severity, coverage was not different among those with acute exacerbations. Vaccination coverage was 41.8% among persons with at least one emergency department or urgent care visit for asthma within the preceding 12 months and 35.4% with no such visits (p=0.2). Influenza vaccination coverage did not differ significantly between persons with asthma who had an exacerbation in the past 12 months and those who did not (37.5% versus 34.8%, p=0.5). Vaccination coverage also did not differ significantly by race/ ethnicity, ranging from 30.8% of Hispanics (CI = 24.4– 38.1) to 37.9% (CI = 33.4-42.5) of non-Hispanic whites (p=0.09).

Reported by: CB Ligon, RA Rudd, MSPH, DB Callahan, MD, Div of Environmental Hazards and Health Effects, National Center for Environmental Health; GL Euler, DrPH, Immunization Svcs Div, National Center for Immunization and Respiratory Diseases, CDC Editorial Note: This report presents the first estimates of influenza vaccination coverage in the United States among the civilian, noninstitutionalized population of persons with asthma and reinforces the need to increase vaccination throughout this at-risk population. Health-care visits provide an opportunity for vaccination, but even among persons with the highest number of visits, nearly half remained unvaccinated in the 2005-06 influenza season. Even so, access to health care is an important factor associated with receiving influenza vaccination. Persons with asthma who had health insurance had a greater rate of influenza vaccination than did those who lacked insurance. Likewise, the vaccination rate for persons with asthma who had a usual place for health care was significantly greater than the rate for those who did not have a regular place for health care. After the vaccine shortage of the 2004-05 influenza season, vaccination coverage of persons with asthma in 200506 failed to improve among households with the lowest incomes, among persons without health insurance, and among persons without a regular place for medical care, emphasizing the need for interventions that include the medically underserved.

During the 2005-06 influenza season, the oldest age groups (50-64 years and ≥65 years) had the highest vaccination coverage. Influenza vaccination is recommended for both age groups, regardless of asthma status, because the influenza-related death rate increases sharply among older adults (3). In February 2006, ACIP recommended that all children aged 24-59 months be vaccinated against influenza, regardless of risk status. Examination of the 2007 NHIS data could determine whether the expanded recommendation affected coverage among the subset of children with asthma, who already had been recommended for vaccination under previous guidelines. Because ACIP voted in

February 2008 to recommend influenza vaccination for children, data soon will be available to also study the effects on coverage for older children.*

The findings in this report are subject to at least three limitations. First, the sample size of the survey (34,1) adults and children, 2,700 of whom reported having cur rent asthma) limits reliable identification of patterns among subgroups of persons with asthma potentially of interest but smaller in number than the subgroups examined here Second, determination of vaccination status in NHIS i made by self-report, which introduces recall bias and likel overestimation of vaccination rates (8). Finally, NHIS doe not ascertain whether a child received a second vaccine dose as is recommended by ACIP for children aged 6 months to 8 years who previously have not received the influenza vac cination; therefore, NHIS overestimates full coverage for this age group (3).

The findings in this report emphasize the need for measures to uniformly increase influenza vaccination rates among persons with asthma. Interventions that target patients, health-care access, and health-care providers have demonstrated benefits in similar settings and should be implemented to improve influenza vaccination coverage, Such interventions include automated reminders, standing orders, multicomponent educational programs, reduction of travel distances or out-of-pocket vaccine costs, and provider performance feedback (9). Persons with inadequate access to health care and those treated at multiple facilities would be less likely to miss opportunities for vaccination i they consistently sought care at a single medical facility That continuity of care could reduce the diffusion of responsibility that occurs when patients are treated at mul tiple health-care facilities (10). Providing vaccination through at least January and February of the influenza season can further reduce missed opportunities for effective vaccination of persons in this group at high risk.

à CDC. Self-reported influenza vaccination coverage trends 1989-2006 among adults by age group, risk group, race/ethnicity, health-care worker status, and pregnancy status, United States, National Health Interview Survey (NHIS). Available at http://www.cdc.gov/flu/ professionals/vaccination/pdf/vaccinetrend.pdf.

CDC. Influenza vaccination coverage among children with asthma— United States, 2004-05 influenza season. MMWR 2007;56:193–6. . US Department of Health and Human Services. Healthy people 2010 (conference ed, in 2 vols). Washington, DC: US Department of Health and Human Services; 2000. Available at http://www.healthypeople.gov. Mangtani P, Shah A, Roberts JA. Validation of influenza and pneumococcal vaccine status in adults based on self-report. Epidemiol Infect : 2007;135:139–43.

Task Force on Community Preventive Services. Recommendations regarding interventions to improve vaccination coverage in children, adolescents, and adults. Am J Prev Med 2000;18(1 Suppl):92–6. . Smith PJ, Santoli JM, Chu SY, Ochoa DQ, Rodewald LE. The association between having a medical home and vaccination coverage among children eligible for the Vaccines for Children program. Pediatrics 2005;116:130–9.

Recommendations from an Ad Hoc Meeting of the WHO Measles and

Rubella Laboratory Network (LabNet) on Use of Alternative Diagnostic Samples for Measles

and Rubella Surveillance

Laboratory confirmation of measles and rubella is an portant component of disease surveillance in all settings. cause the use of clinical diagnosis for surveillance is unliable, case-based laboratory confirmation of disease is itically important in settings with measles or rubella elimition goals. The World Health Organization (WHO) easles and Rubella Laboratory Network (LabNet) was tablished in 2000 to provide a standardized testing and porting structure and a comprehensive, external qualitysurance program (1). LabNet currently consists of 679 boratories serving 166 countries. However, measles and bella surveillance remains incomplete in certain areas cause of difficulties with the collection and transport of rum specimens. Recently, LabNet evaluated two alternae sampling approaches to serum samples, the use of dried ood spots (DBS) and oral fluid (OF) samples. Both of ese approaches have potential to be useful tools for measles d rubella control programs. In June 2007, WHO conned an ad hoc meeting in Geneva, Switzerland, to review ailable data and provide recommendations on use of DBS d OF samples for measles and rubella diagnostics. tendees included LabNet staff members and scientists no had been conducting studies to evaluate use of these ernative diagnostic samples. The attendees concluded.

that 1) although serum-based diagnostics remain the "gold standard," the use of these two alternative sampling techniques would not adversely affect routine measles and rubella surveillance and might enhance surveillance; 2) regions in the elimination phase* that already have established serum-based testing for rash illness surveillance would not likely benefit from converting to DBS or OF sampling methods, except in special circumstances; and 3) DBS or OF sampling are viable options for measles and rubella surveillance in all regions, especially where patients might resist venipuncture for blood collection, or where special challenges exist with transport or refrigeration of diagnostic samples.

Background on Use of Alternative
Diagnostic Samples

Conventional laboratory confirmation of suspected cases of measles and rubella is based on the detection of virusspecific immunoglobulin M (IgM) in a single serum sample collected soon after the onset of symptoms (2). In addition, detection of viral RNA by reverse transcriptionpolymerase chain reaction (RT-PCR), usually in a throat swab or urine sample, and subsequent genotyping of strains is valuable for diagnosis and molecular epidemiology (2). Accurate laboratory results for detection of IgM and viral RNA are dependent on proper collection, processing, shipment, and storage of clinical samples and use of accurate tests performed by a proficient laboratory. However, collection of blood samples by venipuncture, particularly from children, can be a challenge, and the sustained refrigeration required for diagnostic samples during transport is not always achievable. In these situations, alternatives to serum collection can be useful.

DBS has been used for various epidemiologic studies for the detection of measles- and rubella-specific IgG and IgM antibodies and viral RNA (3–5). Antibody and viral RNA are sufficiently stable on DBS at ≤98.6°F (≤37.0°C) to allow this sample collection method to be used for case confirmation or molecular epidemiology in areas where sample refrigeration is not feasible. OF has been used in similar studies and for the national measles, mumps, and rubella (MMR) surveillance program in the United Kingdom (UK) for approximately 10 years (6,7). OF is easy to

'As of 2008, four out of six World Health Organization regions have measles elimination goals: the Region of the Americas (by 2000; measles declared eliminated since late 2002), the European Region (by 2010), the Eastern Mediterranean Region (by 2010), and the Western Pacific Region (by 2012). In addition, two regions have rubella elimination goals: the Region of the Americas and the European Region (both by 2010).

collect, and collection is more acceptable to the population (6), thereby enabling health-care workers to obtain more complete sampling for suspected cases.

Evaluations Comparing Alternative Diagnostic Samples with SerumBased Diagnostics

% patients testing positive

25

25

0

Fever

Rash

IgGt: Serum/DBS OF IgM**: Serum/DBS OF Virus detection": OF Virus detection": DBS Virus culture

-3 -1 1 3

§ Dried blood spots. 1 Oral fluid.

Immunoglobulin M.

chain reaction.

Since 2001, LabNet reference laboratories in Australia, Cote d'Ivoire, Netherlands, Turkey, Uganda, the UK, and the United States have been working to 1) determine IgM and RNA stability in DBS and OF samples and 2) optimize the methods for IgM antibody assay and protocols for RNA detection in DBS and OF samples (8-10). This work has provided data on sensitivity and specificity of OF and DBS samples compared with serum and also has identified logistic challenges in implementing alternative sampling techniques. Three different types of data were available for review during the ad hoc meeting. First, beginning in 2001, LabNet laboratories conducted studies that collected OF, DBS, and corresponding serum. samples from persons with suspected measles or rubella during outbreaks and tested the samples for the presence of measles- or rubella-specific IgM antibodies. Second, LabNet reviewed data from the MMR surveillance program in the UK, where 1,000-3,000 OF samples have been collected annually during the past decade. Third, LabNet reviewed data from seven countries in the WHO African Region that used DBS sampling methods for routine measles and rubella surveillance during 2005-2007. DBS was either the only sample collected (Sierra Leone) or was collected in conjunction with routine serum collection (Burkina Faso, the Democratic Republic of Congo, Ethiopia, Ghana, Senegal, and Zambia). Standard protocols for sample collection and laboratory testing recommended by LabNet were used (2).

Data from all three sources indicated that the sensitivity and specificity of DBS and OF for detecting measles and rubella virus-specific IgM parallels that of serum; however, a moderate decline in sensitivity for detecting rubella virusspecific IgM in OF during the first 4-5 days after disease onset was observed (Figures 1 and 2; Table). Detection of

RNA in serum and DBS was shown to be possible with nested or real-time RT-PCR (but not conventional RT-PCR. if samples are collected within 5-7 days after rash onset. This procedure has proven invaluable for collecting viral sequence information where urine or throat swabs were not available. In the MMR surveillance program in the UK. using OF, the rate of measles RNA detection by nested RT-PCR ranged from 80% to 90% when collected during the first week after rash onset, and reached 50% at 3weeks after rash onset. Conventional RT-PCR was sensitive for up to 2 weeks after rash onset, but was still considera useful. For rubella, testing for both IgM and RNA in OF samples substantially increased the sensitivity of surveil lance for confirming cases during the first 4-5 days after rash onset, when many rubella cases are not yet IgM positive. Results of evaluations comparing OF and DBS with serum sampling indicated that OF and DBS sampling hav: a potential role in improving measles and rubella surveil lance. Compared with serum collection, these sampling procedures provide:

D

Good acceptance by patients, because DBS avoids venipuncture and OF is noninvasive.

Stability without refrigeration for periods of up to 7 days (OF) or longer (DBS).

Equivalent cost for collection, extraction, and testing.

Potential to substantially reduce transport costs through avoiding refrigeration.

• Ability to detect both specific IgM and RNA in the same sample. OF can extend the #opportunity for RNA detection after rash onset.

Equivalent sensitivity and specificity for IgG detection and consequent versatility for use in seroepidemiology studies.

However, use of OF and DBS saming also has some disadvantages mpared with serum collection, in rticular:

Collection devices are not commonly available and would need to be provided to health-care facilities by the surveillance program.

• Volume of DBS might be inadequate unless staff are fully trained in sample collection.

• Extraction procedures for DBS and OF require more time of technicians.

• External quality-assurance programs, such as those currently required for testing of serum, have yet to be established for OF and DBS.

nmunoglobulin M.

ata are insufficient for meaningful analysis.

Recommendations

Having considered the evidence described in this report, participants in the ad hoc meeting made the following recommendations.

No single alternative sampling technique has been shown to be optimal for surveillance under every circumstance, and serum should still be considered the “gold standard” for IgM detection. However, DBS and OF sampling techniques are viable options for measles and rubella surveillance (5-10), especially where challenges with specimen transport or refrigeration exist or where patients might resist venipuncture. Alternative sampling techniques would not adversely affect routine measles and rubella surveillance (provided adequate training and resources are provided) and might enhance surveillance through:

• More acceptable noninvasive methods (OF). • Reduced transport costs (DBS and OF).

• Enhanced ability to conduct molecular surveillance (OF and DBS RNA).

• Enhanced sensitivity of rubella case confirmation during the first 4–5 days after rash onset (OF RNA). Offering a confirmatory option for questionable serum IgM results during the early stage of disease for both measles and rubella (OF RNA).

Regions in the elimination phase that already have established a serum-based rash illness surveillance system would not likely benefit from changing to DBS or OF sampling methods except in special circumstances, such as in settings where:

• Timely specimen transport from remote or difficultto-access areas to the laboratory conducting the serologic analysis is especially difficult.

• Collection of OF in addition to serum might improve efficiency of case identification and virologic surveillance by enabling detection of viral RNA from disease

onset.

Implications for Measles and Rubella
Surveillance in the United States

Elimination of indigenous measles and rubella virus was declared in the United States in 2000 and 2004, respectively. High-quality measles and rubella surveillance including timely collection of diagnostic samples for laboratory confirmation, along with sustained high coverage

Additional information available at http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm5718a5.htm and http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm5411a5.htm.

with a combined MMR vaccine, have been critical in achie ing that public health success. At present, routine meas and rubella surveillance in the United States will contin to rely upon already established diagnostic methoc including serum-based assays for detection of virus-speci... antibodies and on nasopharyngeal swab or urine sample for virus detection.

References

1. World Health Organization. Global measles and rubella laborator network—update. Wkly Epidemiol Rec 2005;80:384-8.

2. World Health Organization. Manual for the laboratory diagnosis measles and rubella infection, 2nd ed. Geneva, Switzerland: Works Health Organization; 2007. WHO/IVB/07.01. Available at http www.who.int/immunization_monitoring/LabManualFinal.pdf.

3. Ibrahim SA, Abdallah A, Saleh EA, Osterhaus ADM, De Swart R.. Measles virus-specific antibody levels in Sudanese infants: a prospe tive study using filter paper blood samples. Epidemiol Infec 2006;134:79-85.

4. Riddell MA, Byrnes GB, Leydon JA, Kelly HA. Dried venous blood samples for the detection and quantification of measles IgG using 4 commercial enzyme immunoassay. Bull World Health Organ 2003;81:10.

5. El Mubarak HS, Yüksel S, Mustafa OM, Ibrahim SA, Osterhaus AD de Swart RL. Surveillance of measles in the Sudan using filter paper blood samples. J Med Virol 2004;73:624–30.

6. Vyse AJ, Gay NJ, White JM, et al. Evolution of surveillance of measle mumps, and rubella in England and Wales: providing the platform for evidence-based vaccination policy. Epidemiol Rev 2002;24:125–36. 7. Vyse AJ, Jin L. An RT-PCR assay using oral fluid samples to detect rubella virus genome for epidemiological surveillance. Mol Cell Probes 2002;16:93-7.

8. De Swart RL, Nur Y, Abdallah A, et al. Combination of reverse transcriptase PCR analysis and immunoglobulin M detection on filter paper blood samples allows diagnostic and epidemiological studies c measles. J Clin Microbiol 2001;39:270–3.

9. Riddell MA, Leydon JA, Catton MG, et al. Detection of measles virus specific immunoglobulin M in dried venous blood samples by using a commercial enzyme immunoassay. J Clin Microbiol 2002;40:5–9, 10. Helfand RF, Cabezas C, Abernathy E, et al. Dried blood spots versus sera for detection of rubella virus-specific immunoglobulin M (lg and IgG in samples collected during a rubella outbreak in Peru. Car Vaccine Immunol 2007;14:1522–5.