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MAJOR ARTICLE

Vaccinated Children and Adolescents With
Pertussis Infections Experience Reduced Illness
Severity and Duration, Oregon, 2010–2012
Russell S. Barlow,1,2,3 Laura E. Reynolds,1 Paul R. Cieslak,4 and Amy D. Sullivan1
1

Communicable Disease Services, Multnomah County Health Department, Portland, Oregon; Departments of 2Immunology and 3Global Health, University of
Washington, Seattle and 4Oregon Health Authority, Public Health Division, Portland

Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 15, 2014

(See the Editorial Commentary by Mertsola on pages 1530–2.)

Background. Bordetella pertussis causes severe respiratory illness among infants and adolescents. High proportions of breakthrough infection have been observed. To understand the effect of vaccination in the era of acellular
pertussis vaccines (DTaP and Tdap), we assessed if vaccination status is associated with disease severity and duration.
Methods. The Multnomah County Health Department conducts enhanced pertussis surveillance for 1.7 million
residents in the Portland, Oregon, metropolitan area. Surveillance activities include ascertaining demographics, clinical presentation, cough duration, vaccination history, and other health outcomes. Utilizing Advisory Committee on
Immunization Practices (ACIP) routine vaccination recommendations, we analyzed a cohort of persons aged 6 weeks
to 18 years with confirmed pertussis to assess illness severity and duration by vaccination status. Analysis was conducted using both logistic regression (disease severity) and survival analysis (cough duration).
Results. During 2010–2012, 98.7% (n = 624) of patients with confirmed pertussis in our cohort had vaccination,
treatment, demographic, and outcome information. Among these patients, 45% (n = 286) were ACIP up to date with
vaccinations. Ever-vaccinated cases were significantly less likely to be hospitalized or develop severe illness (adjusted
odds ratio [aOR], 0.2; 95% confidence interval [CI], .1–.8 and aOR, 0.4; 95% CI, .2–.9, respectively). ACIP up-to-date
patients stopped coughing significantly more rapidly than unvaccinated patients (adjusted hazard ratio, 1.7; 95% CI,
1.3–2.2).
Conclusions. Patients with pertussis vaccination had decreased morbidity characterized by less severe illness and
significantly reduced illness duration. Therefore, vaccination is recommended among at-risk individuals, and research into the nature of the residual vaccine immunity is warranted.
Keywords.

Bordetella pertussis; epidemic; vaccines; epidemiology; surveillance.

Pertussis is a highly contagious, vaccine-preventable respiratory infection caused by the bacterium Bordetella
pertussis. Infections typically result in prolonged morbidity characterized by paroxysmal cough, posttussive
vomiting, and inspiratory whoop. Life-threatening
cases can present with acute encephalopathy, seizures,

Received 6 September 2013; accepted 1 February 2014; electronically published
14 March 2014.
Correspondence: Amy D. Sullivan, PhD, MPH, Communicable Disease Services,
Multnomah County Health Department, 426 SW Stark St, 3rd Floor, Portland,
OR 97214 (amy.d.sullivan@multco.us).
Clinical Infectious Diseases 2014;58(11):1523–9
© The Author 2014. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/ciu156

or pneumonia [1]. Children most commonly present
with classic “whooping cough”; life-threatening cases
generally occur in a small subset of infants. The prolonged illness course causes significant morbidity with
its associated social and economic burden [2, 3].
Despite initial successes from immunization, pertussis
has been increasing since the 1980s, especially among adolescents, although the most severe disease is still seen
among infants [4–6]. In 2000, the Advisory Committee
on Immunization Practices (ACIP) recommended immunizations with acellular diphtheria, tetanus, and acellular pertussis (DTaP) vaccine at ages 2, 4, 6, and 15
months and 4 years [7]. In 2005, amidst concerns
about waning immunity, ACIP recommended an additional booster (Tdap) for adolescents and adults [8]. In

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METHODS
Study Population and Oregon’s Reportable Infectious Disease
Surveillance System

In collaboration with the Centers for Disease Control and Prevention’s National Center for Immunization and Respiratory Diseases Meningitis and Vaccine Preventable Diseases Branch and
Oregon’s Acute and Communicable Disease Program, the Multnomah County Health Department conducts enhanced pertussis
surveillance for the Portland metropolitan area. The 1.7 million
people in this area account for 43% of Oregon’s population, with
>25% of the population aged <19 years [19, 20]. Pertussis vaccination is compulsory for Oregon children in school or licensed
childcare facilities. Although Oregon’s nonmedical vaccine exemptions are higher than the national median, DTaP and DTP
(whole cell) coverage reflects national levels (ie, 94% vs 95%,
respectively, for kindergarten-aged children in 2012) [21].
Physicians and laboratories are legally required to report laboratory-confirmed and clinically suspected cases of pertussis to
local health departments, along with patient demographic and
clinical data. Within 24 hours of notification, community health
nurses interview patients about symptoms, hospitalization status, clinical outcomes, and exposures. For enhanced surveillance, data monitoring for consistency and completeness is
performed on a monthly basis; detailed immunization data
are collected; and patients are contacted every 2–3 weeks until

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Barlow et al

cessation of cough, cough duration exceeds 100 days, or inability to contact (3 phone calls and a mailed letter).
Pertussis Case Definition

We used the 1997 CSTE criteria [17]: Confirmed cases involved
cough of any duration with a positive culture; or a cough of ≥14
days’ duration with paroxysms of cough, inspiratory whoop, or
posttussive vomiting accompanied by (1) a positive PCR result
or (2) epidemiological linkage to a confirmed case. We included
CSTE-confirmed cases of B. pertussis from the Portland metropolitan area with onset between 1 August 2010 and 31 July
2012. Given limited availability of vaccination information for
adults, we included only patients <19 years of age. Cases with
nonpertussis Bordetella were excluded.
We considered a patient to have severe pertussis-related illness if the person developed pneumonia, acute encephalopathy,
or seizures; or if the person was hospitalized with these or any
other pertussis-related condition. We evaluated demographic
information and risk factors for hospitalization and pneumonia
separately, as well as assessing any indication of severe illness.
Vaccination Status Determination

Only provider-documented doses of vaccine were included in
our assessment of vaccination status. Vaccination history was
obtained by (1) querying Oregon’s “ALERT” immunizations information system for dates, type, and manufacturer, and (2) faxing providers for vaccination dates and related information. The
ALERT system contains immunization data entered by healthcare providers in Oregon.
Vaccination status was determined according to the ACIP
recommendations for routine and catch-up vaccination schedules. ACIP-recommended doses include DTaP or DTP administered at 2, 4, 6, and 15 months, and 4 years and a single Tdap
booster at age ≥11 years [5, 6]. Patients who had their fourth
DTaP dose after the age of 4, or those who had their Tdap
after age 7 are considered up to date. A 14-day grace period
was allowed for persons to obtain vaccine prior to being considered not up to date. Per the ACIP schedule, shots were considered invalid if they were administered at <6 weeks of age; if
spacing was <28 days for DTaP shots 1–3, <121 days between
shots 3 and 4, and <182 days between shots 4 and 5; and if
any vaccine shot was administered <14 days prior to symptom
onset. Previous immunizations with whole-cell vaccine (DTP)
were also considered valid if dose timing and spacing were
appropriate.
Persons meeting the age-appropriate ACIP criteria for immunization were classified as up to date (UTD). Persons who
received prior pertussis immunizations but failed to meet the
age-appropriate ACIP criteria were classified as previously vaccinated, not up to date (NUTD). Persons with no documented
doses were classified as unvaccinated.

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2010 and 2012, the United States experienced its highest rates of
pertussis in 5 decades [9]. During these years, studies found conflicting results about the effectiveness, durability, and protection
provided by the current vaccines [10–14]. In Oregon during 2012,
the state recorded its highest case counts since the 1950s, with
>60% of patients aged <20 years up to date on their pertussis immunizations. Although vaccine breakthrough infections accounted for a high proportion of disease burden, unvaccinated persons
were up to 50 times more likely to acquire pertussis [15].
Although international studies have reported decreased illness severity among patients with vaccine breakthrough [16,
17], we identified no US studies examining illness outcomes
among such patients in the years since acellular DTaP and
Tdap vaccines were introduced and routine polymerase chain
reaction (PCR) testing was implemented. The latter is important, as the national Council of State and Territorial Epidemiologists (CSTE) case definition was updated to include this test
[18]. Given the significant morbidity and societal costs associated with pertussis infections, reductions in the duration and
magnitude of illness can have an important public health impact [2]. Utilizing data from the Portland metropolitan area’s
enhanced pertussis surveillance program from 1 August 2010
to 31 July 2012, we tested the hypothesis that patients with vaccine breakthrough have decreased illness duration and severity.

Analysis

RESULTS

Table 1. Pertussis Cohort Case Demographics and Clinical
Characteristics—Portland, Oregon, Metropolitan Area, 2010–2012
(n = 624)
Characteristic

No.

%

327

52.4

297

47.6

Sex
Female
Male
Age group
6 wk to <6 mo

52

8.3

6 to <15 mo
15 mo to <4 y

35
85

5.6
13.6

4 to <7 y
7 to <11 y
11 to <19 y
Race
White
Nonwhite
Ethnicity
Hispanic
Non-Hispanic
Unknown
Laboratory test resulta
PCR positive
Culture positive
PCR and culture negative (epi-linked)

84

13.5

148
220

23.7
35.3

548

87.8

76

12.2

131

20.9

473

75.8

20

0.3

440

86.4

88
96

15.9
15.4

466
144

74.8
23.1

14

2.2

12

1.9

Antimicrobial therapy
≤20 d following onset
>20 d following onset
None
Severe illness outcomesa
Hospitalized
Radiography positive for pneumonia
Acute encephalopathy
Seizures
Any severe illness
Vaccination status
Unvaccinated

19

3.0

2
3

<0.1
<0.1

31

5

171

27.4

Previously vaccinated, not up to date

167

26.8

Up to date

286

45.8

Abbreviation: PCR, polymerase chain reaction.
a

Descriptive Epidemiology

Case counts for laboratory test results and severe illness outcomes are not
mutually exclusive.

From 1 August 2010 to 31 July 2012, we received 753 case reports for pertussis that met the CSTE-confirmed case definition.
Among these, 633 were for children aged 6 weeks to 18 years; of
these, 624 (98.7%) had vaccination history and illness data including cough duration.
The median age was 9 years (interquartile range [IQR], 3–12
years). Just over half of patients (52.5%) were female (Table 1).
Seventy-five percent (n = 457) of patients initiated therapy <20
days following cough onset (98% received azithromycin). Nineteen patients (3%) had positive chest radiography for pneumonia, and 12 (2%) were hospitalized. Two children developed

acute encephalopathy, and 3 developed seizures. There were
no deaths.
The majority of patients (54%) were either unvaccinated (171
[27%]) or previously vaccinated, NUTD (167 [27%]); 286 (46%)
were UTD (Table 1). Of the 453 persons ever vaccinated, 93%
(n = 422) received acellular pertussis vaccines only. Among the
31 persons receiving whole-cell vaccines, all were >7 years old
(94% also received acellular vaccine). Nine (approximately 1%)

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We assessed our primary exposure (vaccination status), outcomes (severe illness and cough duration), and potential confounders and effect modifiers using univariate and bivariate
statistics. Potential confounders or effect modifiers included demographic variables (age, sex, race, ethnicity) and receipt of antimicrobial therapy. The latter has been shown to reduce cough
duration [22]. Based on clinical trial findings, antimicrobial
therapy was considered only when initiated within 20 days of
illness onset [23].
To assess vaccination status with respect to severe illness,
multiple logistic regression models were constructed including
variables that were significant at the P < .25 level in unadjusted
analyses. Further consideration was based on clinical importance or relevance for external validity. Predictor variables significant at P < .05 were retained in the final model, adjusted log
odds ratios (aORs) were calculated, and model fit was assessed
via the Hosmer-Lemeshow test.
To assess whether vaccination status influenced cough duration, we performed a time-to-event analysis with cessation of
cough as the event. The Kaplan-Meier method was utilized
for estimation of the cumulative probability of cough cessation.
Demographic variables and risk factors were examined individually and log-rank tests were performed. Related linear regression and nonparametric analysis of variance was performed
using the Kruskal-Wallis test. Cox proportional hazards models
used variables that were significant at the P < .25 value. Variables significant at P < .05 were retained in the final model,
and adjusted hazard ratios (aHRs) were calculated. Interactions
were retained if significant at the P < .05 level. Model proportionality was confirmed in the final main effects model.
All analyses were performed using SAS version 9.2 software
(SAS Institute, Cary, North Carolina). This study was considered public health practice and consisted only of analysis of routinely collected reportable disease data.

patients >10 years old received only a single Tdap (Supplementary Table 1).

Vaccinated Patients Are Less Likely to Develop Severe Illness

Patients were followed for 35 629 person-days (median, 56
[IQR, 33–81]; range, 14–100 person-days). Sixty-seven percent
of patients (n = 420) stopped coughing during the study period
and 19% (n = 117) were lost to follow-up. Persons lost to followup (censored) accounted for 5219 person-days of follow-up
(median, 34 [IQR, 21–70]; range, 14–98 person-days). A higher
proportion of unvaccinated patients were lost to follow-up
(23%) compared with UTD (17%) and NUTD patients (17%),
although this was not significant (P = .08 and P = .17, respectively). There was no significant difference in the follow-up
time among unvaccinated and vaccinated patients who were
censored (median, 36 vs 31 person-days, respectively; P = .41).
To evaluate whether vaccination status was a proxy for access to
healthcare, we examined the interval from illness onset to treatment initiation. Vaccinated patients initiated treatment later
than unvaccinated patients (median, 10 vs 8 days, respectively;
P = .05). The percentage of vaccinated vs unvaccinated patients
who received treatment did not significantly differ (76% vs 68%,
respectively; P = .10). These data suggest that vaccinated and unvaccinated patients did not have healthcare access differences.
Race, ethnicity, sex, and age were not associated with cough
duration. However, any vaccination and antimicrobial therapy
were associated with cough resolution (Figure 1). To confirm
that severe illness outcomes alone did not independently explain these associations, a dichotomous severe illness variable
was fixed in all models. No interactions were identified. The
final model included vaccination status, antimicrobial therapy
(time-dependent), severe illness, and age (Table 3). This
model did not depart from proportionality (P = .16).
To assess whether including treatment in a time-dependent
manner was influencing our results, a treatment interval–
stratified model was constructed with the following strata:

Table 2. Associations of Vaccination Status With Clinical
Outcomes, Multiple Logistic Regression Analysis—Portland,
Oregon, Metropolitan Area, 2010–2012 (n = 624)

Outcome

No.

% Ever
Vaccinated

612

73.5

OR (95% CI)

Age-Adjusted
OR (95% CI)

Hospitalized
No

Referent

Yes
12
25.0
Positive radiograph for pneumonia
No

0.1 (.0–.4)

605

73.1

Referent

Yes
19
Severe illnessa

57.9

0.6 (.2–1.3)

No

593

73.9

Referent

Yes

31

48.4

0.3 (.2–.7)

0.2 (.1–.8)

0.6 (.2–1.6)

0.4 (.2–.9)

Abbreviations: CI, confidence interval; OR, odds ratio.
a

Illness that resulted in hospitalization, pneumonia, acute encephalopathy, or
seizures.

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Barlow et al

Figure 1. Kaplan-Meier estimates of the cessation of cough by patient
vaccination status—Portland, Oregon, metropolitan area, 2010–2012
(n = 624).

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Both UTD and NUTD patients had decreased odds of hospitalization compared with unvaccinated patients (odds ratio [OR],
0.1 [95% confidence interval {CI}, .0–.6] and OR, 0.1 [95% CI,
.0–.9], respectively). Similarly, UTD and NUTD patients had reduced frequencies of pneumonia compared with unvaccinated
patients (OR, 0.5 [95% CI, .2–1.4] and OR, 0.5 [95% CI,
.1–.7], respectively). For the combined outcomes reflecting
any severe illness, both UTD and NUTD patients were significantly less likely than unvaccinated patients to suffer severe illness (OR, 0.4 [95% CI, .2–.8] and OR, 0.3 [95% CI, .1–.8],
respectively).
Given similar point estimates for all illness outcomes, we assessed confounding after collapsing UTD and NUTD groups to
improve statistical power (“ever-vaccinated”). Sex, race, and ethnicity did not confound the observed associations. Treatment
was not assessed as it was coincident with severe illness and
lacked temporality (no patients completed treatment prior to
severe illness onset or diagnosis). Age confounded the association between vaccination status and the severe illness.
After adjusting by age, ever-vaccinated patients were 5 times
less likely to be hospitalized and 2.5 times less likely to develop
severe illness compared with unvaccinated patients (Table 2).
Ever-vaccinated patients were less likely to develop pneumonia,
although this association was not significant. Stratified analysis
of infants aged 6 weeks to <6 months, 6 weeks to <1 year, and
patients aged 1–18 years yielded consistently protective point
estimates, with the largest magnitude of protection observed
among infants (Supplementary Tables 2–4).

Vaccinated Patients Have a Shortened Duration of Illness

Table 3. Hazard Ratios for Cough Cessation Among Patients With Confirmed Pertussis, Cox Proportional Hazards Regression—Portland,
Oregon, Metropolitan Area, 2010–2012 (n = 624)

Variable
Vaccination status
Unvaccinated

No. Events/Total No.

% With Event

HR (95% CI)

Parameter
Estimate

Adjusted HR
(95% CI)a

P Value

97/171

56.7

Referent

118/167

70.7

1.4 (1.1–1.9)

0.38

1.5 (1.1–1.9)

<.01

205/286

71.7

1.6 (1.3–2.1)

0.52

1.7 (1.3–2.2)

<.01

104/167
316/457

62.3
69.2

Referent
1.3 (1.1–1.6)

0.25

1.3 (1.0–1.6)

.03

403/593
17/31

62.3
54.8

Referent
0.6 (.4–1.0)

−0.46

0.6 (.4–1.0)

.07

6 wk to <15 mo
15 mo to <4 y

54/87
54/85

62.1
63.5

Referent
0.8 (.6–1.2)

−0.19

0.8 (.6–1.2)

.33

4 to <7 y

58/84

69.1

1.0 (.7–1.5)

−0.07

0.9 (.6–1.4)

.72

104/148
150/220

70.3
68.2

0.9 (.7–1.3)
0.9 (.7–1.2)

−0.29
−0.35

0.7 (.5–1.1)
0.7 (.5–1.0)

.09
.04

Previously vaccinated,
not up to date
Up to date
Antimicrobial therapy
No
Yes
Severe illnessb
No
Yes

7 to <11 y
11 to <19 y

Abbreviations: CI, confidence interval; HR, hazard ratio.
a

Adjusted by age, vaccination status, antimicrobial therapy, and/or severe illness.

b

Illness that resulted in hospitalization, pneumonia, acute encephalopathy, or seizures.

<8 days, 8 to <14 days, 14 to <21 days, and ≥21 days or no treatment following cough onset. Upon stratification, we found no
significant changes (>10%) for any of our point estimates (Supplementary Table 5). Therefore, we chose to retain antimicrobial therapy in the model as a time-dependent covariate.
Subanalysis including only patients who were retained
throughout the study period produced the same overall
model, and no point estimate was changed by >10% (Supplementary Table 6). Stratified analysis of DTaP-eligible (6 weeks
to 10 years) and Tdap-eligible (10–18 years) patients yielded
similar models (Supplementary Tables 7 and 8). Exclusion of
patients who received any whole-cell pertussis vaccines yielded
the same model (Supplementary Table 9).
In all models, ever-vaccinated patients (UTD and NUTD)
were significantly more likely than unvaccinated patients to
have stopped coughing within 100 days compared with unvaccinated patients (Table 3). Patients who initiated treatment
within 20 days of illness onset were 30% more likely than untreated persons to have stopped coughing, whereas patients
with severe illness were more likely to have had a persistent
cough, although this was not significant. Finally, patients between 11 and 18 years of age were more likely to have a persistent cough compared with patients 6 weeks to 15 months of age.
We also modeled 20-day cough duration separately, as this is
the period when patients are most infectious [21]. During this

study period, UTD patients were significantly more likely than
unvaccinated patients to have stopped coughing (aHR, 3.7 [95%
CI, 1.1–13.2]; Supplementary Table 10). This association was
preserved after adjusting for antimicrobial therapy, and age
and did not violate the proportionality assumption (P = .58).
DISCUSSION
In our cohort of Oregon children and adolescents with pertussis, we found that previously vaccinated patients, especially infants, are less likely than unvaccinated peers to develop severe
illness. Likewise, regardless of age, vaccinated patients exhibited
a significantly reduced duration of cough, the primary cause of
morbidity in uncomplicated pertussis. Vaccinated patients were
also more likely to stop coughing within 20 days of illness onset,
potentially representing a reduction in case infectivity. Our
findings obtained in a US cohort covered by predominantly
acellular pertussis vaccine, utilizing PCR-inclusive case definitions, build upon international studies performed during the
pre–acellular vaccine era that suggested that pertussis vaccination reduces illness severity, duration, and disease transmission
[15, 16].
We found that even incomplete vaccination conferred protection against serious disease. This finding has implications for
future studies, as collapsing undervaccinated patients with

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Age group

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Barlow et al

There are multiple plausible explanations for our findings.
The acellular pertussis vaccines are formulated with 3–5 specific
bacterial antigens and have been shown to induce both humoral
and prolonged cellular immunity [25–27]. However, differentially waning immunity to some antigens could enable susceptibility to infection, whereas the residual immunity could explain
the reduced illness severity. Alternatively, bacterial evasion of
the humoral immune response could allow for establishment
infection, whereas residual cellular immunity may limit severity
and duration [28–30]. Research into the nature of the protective
immune response may aid future vaccine development.
Pertussis has reemerged to epidemic levels in the United
States despite high rates of vaccination [4, 10–14, 31, 32]. Although pertussis vaccination alone may not completely prevent
illness, even incomplete vaccination decreases cough duration
and protects against severe disease manifestations. Our results
suggest that the current ACIP immunization guidelines are
effective at limiting individual-level pertussis severity and morbidity. However, reducing the high proportion of breakthrough
infections at the population level may necessitate improved vaccine formulations and wider coverage. Also, as the protective
effect of vaccination was found to be independent of antimicrobial therapy, both vaccination and early treatment strategies are
likely important for improving outcomes. We recommend adherence to the ACIP vaccination guidelines and early treatment
initiation, and welcome future research into the relationship between pertussis vaccination and disease burden.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online
(http://cid.oxfordjournals.org). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the
sole responsibility of the authors. Questions or messages regarding errors
should be addressed to the author.

Notes
Acknowledgments. We thank Gretchen Barron, Kathy Chilton, James
Gaudino, Sandy Holden, Juventila Liko, Sandra Matossian, and Katherine
Segnitz (Multnomah County Health Department, Oregon Health Authority) for help with contacting providers, obtaining vaccination information,
providing constructive input, and interviewing patients. We also thank the
Oregon residents who participate in disease investigation interviews, and
their contributions to the health of their communities.
Disclaimer. The contents of this work are solely the responsibility of
the authors and do not necessarily represent the official views of the Centers
for Disease Control and Prevention.
Financial support. This publication was supported by the Centers
for Disease Control and Prevention (cooperative agreement number
5U50CK00197).
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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unvaccinated patients in assessments of vaccine efficacy could
obscure important benefits of vaccination [10, 11, 24]. Furthermore, vaccination before and treatment after illness onset may
be important for limiting pertussis transmission. In our cohort,
we found reduced cough duration following receipt of antimicrobial therapy. The dual effects of vaccination before illness
and treatment after onset could decrease disease transmission
as well as severity. This point has programmatic implications
for encouraging parents and providers to pursue a pertussis
control strategy that includes vaccination, early diagnosis, and
treatment, and may prove useful for future pertussis transmission modeling.
A strength of our approach was access to data from a large
metropolitan enhanced surveillance system where 99.5% of reported patients had complete vaccination histories, >98% of patients completed disease interviews, and cough duration was
assessed prospectively. Data was collected on a number of
known and potential confounding factors before vaccination status was ascertained. Because defining vaccination status by calculating the interval from vaccination to illness onset or counting
the number of immunizations can introduce biases due to the cyclical nature of pertussis disease and the age dependency of these
classifications (Supplementary Tables 1 and 11), using the ACIP
vaccination recommendations provided an appropriately conservative measure of vaccination status. These classifications, combined with CSTE case definitions, provided high specificity,
improved generalizability, and minimized biases [5, 6, 18]. Significant findings from our distinct analyses suggest that these associations were unlikely to occur by chance. The pooled analysis of
patients who received acellular and whole-cell pertussis vaccines
was found to be appropriate based on results from acellular-only
subanalyses (Supplementary Table 9).
The observational nature of this study has limitations. All
surveillance data carry a risk of biased case ascertainment,
which could have influenced our analyses if unvaccinated patients with severe illness were more likely to seek healthcare
or be reported. However, analysis of treatment patterns suggested that access to healthcare did not differ by vaccination status.
The use of provider-documented vaccinations and clear vaccine
status definitions reduced the possibility that misclassification
of vaccination status influenced our results. Missing immunizations data for persons ever vaccinated would only have served to
make our groups more alike, resulting in an underestimate of
the true effect. Although differential loss to follow-up for
cough duration could have influenced our results, we found
no significant differences in loss to follow-up or duration of
time followed with respect to vaccination status, suggesting
that this potential bias was nondifferential. Reduced cough duration among vaccinated patients was not explained by a lower
proportion of severe illness in this group, as this factor was controlled for in our analysis.

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