Open Forum Infectious Diseases MAJOR ARTICLE
Risk Factors for Herpes Zoster Among Adults Mona Marin,1 Rafael Harpaz,1 John Zhang,1 Peter C. Wollan,2 Stephanie R. Bialek,1 and Barbara P. Yawn2 1
National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Department of Research, Olmsted Medical Center, Rochester, Minnesota
Background. The causes of varicella-zoster virus reactivation and herpes zoster (HZ) are largely unknown. We assessed potential risk factors for HZ, the data for which cannot be obtained from the medical sector. Methods. We conducted a matched case-control study. We established active surveillance in Olmsted County, Minnesota to identify HZ occurring among persons age ≥50 years during 2010–2011. Cases were confirmed by medical record review. Herpes zoster-free controls were age- and sex-matched to cases. Risk factor data were obtained by telephone interview. Results. We enrolled 389 HZ case patients and 511 matched controls; the median age was 65 and 66 years, respectively. Herpes zoster was associated with family history of HZ (adjusted odds ratio [aOR] = 1.65); association was highest with first-degree or multiple relatives (aOR = 1.87 and 3.08, respectively). Herpes zoster was also associated with prior HZ episodes (aOR = 1.82), sleep disturbance (aOR = 2.52), depression (aOR = 3.81), and recent weight loss (aOR = 1.95). Stress was a risk factor for HZ (aOR = 2.80), whereas a dose-response relationship was not noted. All associations indicated were statistically significant (P < .05). Herpes zoster was not associated with trauma, smoking, tonsillectomy, diet, or reported exposure to pesticides or herbicides (P > .1). Conclusions. We identified several important risk factors for HZ; however, the key attributable causes of HZ remain unknown. Keywords. family history; herpes zoster; risk factors; shingles. Herpes zoster (HZ) is caused by the reactivation of varicellazoster virus (VZV) that establishes latency in sensory ganglia after initial infection as varicella. Herpes zoster is a painful and debilitating illness that affects approximately 1 in 3 persons during their lifetime [1]; its morbidity and impacts on quality of life increase with age [2–4]. Although it affects a large number of persons, with an estimated 1 million HZ cases annually in the United States, the causes of VZV reactivation and HZ are not completely known. Older age and immunosuppression are well documented risk factors, attributed to diminished VZVspecific cell-mediated immunity, but they cannot fully explain the epidemiology of HZ [5]. Several other potential risk factors have been evaluated but are unconfirmed or of insufficient prevalence to explain most episodes [5, 6]. Since 2006, a vaccine to prevent HZ has been available and recommended in the United States for use in immune-competent adults age ≥60 years [7, 8]. Other HZ vaccines are currently undergoing development. An understanding of risk factors for HZ is vitally important. Improved awareness of epidemiological risk factors could help inform mechanistic understanding of VZV reactivation and HZ disease. In the context of HZ vaccines, observational studies of HZ vaccine performance cannot be properly evaluated without recognizing key risk factors to know whether their prevalence is
Received 11 April 2016; accepted 6 June 2016. Presented in part: 2015 IDWeek, San Diego, CA. Correspondence: M. Marin, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS A-47, Atlanta, GA 30333. ([email protected]). Open Forum Infectious Diseases® Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/ofid/ofw119
balanced in vaccine recipients and nonrecipients. Furthermore, for unknown reasons, HZ rates have been increasing in the United States for decades [1, 9, 10]. These increases make it impossible to interpret HZ vaccine impact; indeed, HZ increase has made it challenging to interpret long-range clinical vaccine trials because these trials generally use historic controls for long-range follow up [11, 12]. Recognition of key risk factors for HZ could thus make trends interpretable and allow for better assessment of vaccine impact. In addition, a better understanding of these factors may suggest new approaches for prevention and treatment of HZ. Although there is an enormous amount of literature relating to HZ risk factors, most studies have explored factors that can be assessed using medical records or administrative data [5, 8]. However, there are many plausible risk factors for HZ for which information would not typically be available in the medical sector. Given the important unknowns relating to HZ risk, we attempt to fill this gap by conducting an analysis of a large array of potential risk factors for HZ that are based on patient self-report. METHODS Study
We used a matched case-control study design. Herpes zoster cases were identified through active surveillance among residents of Olmsted County, aged ≥50 years, who had healthcare encounters for HZ with onset of HZ between January 1, 2010 and October 12, 2011. As previously reported [13], cases were identified within 72 hours of diagnosis, based on the International Classification of Diseases, Ninth Revision (ICD-9) codes of 053 using the Rochester Epidemiology Project (REP). The REP uses administrative data to link the diagnostic codes with Herpes Zoster Risk Factors
•
OFID
•
1
visits dates, basic demographic and procedure information for persons visiting clinics and hospitals associated with the healthcare providers in the County: ie, Olmsted Medical Center, Mayo Clinic, and Rochester Family Medical Clinic. All cases were confirmed by trained researchers who conducted medical record reviews, applying strict criteria to identify evidence of HZ: ie, documentation of a physician diagnosis of either acute HZ or acute HZ complication accompanied by a description of an acute onset of dermatomal pain and vesicular rash not attributed to other causes. Controls were selected using ICD-9 codes from REP for residents of Olmsted County who sought non-HZ-related medical care at the same clinic and at the closest time before the HZrelated visit date in the matching case [13]. Controls were matched to case patients by date of birth (96% of all adult immunizations in Olmsted County. Potential risk factors were selected based on theoretical plausibility or on suggestive but controversial or inadequately verified prior work. They include the following: family history, previous episode of HZ, stress, injury/trauma, tonsillectomy, pesticide/ herbicide exposure, smoking and secondhand smoking, diet, and weight loss (questions listed in Appendix). We also collected data on emotional functioning using the 8-item Patient Health Questionnaire depression scale (PHQ-8), an established valid diagnostic and severity measure for depressive disorders [14]. Analysis
Analyses were performed in SAS (version 9.3; SAS Institute Inc., Cary, NC). To evaluate the association between HZ and potential risk factors, we computed adjusted odds ratio (aOR) and confidence intervals using conditional regression for matched pair analysis controlling for age, sex, immune compromise, and vaccination status. Index date for controls was the rash onset date in the matching case. Immunocompromised were patients who, at the time of HZ onset/index date, had the following: hematological malignancies; hematopoietic or solid organ transplant within the 12 months before HZ onset/index date; acquired immune
2
•
OFID
•
Marin et al
deficiency syndrome; treatments associated with immune compromise within 3 months of the onset of HZ (chemotherapy, radiation therapy, systemic immune-suppressive therapy, including chronic systemic use of ≥10 mg prednisone/day). Only persons who had received HZ vaccine >30 days before onset/index date were considered to be vaccinated. For family history of HZ, we defined first-degree relatives as parents, siblings, and children; we defined nonfirst-degree relatives as grandparents, grandchildren, aunts, uncles, and cousins. If a participant indicated a first-degree and a nonfirst-degree relative, the participant was classified as having first-degree relatives. To assess the influence of different levels of stress, a “severe” stress category was created based on participants’ description of new or increased stress in the 3 months before HZ and included death, divorce, separation, major personal illness, major illness in a firstdegree relative, and death of a close family member. To assess depression, a total score of 10 or greater for PHQ-8 was considered indicative of clinically significant depressive symptoms, as previously classified in the literature [14]. Human Subjects
The study was approved by the Institutional Review Boards at Olmsted Medical Center, Mayo Clinic, and the Centers for Disease Control and Prevention (Atlanta, GA). Consent was obtained from all participants; in addition, only persons with previous consent to participate in REP (>93% of all Olmsted County residents) were eligible to be controls. RESULTS
A total of 389 case patients aged ≥50 years with confirmed HZ and 511 matched controls were included in the analysis. Median age of participants was 65 and 66 years for case patients and controls, respectively; more than half were female (Table 1). Case patients were significantly more likely than controls to report blood relatives with a history of HZ (45% vs 35%; aOR = 1.65) (Table 2). When family history was further analyzed by degree of blood relation and number of relatives with HZ, we found a dose-response relationship (P < .001), with the risk being greatest for participants who reported first-degree relatives with HZ or multiple blood relatives with HZ. A family history of HZ did not appear to influence the likelihood of HZ vaccination among either case patients (16% of those with family history vs 22% of those without a family history were vaccinated), controls (34% vs 32%), or the total study population (25% vs 28%) (P > .1). Case patients were significantly more likely than controls to report a previous episode of HZ (13% vs 9%; aOR = 1.82) (Table 2). Most commonly, participants had >20-year interval from the previous HZ episode (40% of case patients and 64% of controls) and were age ≥20 years at the previous HZ episode (90% of case patients and 95% of controls); for these 2 characteristics, differences between case patients and controls were not statistically
Table 1.
Characteristics of Participantsa
Characteristic
HZ Case patients (N = 389) n (%)
Controlsb (N = 511) n (%)
P Valuec
Age at HZ diagnosis/index date (years) Median (range)
65 (50–93)
66 (50–94)
50–54
56 (14.4)
66 (12.9)
55–59
67 (17.2)
76 (14.9)
60–64
67 (17.2)
89 (17.4)
65–69
55 (14.1)
68 (13.3)
70–74
60 (15.4)
88 (17.2)
75–79
32 (8.2)
52 (10.2)
80–84
31 (8.0)
43 (8.4)
85+
21 (5.4)
29 (5.7)
.177d
Sex Male
146 (37.5)
179 (35.0)
Female
243 (62.5)
332 (65.0)
371 (95.8)
480 (95.6)
.179
Race White
.687
Immunocompromised at time of HZ diagnosis/index date Yes
36 (9.3)
16 (3.1)
No
352 (90.7)
494 (96.9)
Yes
74 (19.1)
166 (32.6)
Noe
313 (80.9)
344 (67.4)
Risk Factors for Herpes Zoster Among Adults Mona Marin,1 Rafael Harpaz,1 John Zhang,1 Peter C. Wollan,2 Stephanie R. Bialek,1 and Barbara P. Yawn2 1
National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Department of Research, Olmsted Medical Center, Rochester, Minnesota
Background. The causes of varicella-zoster virus reactivation and herpes zoster (HZ) are largely unknown. We assessed potential risk factors for HZ, the data for which cannot be obtained from the medical sector. Methods. We conducted a matched case-control study. We established active surveillance in Olmsted County, Minnesota to identify HZ occurring among persons age ≥50 years during 2010–2011. Cases were confirmed by medical record review. Herpes zoster-free controls were age- and sex-matched to cases. Risk factor data were obtained by telephone interview. Results. We enrolled 389 HZ case patients and 511 matched controls; the median age was 65 and 66 years, respectively. Herpes zoster was associated with family history of HZ (adjusted odds ratio [aOR] = 1.65); association was highest with first-degree or multiple relatives (aOR = 1.87 and 3.08, respectively). Herpes zoster was also associated with prior HZ episodes (aOR = 1.82), sleep disturbance (aOR = 2.52), depression (aOR = 3.81), and recent weight loss (aOR = 1.95). Stress was a risk factor for HZ (aOR = 2.80), whereas a dose-response relationship was not noted. All associations indicated were statistically significant (P < .05). Herpes zoster was not associated with trauma, smoking, tonsillectomy, diet, or reported exposure to pesticides or herbicides (P > .1). Conclusions. We identified several important risk factors for HZ; however, the key attributable causes of HZ remain unknown. Keywords. family history; herpes zoster; risk factors; shingles. Herpes zoster (HZ) is caused by the reactivation of varicellazoster virus (VZV) that establishes latency in sensory ganglia after initial infection as varicella. Herpes zoster is a painful and debilitating illness that affects approximately 1 in 3 persons during their lifetime [1]; its morbidity and impacts on quality of life increase with age [2–4]. Although it affects a large number of persons, with an estimated 1 million HZ cases annually in the United States, the causes of VZV reactivation and HZ are not completely known. Older age and immunosuppression are well documented risk factors, attributed to diminished VZVspecific cell-mediated immunity, but they cannot fully explain the epidemiology of HZ [5]. Several other potential risk factors have been evaluated but are unconfirmed or of insufficient prevalence to explain most episodes [5, 6]. Since 2006, a vaccine to prevent HZ has been available and recommended in the United States for use in immune-competent adults age ≥60 years [7, 8]. Other HZ vaccines are currently undergoing development. An understanding of risk factors for HZ is vitally important. Improved awareness of epidemiological risk factors could help inform mechanistic understanding of VZV reactivation and HZ disease. In the context of HZ vaccines, observational studies of HZ vaccine performance cannot be properly evaluated without recognizing key risk factors to know whether their prevalence is
Received 11 April 2016; accepted 6 June 2016. Presented in part: 2015 IDWeek, San Diego, CA. Correspondence: M. Marin, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS A-47, Atlanta, GA 30333. ([email protected]). Open Forum Infectious Diseases® Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/ofid/ofw119
balanced in vaccine recipients and nonrecipients. Furthermore, for unknown reasons, HZ rates have been increasing in the United States for decades [1, 9, 10]. These increases make it impossible to interpret HZ vaccine impact; indeed, HZ increase has made it challenging to interpret long-range clinical vaccine trials because these trials generally use historic controls for long-range follow up [11, 12]. Recognition of key risk factors for HZ could thus make trends interpretable and allow for better assessment of vaccine impact. In addition, a better understanding of these factors may suggest new approaches for prevention and treatment of HZ. Although there is an enormous amount of literature relating to HZ risk factors, most studies have explored factors that can be assessed using medical records or administrative data [5, 8]. However, there are many plausible risk factors for HZ for which information would not typically be available in the medical sector. Given the important unknowns relating to HZ risk, we attempt to fill this gap by conducting an analysis of a large array of potential risk factors for HZ that are based on patient self-report. METHODS Study
We used a matched case-control study design. Herpes zoster cases were identified through active surveillance among residents of Olmsted County, aged ≥50 years, who had healthcare encounters for HZ with onset of HZ between January 1, 2010 and October 12, 2011. As previously reported [13], cases were identified within 72 hours of diagnosis, based on the International Classification of Diseases, Ninth Revision (ICD-9) codes of 053 using the Rochester Epidemiology Project (REP). The REP uses administrative data to link the diagnostic codes with Herpes Zoster Risk Factors
•
OFID
•
1
visits dates, basic demographic and procedure information for persons visiting clinics and hospitals associated with the healthcare providers in the County: ie, Olmsted Medical Center, Mayo Clinic, and Rochester Family Medical Clinic. All cases were confirmed by trained researchers who conducted medical record reviews, applying strict criteria to identify evidence of HZ: ie, documentation of a physician diagnosis of either acute HZ or acute HZ complication accompanied by a description of an acute onset of dermatomal pain and vesicular rash not attributed to other causes. Controls were selected using ICD-9 codes from REP for residents of Olmsted County who sought non-HZ-related medical care at the same clinic and at the closest time before the HZrelated visit date in the matching case [13]. Controls were matched to case patients by date of birth (96% of all adult immunizations in Olmsted County. Potential risk factors were selected based on theoretical plausibility or on suggestive but controversial or inadequately verified prior work. They include the following: family history, previous episode of HZ, stress, injury/trauma, tonsillectomy, pesticide/ herbicide exposure, smoking and secondhand smoking, diet, and weight loss (questions listed in Appendix). We also collected data on emotional functioning using the 8-item Patient Health Questionnaire depression scale (PHQ-8), an established valid diagnostic and severity measure for depressive disorders [14]. Analysis
Analyses were performed in SAS (version 9.3; SAS Institute Inc., Cary, NC). To evaluate the association between HZ and potential risk factors, we computed adjusted odds ratio (aOR) and confidence intervals using conditional regression for matched pair analysis controlling for age, sex, immune compromise, and vaccination status. Index date for controls was the rash onset date in the matching case. Immunocompromised were patients who, at the time of HZ onset/index date, had the following: hematological malignancies; hematopoietic or solid organ transplant within the 12 months before HZ onset/index date; acquired immune
2
•
OFID
•
Marin et al
deficiency syndrome; treatments associated with immune compromise within 3 months of the onset of HZ (chemotherapy, radiation therapy, systemic immune-suppressive therapy, including chronic systemic use of ≥10 mg prednisone/day). Only persons who had received HZ vaccine >30 days before onset/index date were considered to be vaccinated. For family history of HZ, we defined first-degree relatives as parents, siblings, and children; we defined nonfirst-degree relatives as grandparents, grandchildren, aunts, uncles, and cousins. If a participant indicated a first-degree and a nonfirst-degree relative, the participant was classified as having first-degree relatives. To assess the influence of different levels of stress, a “severe” stress category was created based on participants’ description of new or increased stress in the 3 months before HZ and included death, divorce, separation, major personal illness, major illness in a firstdegree relative, and death of a close family member. To assess depression, a total score of 10 or greater for PHQ-8 was considered indicative of clinically significant depressive symptoms, as previously classified in the literature [14]. Human Subjects
The study was approved by the Institutional Review Boards at Olmsted Medical Center, Mayo Clinic, and the Centers for Disease Control and Prevention (Atlanta, GA). Consent was obtained from all participants; in addition, only persons with previous consent to participate in REP (>93% of all Olmsted County residents) were eligible to be controls. RESULTS
A total of 389 case patients aged ≥50 years with confirmed HZ and 511 matched controls were included in the analysis. Median age of participants was 65 and 66 years for case patients and controls, respectively; more than half were female (Table 1). Case patients were significantly more likely than controls to report blood relatives with a history of HZ (45% vs 35%; aOR = 1.65) (Table 2). When family history was further analyzed by degree of blood relation and number of relatives with HZ, we found a dose-response relationship (P < .001), with the risk being greatest for participants who reported first-degree relatives with HZ or multiple blood relatives with HZ. A family history of HZ did not appear to influence the likelihood of HZ vaccination among either case patients (16% of those with family history vs 22% of those without a family history were vaccinated), controls (34% vs 32%), or the total study population (25% vs 28%) (P > .1). Case patients were significantly more likely than controls to report a previous episode of HZ (13% vs 9%; aOR = 1.82) (Table 2). Most commonly, participants had >20-year interval from the previous HZ episode (40% of case patients and 64% of controls) and were age ≥20 years at the previous HZ episode (90% of case patients and 95% of controls); for these 2 characteristics, differences between case patients and controls were not statistically
Table 1.
Characteristics of Participantsa
Characteristic
HZ Case patients (N = 389) n (%)
Controlsb (N = 511) n (%)
P Valuec
Age at HZ diagnosis/index date (years) Median (range)
65 (50–93)
66 (50–94)
50–54
56 (14.4)
66 (12.9)
55–59
67 (17.2)
76 (14.9)
60–64
67 (17.2)
89 (17.4)
65–69
55 (14.1)
68 (13.3)
70–74
60 (15.4)
88 (17.2)
75–79
32 (8.2)
52 (10.2)
80–84
31 (8.0)
43 (8.4)
85+
21 (5.4)
29 (5.7)
.177d
Sex Male
146 (37.5)
179 (35.0)
Female
243 (62.5)
332 (65.0)
371 (95.8)
480 (95.6)
.179
Race White
.687
Immunocompromised at time of HZ diagnosis/index date Yes
36 (9.3)
16 (3.1)
No
352 (90.7)
494 (96.9)
Yes
74 (19.1)
166 (32.6)
Noe
313 (80.9)
344 (67.4)
