diagnosis to initial treatment in patients with 30% or more smudge cells was not reached (P=.001). The percentage of smudge cells as a continuous variable correlated with overall survival (P=.04). The estimation of smudge cells on a blood smear could be a universally available prognostic test in early-stage CLL.

Mayo Clinic Proceedings 2007;82(4):449-453

Focus on Education

Biomarkers of Cardiovascular Risk: State of the Art

October 30-31, 2007

Leighton Auditorium Harold W. Siebens Medical Education Building

Mayo Clinic, Rochester, Minnesota

This conference provides an overview of advances in the use of biomarkers in cardiovascular risk stratification in asymptomatic individuals, in particular the use of proteomic markers. Topics will include the assessment of atherosclerotic burden, testing of arterial function, emerging markers, current approaches to cardiovascular risk stratification, statistical approaches to biomarker validation, novel platforms, regulatory issues, and perspectives from industry.

This conference is designed for cardiovascular specialists, preventive cardiologists, internists, research fellows, scientists, and clinical chemists. It is intended for individuals interested in the use of circulating biomarkers in cardiovascular risk stratification.

Real-Time PCR for the Clinical Microbiology Laboratory

November 15-16, 2007

Phillips Hall Harold W. Siebens Medical Education Building

Mayo Clinic, Rochester, Minnesota

Real-time PCR (polymerase chain reaction) has broad applications for clinical microbiology testing. This workshop familiarizes the participant with currently available rapid cycle real-time methods including the principles of rapid thermocycling and probe detection formats with an emphasis on FRET (fluorescence resonance energy transfer) hybridization probes. Preanalytic processing of patient specimens including isolation, concentration and preservation of nucleic acid, quality control, and quality assurance issues are addressed. Applications of this technology for the detection and quantitation of microorganisms and mutation screening for antimicrobial resistance are presented. Participants have a close-up experience with these applications. In addition, primer-probe design, assay optimization, assay performance verification, validation, and interpretation of results using 2 common platforms will be presented.

This course is designed for clinical microbiologists, laboratory directors, supervisors, medical technologists, public health microbiologists, pathologists, and infectious disease specialists. A basic understanding of polymerase chain reaction (PCR) is recommended.

2007 Education Calendar

State-of-the-Art Thrombophilia: A Practical Clinical Conference
October 4–5, 2007

•The Kahler Grand Hotel

Rochester, Minnesota

Biomarkers of Cardiovascular Risk: State of the Art
October 30–31, 2007

•Mayo Clinic

Rochester, Minnesota

Real-Time PCR for the Clinical Microbiology Laboratory
November 15–16, 2007

•Mayo Clinic

Rochester, Minnesota

Disease Management Strategies . . .

Oral Anticoagulation Management Update
October 11, 2007

Presenter: Robert D. McBane, MD

Overview of Inflammatory Bowel Disease
November 13, 2007

Presenter: Edward V. Loftus Jr., MD

Celiac Disease
December 11, 2007

Presenter: Joseph A. Murray, MD

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Communique Issue MC2831-1007

Editorial board	Communiqué Staff
Jane Dale, MD	Medical Editor: Jane Dale, MD
Mary Laven	Managing Editor: Denise Masoner
Denise Masoner	Art Director: Ann Rebidas
Debra Novak
Bradley Ross
Contributors
Charyl Dutton Gibbs	Thomas F. Smith, PhD
Priya Sampthkumar MD

The Communiqué is published by Mayo Medical Laboratories to provide laboratorians with information on new diagnostic tests, changes in procedures or normal values, and continuing medical education programs and workshops.

A complimentary subscription of the Communiqué is provided to Mayo Medical Laboratories’ clients. Please send address changes to or Communiqué, Superior Drive Support Center, 3050 Superior Drive NW, Rochester, MN, 55901, or call us at 800-533-1710.