Pediatric Neuropsychiatric Syndromes: Updates on COVID-19 Infection and Vaccination

Abstract

Introduction:

SARS-CoV-2 (COVID-19) infection has been implicated in the onset of neuropsychiatric symptoms in adults and children. While outcomes of COVID-19 infection and vaccination have been tracked in the general pediatric population, little is known of their impact on children with preexisting neuropsychiatric syndromes, including pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). The aim of this study is to understand the prevalence and severity of COVID-19 symptoms and PANS/PANDAS symptoms following COVID-19 infection or vaccination in children with PANS/PANDAS.

Methods:

We analyzed retrospective COVID-19 survey data from caregivers of youth with PANS/PANDAS at Massachusetts General Hospital (MGH; n = 57) and the International PANS Registry (IPR; n = 478). Surveys were conducted online between late 2021 and early 2022 to collect COVID-19 infection and vaccination histories, side effects, and changes in PANS/PANDAS symptoms. Descriptive results are reported, stratified by case and sibling groups within the IPR sample.

Results:

Among patients with test-confirmed COVID-19 (MGH: n = 20, IPR: n = 65 cases, n = 16 siblings), mild/minor COVID-19 symptoms were common (62–75%). All patients with preexisting PANS/PANDAS-related symptoms at the time of COVID-19 infection experienced an exacerbation of PANS/PANDAS symptoms, while remitted patients did not report any PANS/PANDAS symptoms. Following the first COVID-19 vaccine dose (MGH: n = 45, IPR: n = 150 cases, n = 44 siblings), fatigue was the predominant side effect (30–56%). Most patients did not report new (59–81%) or worsened (71–82%) PANS symptoms post-vaccination, irrespective of symptomatic status at vaccination. Vaccine hesitancy often stemmed from concerns that the vaccination would cause an exacerbation of PANS/PANDAS symptoms.

Conclusions:

In two samples of children with PANS/PANDAS, symptoms of COVID-19 following infection and vaccination were common and generally mild to moderate. Children experiencing PANS/PANDAS symptoms at the time of COVID-19 infection experienced an increase in PANS/PANDAS symptom severity.

Introduction

The SARS-CoV-2 (COVID-19) pandemic greatly increased interest in the relationships between infection, inflammation, and neuropsychiatric symptoms. In addition to common upper-respiratory symptoms such as fever, cough, and fatigue (Alimohamadi et al., 2020), patients with COVID-19 infection report sleep disruptions, anxiety, and mood disorder symptoms (Badenoch et al., 2022; Nalleballe et al., 2020). Neuropsychiatric symptoms following COVID-19 infection have also been found in children. A prospective study of 375 children hospitalized with COVID-19 found that over 15% of children exhibited psychiatric manifestations, including anxiety, depression, sleep disturbance, and oppositional behavior (Zahed et al., 2023). In a review of 102 pediatric studies, neuropsychiatric symptoms were reported to persist in a subset of pediatric patients diagnosed with COVID-19, with executive functioning deficits, sleep disturbances, anxiety, and stress most frequently reported (Avittan and Kustovs, 2023).

Neuropsychiatric symptoms following infection are the defining feature of two related diagnostic entities, termed pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). PANS is a diagnosis defined by an acute, severe onset of neuropsychiatric symptoms, with the principal symptoms being obsessive-compulsive disorder (OCD) and acute restrictive food intake disorder (ARFID). Both infectious and noninfectious causes are hypothesized to initiate and exacerbate PANS symptoms (Swedo, 2012). A related condition, termed PANDAS, is characterized by sudden, new-onset OCD or tic symptoms following a streptococcal infection in a previously healthy child (Swedo et al., 1998). In both conditions, children frequently display new-onset neuropsychiatric symptoms, such as emotional lability, hyperactivity, and separation anxiety. While the onset of symptoms must be temporally associated with a streptococcal infection to meet diagnostic criteria for PANDAS, any kind of subsequent infection can exacerbate symptoms, ranging from viral to bacterial (Swedo, 2012; Swedo et al., 1998).

Given this relationship between infection and PANS/PANDAS symptoms, understanding the unique impact of COVID-19 infection and vaccination on patients with these disorders is important. Case studies of children developing PANS following COVID-19 infection, as well as increased symptom severity in those with a preexisting PANS/PANDAS diagnosis following COVID-19 infection, have been reported (Bez et al., 2022; Efe, 2022). In a survey study of 496 families, parental retrospective reports suggested that following a COVID-19 infection, 46% of parents reported a reemergence (i.e., “flare”) of PANS/PANDAS symptoms (LaRusso and Abadia, 2023). An additional survey study of PANS/PANDAS caregivers (N = 254) found mood lability, sensory sensitivities, and anxiety to be the most frequently exacerbated symptoms in this population following a suspected or diagnosed COVID-19 infection (O’Dor et al., 2024). These results suggest COVID-19 infections may both initiate and exacerbate symptoms of PANS/PANDAS in children, but these findings have yet to be confirmed in a well-characterized sample of patients with PANS/PANDAS.

Safe and effective vaccines for COVID-19 for children have been developed and widely adopted in pediatric populations (Piechotta et al., 2023). In children aged 12–17 years, mild to moderate reactions to the COVID-19 vaccine are common, while serious adverse events are rare (Hause et al., 2021b); However, little is known about the side effect profile of these vaccines in children with PANS/PANDAS. This information is particularly important given that parents of children with PANS/PANDAS have shown apprehensions about vaccinating their children against COVID-19 (O’Dor et al., 2024). A survey of these caregivers reported nearly half were unsure about vaccinating their child for COVID-19, and 25.9% would decline vaccination due to concerns about PANS/PANDAS symptom exacerbation (O’Dor et al., 2024). Results of a retrospective survey of parents showed that 34% of children with PANS/PANDAS experienced exacerbated PANS/PANDAS symptoms after receiving the COVID-19 vaccine (LaRusso and Abadia, 2023).

The current study expands upon this research by examining neuropsychiatric symptoms after COVID-19 infection and vaccination in children with PANS/PANDAS from both a clinical sample and an international patient registry. This study evaluated (1) whether children with PANDAS/PANS show an increase in PANDAS/PANS symptoms following COVID-19 infection or vaccination and (2) whether they report more side effects than a control group of healthy siblings who do not have PANS/PANDAS.

Methods

Study population and data sources

Data were collected from two populations: (1) the Pediatric Neuropsychiatry and Immunology Clinic at the Massachusetts General Hospital (MGH) and (2) the International PANS Registry (IPR).

The MGH sample included caregivers of children aged 3–17 years at the time of initial consultation and diagnosed with PANS/PANDAS by a child psychiatrist with experience in these conditions (K. Williams). All caregivers were literate in English and consented to participate. All aspects of this study were approved by the Mass General Brigham Institutional Review Board (IRB: #2021P003145).

The IPR includes children and adolescents who are suspected to have met diagnostic criteria for PANS/PANDAS, though they may not have been formally diagnosed by a provider, and their siblings who are not currently affected by these symptoms. The rationale, methods, and baseline characteristics of the overall IPR study sample have been previously described (Masterson and Gavin, 2024, 2023). IPR participants were invited to complete the PANS COVID-19 survey if the child was enrolled prior to 12/8/2021. Participants were consented prior to participation. All aspects of the study were approved by the University of Washington (UW) IRB (#STUDY00014420).

Data collection procedures

An online survey was sent to eligible caregivers of current and former MGH patients and current IPR participants. Survey invitations were sent to legal guardians of 251 MGH patients and 1671 households enrolled in the IPR, including 3259 children (cases and their siblings). MGH data was collected from 11/20/2021 to 05/26/2022; IPR data were collected from 12/8/2021 until 2/9/2022. For IPR participants, weekly reminders to complete the surveys were sent for 3 weeks. For MGH patients, caregivers received one follow-up call to answer any questions and request that they complete the survey. Survey data were collected and managed at both study sites using the Research Electronic Data Capture (REDCap) software platform (Harris et al., 2019, 2009) hosted at Mass General Brigham’s Research Information Science & Computing and the UW’s Institute of Translational Health Sciences. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies.

Measures

Survey questions addressed COVID-19 infection history, COVID-19 vaccination status, and, if applicable, side effects following the COVID-19 vaccination. If applicable, parents were asked if their child was experiencing any PANS/PANDAS symptoms at the time of COVID-19 infection or vaccination (“yes/no”). Parents whose children had a suspected or confirmed COVID-19 infection were asked to report on COVID-19 symptoms, as outlined by the CDC (Myers et al., 2023). The IPR cohort was also asked to report on PANS/PANDAS-related symptoms following infection. Side effects of COVID-19 vaccination assessed for both cohorts included cardinal symptoms of PANS/PANDAS, (i.e., OCD, tics, ARFID), symptoms found to accompany the onset or acute exacerbations of PANDAS/PANS symptoms, and side effects of COVID-19 vaccination tracked by the U.S. Centers for Disease Control and Prevention (CDC) (Myers et al., 2023).

If a caregiver endorsed that his/her child had received a vaccination for COVID-19, they were asked to retrospectively report on any side effects their child experienced following the vaccination. If a caregiver endorsed that his/her child had not received a vaccination for COVID-19, the caregiver was asked to provide information about what informed the decision to forgo or delay COVID-19 vaccination.

Statistical analyses

Results were stratified by study sample (MGH/IPR cases/IPR siblings). For survey questions and response options in which the wording differed between the IPR and MGH versions, we report results separately. We used descriptive statistics (i.e., means and standard deviations) to describe continuous measures. Frequencies and proportions are used to describe categorical measures. We analyzed the IPR data using SAS version 9.4 (SAS Institute, Inc., 2023) and the MGH data using SPSS version 28 (IBM Corp., 2021).

Results

Description of study samples

The analytic sample comprised 57 patients from MGH and 478 participants from the IPR, including 371 cases and 107 siblings from 380 households, who completed the COVID-19 survey. Across all sample cohorts (MGH, IPR cases, IPR siblings), the mean age of the subjects was 10–12 years (M yrs [sd] MGH: 11.3 [2.8], IPR cases: 12.0 [4.0], IPR siblings: 10.5 [4.8]). There was a greater frequency of males (MGH: 54.4%, IPR cases: 59.3%, IPR siblings: 51.4%). Among the MGH sample, all patients were diagnosed by a physician with PANS or PANDAS; the majority were diagnosed with PANDAS (78.9%). In the IPR cases, 74.1% were reported by caregivers to have a physician diagnosis of PANS or PANDAS.

Approximately one-third of participants in each cohort reported a COVID-19 infection (MGH: n = 22, 38.6%; IPR cases: n = 104, 28%; IPR siblings: n = 31, 29%). The MGH sample exhibited a higher frequency of confirmed COVID-19 infections (n = 20, 35%) compared with the IPR sample (cases: n = 65, 17%; siblings: n = 16, 15%). In addition, a greater proportion of the MGH sample (79%) reported receiving at least one COVID-19 vaccination, in contrast to 40% in the IPR sample (see Table 1).

Table 1.

Study Sample Description and COVID-19 Infection Exposure and Vaccination Completion, n = 535

	MGH N = 57	IPR N = 478
	MGH N = 57	Cases N = 371	Siblings N = 107
Sex
Male	31 (54.4%)	220 (59.3%)	55 (51.4%)
Female	26 (45.6%)	139 (37.5%)	51 (47.7%)
Missing	0	12 (3.2%)	1 (0.9%)
Age (years) at study enrollment, mean (SD)	11.3 (2.8)	12.0 (4.0)	10.5 (4.8)
Reports diagnosis with PANS/PANDAS, overall	57 (100%)	275 (74.1%)	NA
Diagnosed with PANS	12 (21.1%)	—	NA
Diagnosed with PANDAS	45 (78.9%)	—	NA
Age at reported onset of PANS/PANDAS, mean (SD)	—	5.9 (3.6%)	NA
Age at PANS/PANDAS diagnosis^a, mean (SD)	—	8.0 (3.7%)	NA
COVID-19 Infection, suspected/confirmed^b	22 (38.6%)	104 (28%)	31 (29%)
Subset with confirmed positive infection	20 (35.1%)	65 (17%)	16 (15%)
COVID-19 Vaccination
1st dose complete (type/manufacturer reported below)	45 (78.9%)	150 (40%)	44 (41%)
2nd dose complete	40 (70.2%)	124 (33%)	40 (27%)
Not vaccinated	12 (21.1%)	221 (60%)	63 (59%)
First dose vaccine type/manufacturer
Pfizer-BioNTech^c	43 (95.6%)	145 (96.7%)	43 (97.7%)
Moderna	2 (4.4%)	3 (2.0%)	0
Johnson & Johnson’s Janssen	0	2 (1.3%)	1 (2.3%)

Estimated based on n = 275 IPR cases who reported a diagnosis.

Per parent report, not all children who had suspected COVID-19 were administered a test to confirm. Therefore, we have included totals for both the combined group of children with suspected or confirmed COVID-19 infection, per parent report, as well as the subset of children with a confirmed infection.

At the time of data collection, Pfizer-BioNTech was given emergency use authorization by the FDA for a wider age range than those made by the other two manufacturers.

COVID-19 infection experience

Among participants who reported COVID-19 infection confirmed by a test result, most experienced mild/minor symptoms or were asymptomatic (62%–75%), while 25%–38% reported moderate symptoms. Across all subjects, only one patient required hospitalization (see Table 2).

Table 2.

COVID-19 Infection Experience among Those with a Confirmed Positive Test Result, N = 101

	MGH(n = 20)	IPR cases(n = 65)	IPR siblings (n = 16)
Severity of COVID-19 symptoms
Mild/minor or asymptomatic (could continue normal duties)	13 (65.0%)	40 (62%)	12 (75%)
Moderate (unable to perform normal duties)	6 (27.3%)	25 (38%)	4 (25%)
Severe (required hospitalization)	1 (4.5%)	0	0
COVID-19 symptoms the child developed
Fever or chills	—	27 (42%)	9 (56%)
Cough	—	38 (58%)	7 (44%)
Shortness of breath	—	4 (6%)	1 (6%)
Fatigue	—	40 (62%)	9 (56%)
Muscle or body aches	—	24 (37%)	6 (38%)
Headache	—	33 (51%)	7 (44%)
New loss of taste or smell	—	25 (38%)	4 (25%)
Sore throat	—	30 (46%)	7 (44%)
Congestion or runny nose	—	38 (58%)	10 (63%)
Nausea or vomiting	—	11 (17%)	2 (13%)
Diarrhea	—	3 (5%)	2 (13%)
Other	—	2 (5%)	1 (6%)
None of the above	—	4 (6%)	0

Among IPR cases and siblings, the most frequently reported COVID-19 symptoms included fatigue (62% and 56%, respectively), congestion or runny nose (58% and 63%), cough (58% and 44%), headache (51% and 44%), sore throat (46% and 44%), and fever or chills (42% and 56%).

Changes in PANS-related symptoms after infection

Among IPR cases who were not experiencing any PANS-related symptoms at the time of COVID-19 infection, none reported new PANS/PANDAS symptoms within a week of infection (see Table 3). However, patients with ongoing PANS/PANDAS symptoms at the time of infection reported an exacerbation of certain symptoms following infection. The most frequently reported exacerbated symptoms included emotional lability (58%), “irritability, aggression, severe oppositional behaviors” (45%), and anxiety (45%). Obsessions and compulsions were reportedly exacerbated in 30%–42% of the IPR cases.

Table 3.

PANS-Related Symptoms That Began or Worsened within a Week following Infection with a Confirmed Positive COVID-19 Test Result, N = 65 (IPR Cases Only)^a

Symptoms that began or worsened within one week following COVID-19 infection	At the time of and/or up to one month prior to COVID-19 infection
	NOT experiencing PANS-related symptom n = 32	Experiencing PANS-related symptom(s) n = 33
	Obsessions (unwanted thoughts, fears, and recurring worries)	0	14 (42%)
Compulsions (repetitive behaviors and rituals)	0	10 (30%)
Severe restriction of food intake	0	5 (15%)
Body-Focused Repetitive Behaviors (BFRB)(e.g., hair pulling, skin picking, nail biting)	0	6 (18%)
Anxiety (e.g., separation anxiety, irrational fears)	0	15 (45%)
Emotional lability (e.g., mood changes, depression)	0	19 (58%)
Irritability, aggression, severe oppositional behaviors	0	15 (45%)
Behavioral (developmental) regression (e.g., “baby talk,” temper tantrums and “clingyness”)	0	10 (30%)
Deterioration in school performance (e.g., deficit of certain skills, shortened attention span)	0	7 (21%)
Sensory abnormalities (e.g., unusual sensitivity of the senses)	0	5 (15%)
Motor tics	0	9 (27%)
Other (non-tic) motor abnormalities (e.g., clumsiness, motoric hyperactivity, speech disorders)	0	4 (12%)
Somatic signs and symptoms (e.g., sleep disturbance and urinary symptoms)	0	4 (12%)
None of the above	32 (100%)	0

Data on PANS-related symptoms following COVID-19 infection were not collected in the MGH cohort.

COVID-19 vaccination experience

Among subjects who had received at least one COVID-19 vaccine (MGH: n = 45, 78.9%; IPR cases: n = 150, 40%; IPR siblings: n = 44, 41%), most received a second vaccination (MGH: n = 40, 70.2%; IPR cases: n = 124, 33%; IPR siblings: n = 40, 27%) (see Table 1). For both vaccine doses, pain at the injection site was the most prevalent symptom reported (55%–80% across all cohorts) (see Table 4). Less than half (MGH: 18%; IPR cases: 41%; IPR siblings: 39%) reported no symptoms at the injection site. Fatigue was the most common side effect reported, with varying frequencies across cohorts (MGH: 56%, IPR cases: 42%, IPR siblings: 30%). Headaches (MGH: 31%, IPR cases: 21%, IPR siblings: 18% after the first dose) and muscle or body aches (MGH: 27%, IPR cases: 17%, IPR siblings: 14%) after the first dose were also commonly reported. Approximately one-third (36%) of the MGH sample and half (50%) of the IPR cases reported no postvaccination side effects after the first dose.

Table 4.

COVID-19 Vaccination Side Effects or Adverse Reactions during the 7 Days following COVID-19 Vaccination, Stratified by 1st and 2nd Dose, N = 239

	1st COVID-19 vaccination dose			2nd COVID-19 vaccination dose
	MGH^a , n = 45	IPR cases ^b ,n = 150	IPR siblings, n = 44	MGH, n = 40	IPR cases^b, n = 124	IPR siblings, n = 40
Symptoms at the injection site:
Pain	36 (80%)	83 (55%)	27 (61%)	32 (80%)	71 (57%)	23 (58%)
Mild	26 (46%)	—	—	23 (40%)	—	—
Moderate	10 (18%)	—	—	9 (16%)	—	—
Redness	13 (29%)	18 (12%)	5 (11%)	12 (30%)	20 (16%)	3 (8%)
Mild	10 (18%)	—	—	10 (18%)	—	—
Moderate	3 (5%)	—	—	2 (4%)	—	—
Swelling	10 (22%)	13 (9%)	5 (11%)	9 (23%)	12 (10%)	6 (15%)
Mild	7 (12%)	—	—	7 (2%)	—	—
Moderate	3 (5%)	—	—	2 (4%)	—	—
Itching	4 (9%)	10 (7%)	0	2 (5%)	5 (4%)	0
Mild	4 (7%)	—	—	2 (4%)	—	—
Moderate	0	—	—	0	—	—
None of the above	8 (18%)	61 (41%)	17 (39%)	8 (20%)	47 (38%)	17 (43%)
Vaccination side effects:
Fever or felt feverish	3 (7%)	15 (10%)	5 (11%)	4 (10%)	29 (23%)	9 (23%)
Mild	2 (4%)	—	—	1 (2%)	—	—
Moderate	0	—	—	2 (4%)	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Chills	4 (9%)	9 (6%)	3 (7%)	4 (10%)	15 (12%)	6 (15%)
Mild	3 (5%)	—	—	1 (2%)	—	—
Moderate	0	—	—	2 (4%)	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Headaches	14 (31%)	31 (21%)	8 (18%)	18 (45%)	36 (29%)	13 (33%)
Mild	9 (16%)	—	—	14 (25%)	—	—
Moderate	5 (9%)	—	—	3 (5%)	—	—
Severe	0	—	—	1 (2%)	—	—
Joint pains	9 (20%)	10 (7%)	1 (2%)	7 (18%)	11 (9%)	4 (10%)
Mild	5 (9%)	—	—	5 (9%)	—	—
Moderate	4 (7%)	—	—	2 (4%)	—	—
Muscle or body aches	12 (27%)	26 (17%)	6 (14%)	15 (38%)	29 (23%)	8 (20%)
Mild	7 (12%)	—	—	13 (23%)	—	—
Moderate	4 (7%)	—	—	1 (2%)	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Fatigue or tiredness	26 (56%)	63 (42%)	13 (30%)	24 (60%)	60 (48%)	14 (35%)
Mild	17 (30%)	—	—	14 (25%)	—	—
Moderate	7 (12%)	—	—	9 (16%)	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Nausea	3 (7%)	7 (5%)	3 (7%)	3 (8%)	8 (6%)	5 (13%)
Mild	1 (2%)	—	—	2 (4%)	—	—
Moderate	1 (2%)	—	—	0	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Vomiting	2 (4%)	2 (1%)	0	1 (3%)	1 (1%)	1 (3%)
Mild	0	—	—	0	—	—
Moderate	1 (2%)	—	—	0	—	—
Severe	1 (2%)	—	—	1 (2%)	—	—
Diarrhea	1 (2%)	1 (1%)	0	2 (5%)	3 (2%)	0
Mild	1 (2%)	—	—	2 (4%)	—	—
Abdominal pain	1 (2%)	5 (3%)	0	2 (5%)	5 (4%)	0
Mild	0	—	—	2 (4%)	—	—
Moderate	1 (2%)	—	—	0	—	—
Rash (not including the immediate area around the injection site)	2 (4%)	1 (1%)	0	1 (3%)	1 (1%)	0
Mild	0	—	—	1 (2%)	—	—
Moderate	2 (4%)	—	—	0	—	—
None of the above	16 (36%)	75 (50%)	30 (68%)	14 (35%)	51 (41%)	21 (53%)

Severity of CDC-tracked side-effects following COVID-19 vaccination in clinic population (MGH sample only).

74% report formal diagnoses of PANS and/or PANDAS.

Mild—you notice symptoms, but they aren’t a problem.

Moderate—symptoms limit your normal daily activities.

Severe—symptoms make normal daily activities difficult or impossible.

Changes in PANS-related symptoms after vaccination

Following vaccination, the majority of children did not experience new or worsened PANS/PANDAS-related symptoms. Among those without PANS/PANDAS symptoms at the time of their first vaccination, 59% of the MGH sample and 81% of the IPR cases reported no new symptoms in the week following vaccination. Similarly, among those with existing symptoms at the time of their first dose, 82% of the MGH sample and 71% of the IPR cases reported no worsening of symptoms (see Table 5).

Table 5.

PANS-Related Symptoms* That Began or Worsened within a Week following First COVID-19 Vaccination in MGH/IPR Cases, N = 195

Symptoms that began or worsened within one week following COVID-19 vaccination	At the time of and/or up to one month prior to first COVID-19 vaccination
	NOT experiencing PANS/PANDAS-related symptom(s)		Experiencing PANS/PANDAS-related symptom(s)
	MGH^a n = 34	IPR cases^b n = 53	MGH^a n = 11	IPR cases^b n = 97
Obsessions (unwanted thoughts, fears, and recurring worries)	—	3 (6%)	—	12 (12%)
Compulsions (repetitive behaviors and rituals)	—	3 (6%)	—	7 (7%)
Obsessive-compulsive symptoms, overall	6 (17.6%)	—	7 (38%)	—
Mild	6 (17.6%)	—	6 (24%)	—
Moderate	0	—	1 (4%)	—
Severe restriction of food intake	—	0	—	6 (6%)
Changes in appetite (e.g., restricted eating), overall	1 (3%)	—	0	—
Mild	1 (3%)	—	0	—
Moderate	0	—	0	—
Body-Focused Repetitive Behaviors (BFRB) (e.g., hair pulling, skin picking, nail biting)	1 (3%)	1 (2%)	2 (18%)	5 (5%)
Mild	1 (3%)	—	2 (18%)	—
Moderate	—	—	—	—
Anxiety (e.g., separation anxiety, irrational fears), overall	8 (24%)	5 (9%)	1 (9%)	15 (15%)
Mild	3 (9%)	—	0	—
Moderate	4 (12%)	—	1 (9%)	—
Severe	1 (3%)	—	0	—
IPR: Emotional lability (e.g., mood changes, depression)	—	5 (9%)	—	16 (16%)
MGH: Mood lability, overall	11 (34%)	—	0	—
Mild	7 (22%)	—	0	—
Moderate	4 (12%)	—	0	—
Irritability, aggression, severe oppositional behaviors	—	5 (9%)	—	16 (16%)
Behavioral (developmental) regression (e.g., “baby talk,” temper tantrums and “clingyness”), overall	7 (21%)	0	0	8 (8%)
Mild	3 (9%)	—	0	—
Moderate	4 (12%)	—	0	—
Deterioration in school performance (e.g., deficit of certain skills, shortened attention span)	6 (18%)	4 (8%)	1 (9%)	10 (10%)
Mild	3 (9%)	—	1 (9%)	—
Moderate	3 (9%)	—	0	—
IPR: Sensory abnormalities (e.g., unusual sensitivity of the senses)	—	5 (9%)	—	6 (6%)
MGH: Sensory symptoms (e.g., increased sensory sensitivities to noises, textures, etc.), overall	4 (6%)	—	0	—
Mild	2 (3%)	—	0	—
Moderate	2 (3%)	—	0	—
Motor tics	—	3 (6%)	—	9 (9%)
Tics, overall	4 (12%)	—	0 (0%)	—
Mild	4 (12%)	—	0	—
Moderate	0	—	0	—
Other (non-tic) motor abnormalities (e.g., clumsiness, motoric hyperactivity, speech disorders)	—	0	—	2 (2%)
Motor symptoms (e.g., handwriting changes, hyperactivity), overall	4 (12%)	—	0 (0%)	—
Mild	4 (12%)	—	0	—
Moderate	0	—	0	—
IPR: Somatic signs and symptoms (e.g., sleep disturbance and urinary symptoms)	—	5 (11%)	—	9 (9%)
MGH: Sleep changes, overall	7 (21%)	—	1 (9%)	—
Mild	6 (18%)	—	1 (9%)	—
Moderate	1 (3%)	—	0	—
MGH: Increased urinary frequency, incontinence, or bed-wetting, overall	0	—	0	—
Mild	0	—	0	—
Moderate	0	—	0	—
None of the above	20 (59%)	43 (81%)	9 (82%)	69 (71%)

Severity of symptoms following COVID-19 vaccination in clinic population (MGH sample only).

74% report formal diagnoses of PANS and/or PANDAS.

Mild—you notice symptoms, but they aren’t a problem.

Moderate—symptoms limit your normal daily activities.

Severe—symptoms make normal daily activities difficult or impossible.

Vaccine hesitancy

Among parents of PANS/PANDAS patients who had not yet vaccinated their children for COVID-19 at the time of the study (MGH: 21.1%, IPR: 60%), 67% of MGH and 73% of IPR cases reported no plan to vaccinate them (see Table 6). The most frequently reported reason (81% and 43%, respectively) was uncertainty about potential increases in PANS/PANDAS-related symptoms. Among the small number of MGH subjects who had received one dose but not the second (n = 5), all planned to get the second dose. The six IPR cases not committed to a second dose cited fear of triggering a PANS/PANDAS flare (n = 4) or side effects from the first dose (n = 2) as the reason.

Table 6.

Explanations for COVID-19 Non-Vaccination (First and/or Second Dose) at the Time of Survey, N = 296

	MGH(n = 12)	IPR cases^a (n = 221)	IPR siblings(n = 63)
At this point in time, are you planning to vaccinate your child against COVID-19 (first dose)?
Yes	1 (8%)	15 (7%)	9 (14%)
No	8 (67%)	162 (73%)	38 (60%)
Unsure	3 (25%)	44 (20%)	16 (25%)
Among those who had not been vaccinated: What is/are the main reason(s)^b you hesitate or don’t plan to vaccinate your child against COVID-19 (for the first dose)?	n = 11	n = 206	n = 54
My child is allergic to other vaccine	2 (18%)	14 (7%)	2 (4%)
Not sure if it is safe	6 (55%)	22 (11%)	12 (22%)
Not enough information is available on the vaccine	5 (45%)	25 (12%)	10 (19%)
Not sure if it will cause a flare up of my child’s PANS/PANDAS	9 (81%)	90 (43%)	NA
I do not believe in vaccines	0	10 (5%)	3 (6%)
Other	2 (18%)	45 (22%)	27 (50%)
Among those who completed a first dose but not a second: Are you planning to give your child a second dose of the COVID-19 vaccine?	n = 5	n = 26	n = 4
Yes	5 (100%)	20 (77%)	4 (100%)
No	0	1 (4%)	0
Unsure	0	5 (19%)	0

74% report formal diagnoses of PANS and/or PANDAS.

MGH allowed for more than one response; IPR allowed for one response.

Discussion

The aim of this study was to understand the impact of COVID-19 infection and vaccination on children with PANS/PANDAS. Data were collected from caregivers of a large sample of children who were diagnosed with or suspected of having PANS/PANDAS and from a clinical sample of children who had a verified diagnosis of PANS/PANDAS. Similar to findings in the general pediatric population (Hause et al., 2021b, 2021a), our results found that children with PANS/PANDAS generally had mild to moderate symptoms of COVID-19 following a COVID-19 infection, with only 1 of the 85 patients across samples requiring hospitalization. Prevalence of specific COVID-19 symptoms reported were similar between both IPR cases and unaffected siblings, suggesting that children with PANS/PANDAS may not be at increased risk for severe symptoms following COVID-19 infection.

New or worsening PANS/PANDAS symptoms after COVID-19 infection were also evaluated. Caregivers reported that IPR cases who were experiencing PANS/PANDAS symptoms at the time of COVID-19 infection had exacerbations of various PANS/PANDAS symptoms, while those who were not experiencing symptoms of PANS/PANDAS at the time of COVID-19 infection did not endorse any new or worsening symptoms. Our findings are in line with a survey study by LaRusso and Abadia, which found that children who were exhibiting PANS/PANDAS symptoms were more likely to experience an increase in symptoms, compared to their remitted counterparts (LaRusso and Abadia, 2023). While the CDC did not explicitly track these symptoms in the general population (Myers et al., 2023), this is consistent with case reports showing exacerbations of psychiatric symptoms in other anxiety and OCD-related disorders (Bartley et al., 2021; Efe, 2022; Jayakumar et al., 2023; Nazeer and Reddy, 2022).

Similar to COVID-19 infections, COVID-19 vaccinations were associated with generally mild to moderate COVID-19 symptoms in both patients with PANS/PANDAS and unaffected siblings. Approximately 59% of the MGH sample and 82% of the IPR cases experienced mild to moderate local reactions at the injection site in the week following the first COVID-19 vaccination, and 64% (MGH) and 50% (IPR cases) of children experienced some type of systemic reaction, most commonly fatigue or headache. This is comparable to the reported prevalence observed in the general population. A randomized control trial of the Pfizer BioNTech (BNT162b2) COVID-19 vaccine found that most local and systemic reactions in children ages 5–11 years were mild to moderate. The most common local reaction was injection site pain (71%–74% of the sample), and the most common systemic events were also fatigue and headache (Walter et al., 2022). Overall, rates of side effects from COVID-19 vaccination in this population of children with PANS/PANDAS appear to be comparable to the general population both in prevalence and severity.

In the general population, rates of vaccination among children are high. For example, approximately 90.8% of children in the US are vaccinated for measles, mumps, and rubella (CDC, 2021). In March of 2021, before COVID-19 vaccines were available, vaccine hesitancy among parents of children ages 12–15 years in the general population was around 28.9% (Ruiz and Bell, 2022). Parents of children with PANS/PANDAS also endorsed vaccine refusal (29.9%) and hesitancy (44.2%) in anticipation of a vaccine becoming available (O’Dor et al., 2024).

By the start of data collection for this study, all children ages ≥5 were eligible to receive vaccinations for COVID-19 under an Emergency Use Authorization by the Food and Drug Administration (Hause et al., 2021a, 2021b), but a subset of our sample did not plan to vaccinate their children with PANS/PANDAS. Our data suggest vaccine refusal and hesitancy were variable based on the study sample. For the MGH sample, approximately 14% said they would refuse to vaccinate their child, and 5% were hesitant to vaccinate. For the IPR cases, the results were higher at 44% and 12%, respectively. Vaccine refusal and hesitancy were similar among IPR-unaffected siblings at 36% and 15%, respectively, suggesting that parental attitudes towards COVID-19 vaccination were consistent within individual parents and were not specific to their children with PANS/PANDAS. Despite the strong concordance between the MGH and IPR samples in other metrics assessed (e.g., vaccine and COVID-19 side effect rates), the large discrepancy in refusal and hesitance rates was noteworthy. While the sample from MGH consisted primarily of children residing in Massachusetts, where coverage with at least one vaccine dose was relatively high (∼89%) by the end of data collection (Massachusetts Departments of Public Health, 2022; U.S. Census Bureau, 2022), the IPR survey sample consisted of families residing across the United States and Canada (Masterson and Gavin, 2024). Previous research suggests that, among parents of children with PANDAS, vaccine refusal and hesitancy are highly correlated with voting trends in the 2020 presidential election and the geographic area of residence (O’Dor et al., 2024). Therefore, it is possible that differing cultural influences between the two samples may have played a factor in vaccine refusal and hesitancy.

Reasons for vaccine refusal and hesitancy may also provide insights into parents’ decision-making. The primary reason cited by parents in both groups was the concern that the COVID-19 vaccine would cause an exacerbation of PANS/PANDAS symptoms in their child with PANS/PANDAS. Prior to the COVID-19 pandemic, a panel of experts in PANS/PANDAS advised that children with PANS/PANDAS should receive all standard childhood vaccines as well as yearly influenza immunizations (Cooperstock et al., 2017). They stated that PANS/PANDAS symptom flares were found to be uncommon, brief, and manageable with medication, though no controlled study has been conducted (Cooperstock et al., 2017). Our results suggest that COVID-19 vaccination may follow a similar pattern in children with PANS/PANDAS, with most subjects not experiencing any new or worsening PANS/PANDAS symptoms, while those with symptoms at the time of vaccination experienced a mild increase in symptom severity.

While our data suggest that children with PANS/PANDAS symptoms at the time of vaccination experienced a mild increase in PANS/PANDAS symptoms following vaccination, this finding should be interpreted with caution. This study was limited by retrospective reporting, and therefore conclusions about causality cannot be drawn. Additional research that utilizes a prospective longitudinal design is needed before implementing changes to the standards of care for vaccine schedules in children with PANS/PANDAS.

The data for this study were taken during the COVID-19 pandemic, and therefore, there were several external elements for which we could not control. Most children in this study received the Pfizer-BioNTech SARS-CoV-2 vaccine due to its authorization in a broader age range. Few in our cohorts received vaccines from other manufacturers, and therefore we were underpowered to analyze whether results differed by vaccine manufacturer. The utilization of two independent populations increased the robustness and generalizability of study results, but key differences should be noted. The data for each sample was collected at overlapping but slightly different times (MGH: 11/21-05/22; IPR: 12/21-2/22). Therefore, there may be differences between samples related to infection rates, COVID-19 strains, and availability of vaccines. These factors may also impact the generalizability of these results at other timeframes and may not speak to the impact of COVID-19 infections from strains that were not prevalent in 2021–2022. For the IPR sample, a diagnosis of PANS was based solely on parent report. Although a large portion of parents said that a clinician had provided the diagnosis of PANS, this could not be verified. This study included patients with both PANS and PANDAS, though only the MGH sample specified whether a patient met criteria for PANS or PANDAS. In both cohorts, there may be selection bias based on which individuals chose to participate in this voluntary study. Attempts were made within each sample to obtain prospective reporting of the child’s side effects following vaccination, but too few individuals completed this portion of the study to allow for the analysis of these results. Therefore, results are based entirely on retrospective reporting and may be subject to recall bias. Since vaccination status at the time of infection was unknown, we could not evaluate whether outcomes differed based on vaccination status. It is highly recommended that additional research be conducted to evaluate the impact of COVID-19 infections and vaccinations on children with PANS/PANDAS. As COVID strains evolve and a variety of vaccines are available, studies are needed to determine outcomes of COVID-19 infection, side effects of COVID-19 vaccination, and subsequent treatments for exacerbations of PANS/PANDAS symptoms that may be related to infection/vaccination.

Despite these limitations, our study design using two samples of children with PANS/PANDAS, including the healthy siblings from the IPR, helps to provide additional insights into the relationship between COVID-19 infection and vaccination in this unique population. Our results suggest that COVID-19 symptoms in children with PANS/PANDAS are typically mild to moderate. Similar to the general population, side effects from the COVID-19 vaccine for children with PANS/PANDAS are relatively common and tend to be mild to moderate in severity. Symptoms of PANS/PANDAS may be exacerbated following COVID-19 vaccination and infection, although this is more likely for children who were already symptomatic with PANS/PANDAS. Given variable rates of vaccine refusal and hesitancy among parents of children with PANS/PANDAS, this data may aid parents in making an informed choice for their children with regard to COVID-19 vaccination.

Conclusions

In two samples of children with PANS/PANDAS, mild/minor COVID-19 symptoms were common (62%–75%) following COVID-19 infection. Only patients currently experiencing PANS/PANDAS-related symptoms at the time of infection experienced an exacerbation of PANS/PANDAS symptoms, while those who had remitted did not report any PANS/PANDAS symptom exacerbations after infection. Following the first COVID-19 vaccine dose, side effects were common and were mostly mild to moderate. Most patients did not report new or worsening PANS/PANDAS-related symptoms post-vaccination, irrespective of symptomatic status at vaccination.

Clinical Significance

Similar to the general population, few children with PANS/PANDAS seem to develop serious complications following COVID-19 infection and vaccination. While most children reportedly did not experience new or worsening PANS/PANDAS symptoms after a COVID-19 infection or vaccination, PANS/PANDAS symptom exacerbation may be more likely following COVID-19 infection in children who are currently experiencing PANS/PANDAS symptoms compared to those that have remitted.

Footnotes

Acknowledgments

The authors thank the participating families for their dedicated time and commitment to their community goal of building the IPR. The authors would also like to thank the families of the Pediatric Neuropsychiatry and Immunology Program at MGH who participated in this project.

Disclosures

K.A.W. has received research support from PANDAS Network, PANDAS Physician’s Network, the International Obsessive Compulsive Foundation, Alex Manfull Foundation, and the Fidelity Research Bioscience Initiative. He has also received consultation reimbursement from Pfizer and Octapharma. S.O’D. has received research support from the American Psychological Foundation and the International Obsessive Compulsive Foundation. J.G. has received consultation reimbursement from Octapharma.

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