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(Chest. 2006;130:1109-1116.)
© 2006 American College of Chest Physicians

Impact of a Winter Respiratory Virus Season on Patients With COPD and Association With Influenza Vaccination*

Geoffrey J. Gorse, MD; Theresa Z. O’Connor, PhD; Stephen L. Young, MD; Michael P. Habib, MD; Janet Wittes, PhD; Kathleen M. Neuzil, MD and Kristin L. Nichol, MD

* From the Department of Veterans Affairs Medical Center and Saint Louis University (Dr. Gorse), St. Louis, MO; Department of Veterans Affairs (Dr. O’Connor), Cooperative Studies Program Coordinating Center, West Haven, CT; Department of Veterans Affairs Medical Center (Dr. Young), Durham, NC; Department of Veterans Affairs Medical Center (Dr. Habib), Tucson, AZ; Statistics Collaborative (Dr. Wittes), Washington, DC; VA Puget Sound Health Care System and University of Washington (Dr. Neuzil), Seattle, WA; and Department of Veterans Affairs Medical Center and University of Minnesota (Dr. Nichol), Minneapolis, MN.

Correspondence to: Geoffrey J. Gorse, MD, Division of Infectious Diseases and Immunology, Saint Louis University Health Sciences Center, 3635 Vista Ave (FDT-8N), St. Louis, MO 63110; e-mail: gorsegj{at}slu.edu

Abstract

Background: We assessed the effects of an influenza season on patients with COPD. Data from 2,215 veterans in a multicenter, randomized, double-blind influenza vaccine efficacy study were analyzed for changes in spirometric and functional status, comparing patients with laboratory-documented influenza (LDI)-caused illness, non-LDI-caused respiratory illness, or no illness, and for association with influenza vaccination.

Methods: Patients received either IM trivalent inactivated influenza virus vaccine (TIV) plus intranasal trivalent, live attenuated, cold-adapted influenza virus vaccine (TC) or TIV plus intranasal placebo (TP). We performed spirometry, measured the chronic lung disease severity index (CLDSI) score to assess functional status and well-being, and tested for influenza virus infection.

Results: Worsening in FEV1, percentage of predicted FEV1, and CLDSI score (p < 0.001) was associated with acute respiratory illness in 585 illnesses including 94 LDI-caused illnesses. LDI-caused illness was more likely to be associated with worsening in FEV1 and CLDSI score acutely than non-LDI-caused illness (p < 0.01). Logistic regression showed acute respiratory illness (odds ratio [OR], 1.78; 95% confidence limit [CL], 1.40 to 2.26) to be associated with worsening in CLDSI score, and receipt of TC (OR, 1.39; 95% CL, 1.10 to 1.74) and no illness (OR, 0.70; 95% CL, 0.53 to 0.91 for acute respiratory illness) to be associated with better CLDSI score at the end of the study. Hospitalization was more frequent in patients with acute respiratory illness (p < 0.0001).

Conclusions: Acute respiratory illness was associated with increased health-care utilization and obstruction to airflow, and worse functional status and well-being. At the end of the study, receipt of TC was associated with improvement and acute respiratory illness was associated with worsening in functional status and well-being.

Key Words: COPD • health-related quality of life • influenza virus • pulmonary function • vaccine

Influenza virus infections cause significant morbidity and mortality particularly in patients with underlying chronic diseases.123456789101112 Influenza causes exacerbations of COPD and reduced pulmonary function, and as many as 24 million persons in the United States may have underlying COPD.1013141516 Immunization with standard influenza virus vaccine is associated with reduced risk of influenza-related illness, reduced hospitalization rates, fewer outpatient visits, less severe illness, and lower mortality related to pneumonia and influenza in older patients and in those with chronic lung disease.7891718192021 Besides influenza virus, other respiratory pathogens are associated with influenza-like illness and acute respiratory illness; and respiratory viruses are associated with 15 to 50% of acute exacerbations of COPD.222324252627282930313233343536

The effect of a winter respiratory virus season on pulmonary function, performance status, and health-related quality of life in a large cohort of patients with COPD has not been reported. In the Department of Veterans Affairs (VA) Cooperative Study, 448 patients aged ≥ 50 years who had COPD received IM trivalent inactivated influenza virus vaccine (TIV). They were also randomized to receive intranasal trivalent, live attenuated, cold-adapted influenza virus vaccine (LAIV) [TC group] or intranasal placebo (TP group) in a double-blind manner.15 The purpose of this report is to compare changes in lung function, performance status, and health-related quality of life among these older, vaccinated individuals who had laboratory-documented influenza (LDI)-caused illness, other acute respiratory illnesses not documented to be influenza (non-LDI-caused illnesses), or no acute respiratory illness.

Materials and Methods

Volunteers aged ≥ 50 years who met spirometric criteria for COPD were recruited at 20 VA Medical Centers, as described.15 All study subjects gave written informed consent. The study was approved by the institutional review boards at the participating sites, and followed procedures in accordance with the recommendations found in the Helsinki Declaration of 1975.

Pulmonary function tests performed included FEV1, percentage of predicted FEV1 (PPFEV1), and FEV1/FVC ratio.3738 COPD was defined as FEV1 ≤ 80% of the predicted value and FEV1/FVC ratio < 0.70. The study required spirometry within 4 weeks prior to immunization. Spirometric criteria were not met in 11 subjects who had a baseline FEV1/FVC ratio ≥ 0.70, and in 1 subject who had a baseline PPFEV1 of 91%. The analysis included these 12 subjects because of their history of chronic lung disease.

Immunizations occurred in October 1998 through January 1999. All subjects received TIV for the 1998 to 1999 influenza season. Subjects were randomly assigned in a 1:1 ratio to receive intranasally either LAIV (MedImmune Vaccines, Inc, formerly Aviron; Mountain View, CA) [TC group] or placebo (TP group).15 Subjects underwent clinical evaluation, spirometry, and serum collection for antibody 3 to 4 weeks after immunization. From November 1998 through April 1999, the subjects were evaluated when they had either three symptoms of acute respiratory illness (new-onset or increased chronic cough, new-onset or increased sputum production, increased dyspnea, chills, headache, myalgias, widespread aches and pains, malaise, sore throat, and nasal congestion) or fever accompanied by two symptoms of acute respiratory illness.

Nasopharyngeal swab specimens and serum samples were obtained for viral culture and antibody, respectively, to detect influenza virus infection. If the subjects could not come to the clinic, information regarding the acute respiratory illness was gathered by telephone. Three to 4 weeks after the onset of acute respiratory illness, the subjects were asked to return to clinic to provide a second serum sample for antibody testing. LDI was defined as the sudden onset of respiratory illness plus the following: (1) a nasal swab culture positive for wild-type influenza virus A or B; and/or (2) a fourfold increase in the end point titer of serum hemagglutination inhibition antibodies to influenza A or B.153940 A final study visit consisting of a clinical evaluation and spirometry was scheduled for each subject between April and July 1999.

Severity of illness was assessed using the symptom-based, chronic lung disease severity index (CLDSI) that was developed as part of the Veteran’s Health Study414243 to evaluate functional status and well-being and the effects of chronic lung disease on general health-related quality of life. The chronic lung disease questionnaire is a self-reported rating of the severity of six symptoms: frequency of dyspnea, severity of dyspnea on exertion, frequency of wheezing, severity of wheezing on exertion, frequency of cough, and quantity of sputum production in the preceding three months. The CLDSI combines the unweighted raw scores from the scales used to quantify the rating of each of the six symptoms. The raw CLDSI score ranges from 6 (best) to 27 (most severe).41

The statistical analysis included the first episode of acute respiratory illness for each subject that occurred > 7 days after vaccination, and that met the study definition of acute respiratory illness. The analysis included only the first episode of illness, not later episodes in the same subject, because the earlier illness could affect the characteristics of the later illness and the number of later illnesses was small. The study population was divided into three "illness groups": those whose first respiratory illness was an LDI-caused illness, those whose first respiratory illness was a non-LDI-caused illness, and those who did not have a respiratory illness.

We compared changes in mean FEV1, PPFEV1, and CLDSI score between study visits. A 15% change in FEV1 between study visits was considered clinically significant, as described.3844 A 15% change in CLDSI score between study visits was an arbitrary change chosen to categorize study subjects.

The {chi}2 test or Fisher exact test were used to compare categorical characteristics of the three illness groups, and the Wilcoxon rank-sum test was used to compare continuous characteristics. As a correction for multiple comparisons, p < 0.01 was considered statistically significant.

Logistic regression and {chi}2 analysis were used to identify the univariate association of the following seven preselected variables with change in spirometry and change in CLDSI score: vaccine treatment group, illness group, and baseline current smoking status, age, FEV1, PPFEV1, and CLDSI score. Stepwise multiple logistic regression that included these seven variables was used to identify factors independently associated with 15% changes in FEV1 and CLDSI score. The p value for entry into the logistic model was 0.10, and the p value to stay in the model was 0.05. Similar logistic regression and {chi}2 analysis within each illness group were used to identify associations of the remaining six variables with at least a 15% improvement in CLDSI score.

Results

Characteristics of the Study Population
We enrolled and vaccinated 2,215 subjects. During the study follow-up, 715 acute respiratory illnesses were identified. Excluding 37 illnesses that were not assessed for influenza or that occurred within 7 days of vaccination, and 93 illnesses that occurred after the first acute respiratory illness, our present analysis includes 585 subjects with first episodes of acute respiratory illness (94 LDI-caused and 491 non-LDI-caused illnesses) and 1,630 subjects who did not have an illness. Of the 94 patients whose first illness was an LDI, 59 patients had type A/H3N2, 5 patients had A/H1N1, 24 patients had B virus, 3 patients had influenza viruses A and B, and 3 patients had both influenza A subtypes. Nineteen of the 94 LDI-caused illnesses (20%) were confirmed by culture, and the remainder were confirmed by serologic testing. A change in serum antibody titer was not used to diagnose an LDI-caused illness if the acute respiratory illness occurred within 28 days after vaccination.

Characteristics of the study population are shown in Table 1 . The LDI and non-LDI groups were more likely than the group without acute respiratory illness to be hospitalized, and the non-LDI group was more likely to be treated with prednisone during the study and have at least one additional acute respiratory illness (Table 1).


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  		Table 1. Characteristics of Enrolled Subjects*

 
Near-Term Effects of Acute Illness
Mean FEV1 and PPFEV1 were significantly lower at the time of the acute respiratory illness in both the LDI and non-LDI groups compared to the other time points (Table 2 ). Both groups recovered to preillness levels 3 to 4 weeks after the acute illness visit. Higher proportions of subjects in both illness groups at the acute illness visit had at least a 15% decrement in FEV1 compared to the prevaccination time point than at either the time point 3 to 4 weeks after vaccination or the time point 3 to 4 weeks after illness. The proportion of subjects with an LDI-caused illness who had least a 15% decrement in FEV1 at the acute illness visit compared to the time point 3 to 4 weeks after vaccination (48%) was twice the proportion of subjects with a non-LDI-caused illness and a 15% decrement (24%) [Table 3 ].


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  		Table 2. Means of FEV1, PPFEV1, and CLDSI Score by Illness Group and Study Time Point*

 

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  		Table 3. Proportions of Subjects With at Least 15% Changes in FEV1 and CLDSI Score at Follow-up in Association With First Acute Respiratory Illness*

 
The mean CLDSI score was higher, indicating worse score, at the acute illness visit than at the two previous visits in both illness groups (Table 2). Compared to the prevaccination time point, higher proportions of subjects in both illness groups at the acute illness visit and at the time point 3 to 4 weeks after illness had at least a 15% worsening in CLDSI score compared to before vaccination than at the time point 3 to 4 weeks after vaccination (LDI-caused illness group, 56% and 46% vs 25%; non-LDI-caused illness group, 44% and 37% vs 24%) [Table 3]. The proportion of subjects with an LDI-caused illness who had at least a 15% worsening in CLDSI score at the acute illness visit compared to 3 to 4 weeks after vaccination (52%) was greater than among subjects with a non-LDI-caused illness (35%) [Table 3]. A higher proportion of subjects with a non-LDI-caused illness had at least a 15% improvement in CLDSI score at 3 to 4 weeks after illness compared to 3 to 4 weeks after vaccination (15%) than subjects with an LDI-caused illness (5%) [Table 3].

Longer-Term Effects of Acute Illness
The three groups had similar proportions of subjects with at least a 15% decrement in FEV1 at the end of the study compared to before vaccination (LDI-caused illness group, 15 of 88 subjects [17%]; non-LDI-caused illness group, 99 of 462 subjects [21%]; and no-illness group, 297 of 1,365 subjects [22%]). Stepwise logistic regression with the seven prespecified variables found that a decrement in FEV1 of at least 15% at the end of study time point compared to the prevaccination time point was statistically associated only with higher prevaccination CLDSI score (≥ 15% decrement in FEV1 vs < 15% decrement in FEV1: mean prevaccination CLDSI score ± SD, 18.0 ± 4.1 vs 17.3 ± 4.4, respectively; odds ratio [OR], 1.04; 95% confidence limit [CL], 1.01 to 1.07; p < 0.01).

Stepwise logistic regression with all seven variables found that receipt of TC (p < 0.01), not having either an LDI-caused or non-LDI-caused illness (p < 0.01), higher baseline PPFEV1 (p < 0.0001), and higher CLDSI score (p < 0.0001) were statistically associated with at least a 15% improvement in CLDSI score (Table 4 ). LDI-caused or non-LDI-caused illness, lower PPFEV1, better baseline CLDSI score (each at p < 0.0001), and older age (p < 0.05) were associated with at least a 15% worsening in CLDSI score (Table 4).


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  		Table 4. Univariate and Stepwise Multivariate Logistic Regression Analyses of Associations With at Least a 15% Improvement and Worsening in the CLDSI Score at the End of the Study Compared to the Prevaccination Time Point*

 
We further examined the LDI-caused illness, non-LDI-caused illness, and no-illness groups separately to test whether the six remaining independent variables were statistically associated with at least a 15% improvement in CLDSI score at the end of study time point compared to the prevaccination time point. Only the non-LDI-caused illness group showed a statistical association between receipt of TC and an improvement in CLDSI score of at least 15%: 48 of 237 subjects (20%) in the TC group, and 24 of 239 subjects (10%) in the TP group with a ≥ 15% improvement in CLDSI score (OR, 2.23; 95% CL, 1.30 to 3.83; p < 0.01).

Discussion

These chronically ill patients with COPD showed statistically significant changes in FEV1 and PPFEV1 during acute respiratory illness, whether due to influenza or another respiratory pathogen. The proportion of subjects with a clinically significant worsening in FEV1 was twice that among subjects with LDI-caused illness than among those with a non-LDI-caused illness (48% vs 24%). Changes in the CLDSI score corroborated the worsening in obstruction to airflow observed early during acute respiratory illness. A worsening in CLDSI score was also observed more frequently in patients early during LDI-caused illness than in non-LDI-caused illness (52% vs 35%). The lower proportion of subjects with improvement in CLDSI score 3 to 4 weeks after an LDI-caused illness than a non-LDI-caused illness (5% vs 15%) suggested slower clinical recovery after an LDI-caused illness.

Interestingly, the LDI-caused and non-LDI-caused illness groups were more likely to be hospitalized and the non-LDI-caused illness group to receive treatment with prednisone during the study than the group without acute respiratory illness. These measures of health-care utilization corroborate the severity of illness suggested by the worsening in CLDSI score in the two illness groups and the improvement in CLDSI score in the no-acute illness group over the course of the study. These findings emphasize the clinical importance of acute respiratory illness and suggest longer-term effects continued at the end of the winter season.

Receipt of TC, as compared to receipt of TP, was independently associated with improvement in CLDSI score over the course of the study. Although the primary analysis of efficacy did not show a relationship between LDI-caused illness and vaccine group,15 possible interpretations of the current analysis and that of the primary report15 support an effectiveness advantage for TC. The association between TC and improved CLDSI score was strongest in the non-LDI-caused illness group; however, influenza vaccine would be expected to protect only against influenza. One possible explanation may be a nonspecific innate antiviral resistance to other heterotypic viral infections for a period of time after receipt of live attenuated influenza virus vaccine.454647 Also, some illnesses due to influenza may not have been detected by culture and serology, and other illnesses due to influenza may have been mild enough to not have met study criteria for assessment of LDI at all. These possible vaccine effects may have affected clinical course without detectable differences in LDI rates between vaccine groups.

We did not attempt to characterize non-LDI-caused illnesses microbiologically; therefore, we can only speculate that some were due to one of a variety of respiratory viruses and others due to bacterial infection. Among patients with LDI-caused illness in our study, despite influenza vaccination, acute illness was more severe than in patients with non-LDI-caused illness. Smith et al14 reported that influenza was associated with a greater decline in FEV1 than other viral infections. We previously reported that fever and myalgia were symptoms most closely associated with LDI.48

In summary, acute respiratory illnesses were associated with worsening in functional status and health-related quality of life and higher health-care utilization at the end of the winter respiratory virus season. In this influenza-vaccinated population, non-LDI-caused illness was an important contributor to longer-term effects of acute respiratory disease, and LDI-caused illness was associated with worse changes in obstruction to airflow and functional status acutely. Receipt of TC was associated with a better CLDSI score at the end of the study. Thus, further evaluation of TC in older adults with COPD may be warranted.

Acknowledgements

We thank Joseph N. Vitale for data analysis and statistical programming and Eric Valdivia for secretarial assistance.

Footnotes

Abbreviations: CL = confidence limit; CLDSI = chronic lung disease severity index; LAIV = trivalent, live-attenuated, cold-adapted influenza virus vaccine; LDI = laboratory-documented influenza; OR = odds ratio; PPFEV1 = percentage of predicted FEV1; TC = trivalent inactivated influenza virus vaccine and intranasal trivalent, live-attenuated, cold-adapted influenza virus vaccine; TIV = trivalent inactivated influenza virus vaccine; TP = trivalent inactivated influenza virus vaccine plus intranasal placebo; VA = Veterans Affairs

Financial support was provided by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development and by Aviron.

This study was performed at 20 VA clinical study sites: Ann Arbor, MI; Bay Pines, FL; Birmingham, AL; Boston, MA; Cleveland, OH; Dallas, TX; Dayton, OH; Durham, NC; Gainesville, FL; Houston, TX; Long Beach, CA; Minneapolis, MN; North Chicago, IL; Palo Alto, CA; Richmond, VA; Salt Lake City, UT; San Juan, Puerto Rico; Sepulveda, CA; St. Louis, MO; and Tucson, AZ. The biostatistical center site was the VA Cooperative Studies Program Coordinating Center, West Haven, CT.

Dr. Wittes is a consultant of MedImmune Vaccines, Inc. (formerly Aviron) [Mountain View, CA], which is the manufacturer of the trivalent, live-attenuated, cold-adapted influenza virus vaccine. The other authors have no financial or other potential conflicts of interest.

Received for publication October 31, 2005. Accepted for publication March 21, 2006.

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