Association of Streptococcal Throat Infection With Mental Disorders Testing Key Aspects of The PANDAS Hypothesis in A Nationwide Study
Association of Streptococcal Throat Infection With Mental Disorders Testing Key Aspects of The PANDAS Hypothesis in A Nationwide Study
Association of Streptococcal Throat Infection With Mental Disorders Testing Key Aspects of The PANDAS Hypothesis in A Nationwide Study
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IMPORTANCE Streptococcal infection has been linked with the development of
obsessive-compulsive disorder (OCD) and tic disorders, a concept termed pediatric
autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).
However, previous studies of this association have been small, and the results have been
conflicting.
OBJECTIVE To investigate the risk of mental disorders, specifically OCD and tic disorders,
after a streptococcal throat infection.
DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study was conducted using
data from the nationwide Danish registers from January 1, 1996, to December 31, 2013, with
up to 17 years of follow-up. The Danish National Health Service Register provided information
on individuals with the registration of a streptococcal test. Data analysis was conducted from
January 1, 2016, to February 28, 2017.
MAIN OUTCOMES AND MEASURES Individuals were followed up in the nationwide Psychiatric
Central Register for a diagnosis of any mental disorder, OCD, or tic disorders. Incidence rate
ratios (IRRs) were calculated by Poisson regression analysis.
RESULTS Of the 1 067 743 children (<18 years of age) included in the study (519 821 girls and
547 922 boys), 638 265 received a streptococcal test, 349 982 of whom had positive test
results at least once. Individuals with a positive streptococcal test result had an increased risk
of any mental disorder (n = 15 408; IRR, 1.18; 95% CI, 1.15-1.21; P < .001), particularly of OCD
(n = 556; IRR, 1.51; 95% CI, 1.28-1.77; P < .001) and tic disorders (n = 993; IRR, 1.35; 95% CI,
1.21-1.50; P < .001), compared with individuals without a streptococcal test. Furthermore, the
risk of any mental disorder and OCD was more elevated after a streptococcal throat infection Author Affiliations: Mental Health
than after a nonstreptococcal infection. Nonetheless, individuals with a nonstreptococcal Centre Copenhagen, Faculty of
throat infection also had an increased risk of any mental disorder (n = 11 315; IRR, 1.08; 95% Health Sciences, University of
Copenhagen, Copenhagen, Denmark
CI, 1.06-1.11; P < .001), OCD (n = 316; IRR, 1.28; 95% CI, 1.07-1.53; P = .006), and tic disorders (Orlovska, Nordentoft, Benros);
(n = 662; IRR, 1.25; 95% CI, 1.12-1.41; P < .001). iPSYCH–The Lundbeck Foundation
Initiative for Integrative Psychiatric
Research, Aarhus, Denmark
CONCLUSIONS AND RELEVANCE This large-scale study investigating key aspects of the
(Orlovska, Nordentoft, Benros);
PANDAS hypothesis found that individuals with a streptococcal throat infection had elevated Department of Public Health,
risks of mental disorders, particularly OCD and tic disorders. However, nonstreptococcal Research Unit and Section for
throat infection was also associated with increased risks, although less than streptococcal General Practice, Aarhus University,
Aarhus, Denmark (C. H. Vestergaard,
infections for OCD and any mental disorder, which could also support important elements of Bech, M. Vestergaard); Department
the diagnostic concept of pediatric acute-onset neuropsychiatric syndrome. of Public Health, Section for
Epidemiology, Aarhus University,
Aarhus, Denmark (Bech).
Corresponding Author: Sonja
Orlovska, MD, Mental Health Centre
Copenhagen, Faculty of Health
Sciences, University of Copenhagen,
Kildegaardsvej 28, Entrance 15,
JAMA Psychiatry. 2017;74(7):740-746. doi:10.1001/jamapsychiatry.2017.0995 4th Floor, 2900 Hellerup, Denmark
Published online May 24, 2017. (sonja.orlovska@regionh.dk).
I
n recent years, an increasing body of evidence has pointed
toward a critical role of the immune system and infec- Key Points
tions in the development of mental disorders.1-3 Child-
Question Is streptococcal throat infection associated with
hood obsessive-compulsive disorder (OCD) and tic disorders obsessive-compulsive disorder (OCD) and tic disorders, as
have been suggested to be associated with infections caused suggested by the pediatric autoimmune neuropsychiatric
by group A β-hemolytic streptococcus, a hypothesis termed disorders associated with streptococcal infection (PANDAS)
pediatric autoimmune neuropsychiatric disorders associated with hypothesis?
streptococcal infection (PANDAS),4 which are suggested to be Findings In this population-based cohort study, streptococcal
caused by molecular mimicry in which antibodies directed to- throat infections increased the risk of any mental disorder, OCD,
ward the streptococcal bacteria cross-react with the basal gan- and tic disorders; however, compared with nonstreptococcal
glia of the brain, possibly owing to structural similarities be- throat infections, only the risk of any mental disorder and OCD
tween the streptococcal cell surface and proteins of the basal was significantly higher after a streptococcal infection.
ganglia.5 This hypothesis is supported by findings of autoan- Meaning The PANDAS hypothesis was supported to some extent,
tibodies directed toward the basal ganglia in the serum of but because other infections also increased the risk of mental
children with PANDAS compared with that of controls6,7 and disorders, our results could also support aspects of the wider
by the results of imaging studies suggesting inflammation in diagnostic concept of pediatric acute-onset neuropsychiatric
syndrome.
these parts of the brain in individuals with PANDAS com-
pared with controls.8 Moreover, a study observing 12 chil-
dren with PANDAS for 3 years found that exacerbations of OCD
and tic disorders were associated with preceding streptococ- Register,21 and somatic inpatient contacts since 1977 are avail-
cal infections.9 Furthermore, studies have found that immu- able in the National Hospital Register22; since 1995, both reg-
notherapy has a positive effect on symptoms of OCD and tic isters also include outpatient contacts.21,22 The Danish Na-
disorders in children with PANDAS,10,11 indicating that auto- tional Health Service Register documents activities of general
immune-based mechanisms may play a causal role. practitioners since 1990.23 Data on filled prescriptions since
However, the PANDAS hypothesis remains controversial, 1994 are accessible in the Danish National Prescription
and most prior studies are small and have methodological Registry.24 Registered diagnoses are defined according to the
shortcomings. Furthermore, not all studies confirmed the find- International Statistical Classification of Diseases and Related
ings of autoantibodies against the basal ganglia in children with Health Problems, Tenth Revision, codes. The study was ap-
PANDAS,12-14 and several other studies also did not support the proved by the Danish Data Protection Agency, who waived the
PANDAS hypothesis,15-18 including recent investigations of the need for patient consent.
effect of immunotherapy.19 Studies with the most intensive
clinical observation and testing either did not find recent strep- Study Population
tococcal infections to worsen neuropsychiatric symptoms in Individuals born in Denmark between January 1, 1996, and
individuals with PANDAS17 or found that most of the neuro- December 31, 2013, were identified by their identification
psychiatric worsening occurred in individuals with no asso- number and followed up until death, emigration, or Decem-
ciation with a preceding streptococcal infection,18 thereby ber 31, 2013. Individuals were followed up in the Danish
questioning the core criterion of PANDAS. Furthermore, many National Health Service Register for a record of a rapid anti-
studies are limited by short-term follow-up, recall bias, and gen diagnostic test for group A β-hemolytic streptococcal
cross-sectional design. throat infection (streptococcal test) performed by the gen-
We investigated the risk of any mental disorders, with par- eral practitioner and in the Danish National Prescription
ticular focus on OCD and tic disorders, in children exposed to Registry for a history of subsequently filled antibiotics. Indi-
streptococcal throat infection in the largest population- viduals with a record of a streptococcal test were followed
based cohort study to date, to our knowledge, using the na- up in the Danish Psychiatric Central Register using the first-
tionwide Danish registers. We observed the cohort for up to time psychiatric diagnoses during the period from 1996 to
17 years without loss to follow-up with an investigation of age 2013. Because hospital contact, including emergency depart-
at the time of streptococcal throat infection, the timing and ment contact, for infections is a known risk factor for mental
number of streptococcal infections, and stratified by sex and disorders,1,2 individuals with a record of hospital treatment
personal or parental history of autoimmune disease. for infections were censored, as were individuals with a psy-
chiatric diagnosis.
jamapsychiatry.com (Reprinted) JAMA Psychiatry July 2017 Volume 74, Number 7 741
Table 1. Risk of Mental Disorders in Individuals With Positive or Negative Streptococcal Test Resultsa
Result of Any Mental Disorder OCD Tic Disorders
Streptococcal
Test No. IRRb (95% CI) IRRc (95% CI) No. IRRb (95% CI) IRRc (95% CI) No. IRRb (95% CI) IRRc (95% CI)
No test 13 712 1 [Reference] 1 [Reference] 206 1 [Reference] 1 [Reference] 522 1 [Reference] 1 [Reference]
performed
Positive 15 408 1.18 (1.15-1.21)d 1.16 (1.14-1.20)d 556 1.51 (1.28-1.77)d 1.49 (1.27-1.76)d 993 1.35 (1.21-1.50)d 1.34 (1.20-1.49)d
d d d d
Negative 11 315 1.08 (1.06-1.11) 1.07 (1.04-1.09) 316 1.28 (1.07-1.53) 1.27 (1.07-1.52) 662 1.25 (1.12-1.41)d 1.24 (1.10-1.39)d
c
Abbreviations: IRR, incidence rate ratio; OCD, obsessive-compulsive disorder. Further adjusted for parental educational level, income, marital status, family
a
The streptococcal test was the rapid antigen diagnostic test for group A history of psychiatric disorders, and personal or parental history of
β-hemolytic streptococcal throat infections. autoimmune diseases.
d
b
Adjusted for sex, age, and calendar year. The reference interval did not include 1 [Reference].
been diagnosed by pediatricians instead of psychiatrists, psy- dependent variable. P < .05 was considered significant. Fur-
chiatric diagnoses were also obtained from the National Hos- ther information regarding statistical analyses is available in
pital Register. the eAppendix in the Supplement.
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Table 2. Risk of Mental Disorders in Individuals With Positive or Negative Streptococcal Test Results, by the Number of Tests Performeda
Table 3. Risk of Mental Disorders in Individuals With Positive Streptococcal Test Results, by Time Since the Last Positive Test Resulta
Table 4. Risk of Mental Disorders in Individuals With Positive Streptococcal Test Results, by Age at the First Positive Testa
association. Other studies have found that the debut and wors- studies have supported the PANDAS hypothesis.15-18 The pre-
ening of OCD and tic disorders can also be linked to nonstrep- viously largest study of streptococcal infection and mental dis-
tococcal infectious agents,27,28,30,31 including the study by orders investigated 2596 individuals with streptococcal infec-
Swedo et al4 describing the first 50 cases of PANDAS. Another tion based on a research database and found that only
aspect that does not seem to entirely confirm PANDAS in our inpatients (ie, patients with severe streptococcal infections)
study is the increased risk of any mental disorder, not only OCD had an increased risk of all outcomes as a combined group and
and tic disorders, after a streptococcal infection. In line with an increased risk of attention-deficit/hyperactivity disorder,
this finding, psychiatric comorbidity is common when inves- whereas the risk of OCD and tic disorders was only insignifi-
tigating children who received a diagnosis of PANDAS.4,17,18,25 cantly increased.32 Other studies did not find a temporal link
However, in our study, individuals with streptococcal infec- between neuropsychiatric worsening and streptococcal
tion did have a larger risk of the subsequent development of infection17 or found a temporal link in only a few of the cases
OCD and tic disorders than of any mental disorders; this find- but with more than 75% of the neuropsychiatric worsening oc-
ing favors a specific association between streptococcal infec- curring without an association with streptococcal infection.18
tion and OCD and tic disorders. Furthermore, not all previous We did not find the risk of the outcomes to be highest in close
744 JAMA Psychiatry July 2017 Volume 74, Number 7 (Reprinted) jamapsychiatry.com
proximity to the streptococcal infection, which can probably tive streptococcal test result, which allowed us to interpret this
not be explained merely by a diagnostic delay. finding only as a presumed streptococcal throat infection. Fur-
The association between streptococcal and nonstrepto- thermore, misclassification would occur in cases in which an
coccal infections and mental disorders could also be an epi- antibiotic was prescribed to an individual with a negative test
phenomenon instead of representing causality. Some par- result to treat a nonstreptococcal bacterial infection or in cases
ents might have an increased focus on somatic and psychiatric in which an individual received an antibiotic for a streptococ-
symptoms, prompting more frequent visits to the general prac- cal throat infection based only on the clinical symptoms with-
titioner in spite of only few symptoms of throat infection, in- out undergoing a streptococcal test. Hence, it might have been
ducing the registration of streptococcal tests and likewise more appropriate to perform sensitivity analyses excluding indi-
frequent examination and diagnosis by a psychiatrist. We might viduals in the control group who were receiving antibiotics;
partially adjust for this medical care–seeking behavior by ad- however, such analyses were beyond the extent of our study.
justing for socioeconomic factors and probably adjusting even The streptococcal test is targeted at group A β-hemolytic strep-
more in our case-sibling design, which still found an in- tococcus, so throat infection with other types of streptococ-
creased risk of OCD in patients with a streptococcal throat in- cus would lead to a negative test result, which probably di-
fection compared with control siblings. However, our results lutes the effect of a positive test result. Also, a meta-analysis36
for both positive and negative streptococcal test results did not found that 14% of the streptococcal test results are false nega-
change significantly in the fully adjusted model that in- tives, which might add to the diluting effect. Only hospital con-
cluded socioeconomic factors and a family history of mental tacts for mental disorders are covered by the registers; hence,
disorders, which is also in line with previous contradictory find- individuals treated by general practitioners or private pedia-
ings regarding socioeconomic status as a risk factor for OCD.33 tricians or psychiatrists are not included in our study. Even
Moreover, mental disorders have been linked to immune- though the onset of OCD and tic disorders might have been
related genes and genetic susceptibility to infections.34 Auto- abrupt and accompanied by other co-occurring psychiatric
immune diseases might account for the increased occurrence symptoms, which are important elements of PANDAS,4 the reg-
of infections in these individuals; previous studies have also isters did not provide such information, which is why we were
found that a family history of autoimmune diseases appears able to explore only key aspects of PANDAS, and might not have
more frequently among children who received a diagnosis of been able to identify the rare and true cases of PANDAS. Al-
PANDAS.18,35 However, we did not find that individuals with though we found an association, the absolute risk of OCD and
a history of personal or parental autoimmune diseases had a tic disorders after a streptococcal throat infection is still small.
more elevated risk of any of the outcomes after a streptococ- In addition, other noninfectious environmental factors that we
cal or nonstreptococcal throat infection. were not able to include could have influenced the associa-
tion with OCD, tic disorders, and Tourette syndrome.33,37,38
Strengths and Limitations
This large nationwide cohort had up to 17 years of follow-up
without any loss to follow-up, which are major strengths of our
study and make selection bias an unlikely explanation for our
Conclusions
findings. In addition, information on streptococcal tests and We found that both individuals with a streptococcal throat in-
outcomes were registered prospectively, which excludes re- fection and individuals with a nonstreptococcal throat infec-
call bias. The inclusion of a case-sibling design allowed us to tion had an increased risk of any mental disorder, OCD, and
account for unmeasured social and environmental factors even tic disorders; however, the risk of all mental disorders and of
though these analyses included fewer cases and the control OCD was greatest in individuals with streptococcal throat in-
siblings might also have been exposed to a streptococcal throat fections. Our results could favor essential elements of the wider
infection without receiving treatment. The limitations of the diagnostic concept of pediatric acute-onset neuropsychiatric
study include the use of a proxy method for defining a posi- syndrome.
ARTICLE INFORMATION Critical revision of the manuscript for important Role of the Funder/Sponsor: The funding sources
Accepted for Publication: March 26, 2017. intellectual content: All authors. had no role in the design and conduct of the study;
Statistical analysis: Orlovska, C. H. Vestergaard, collection, management, analysis, and
Published Online: May 24, 2017. Nordentoft, Benros. interpretation of the data; preparation, review, or
doi:10.1001/jamapsychiatry.2017.0995 Obtained funding: M. Vestergaard. approval of the manuscript; and decision to submit
Author Contributions: Dr Orlovska and Administrative, technical, or material support: the manuscript for publication.
Mr C. H. Vestergaard had full access to all the Orlovska, Nordentoft, Benros.
data in the study and take responsibility for the Study supervision: C. H. Vestergaard, Nordentoft, REFERENCES
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