Abstract
Background
COVID-19 infection and/or vaccination has been repeatedly reported to be the cause of initiating thyroid disease. Limited studies explored the impact of COVID-19 infection and/or vaccination on patients with thyroiditis history.
Objectives
This study aimed to relate COVID-19 infection and vaccination to the development of anti-Thyroid Peroxidase (TPO) auto-antibodies in groups of participants naturally infected with and/or vaccinated for COVID-19, with or without prior history of thyroid disease.
Methods
Participants were grouped into infected only (n = 75), vaccinated only (n = 122), infected and vaccinated (n = 97), infected/vaccinated with prior thyroid disease (n = 35), children (n = 69) and pre-COVID controls (n = 146). Participants were screened for anti-Spike and anti-Nucleocapsid, and anti- TPO antibodies. Anti-TPO positive participants were tested for thyroid function by measuring TSH, free T3 and free T4.
Results
Significantly highest anti-TPO titers (mean = 91.45 IU/mL) and seropositivity rates (42.49%) were found in participants with pre-established thyroid disease. Combined infected and vaccinated participants with no history of thyroid disease also showed significantly higher anti-TPO titers (mean = 74.22 IU/mL, 17.5%) compared to vaccinated only (mean = 48.04 IU/mL, 15.6%), infected only (mean = 31.54 IU/mL, 12%), and control pediatric (mean = 4.8 IU/mL, 1.4%) and pre-COVID (mean = 20.16 IU/mL, 11%) groups. Among anti-TPO positive participants, TSH levels positively correlated with anti-TPO titers. Anti-TPO titers were significantly affected by number of vaccine doses but not with anti-Spike titers, anti-Nucleocapsid titers, number of COVID-19 infections or vaccine types. Age formed a significant factor correlating positively with mean anti-TPO titers. Elevated anti-TPO titers appeared more frequently months after infection and/or vaccination.
Conclusions
With accumulation of COVID-19 related immune events, patients with pre-established thyroid disease showed higher anti-TPO titers compared to those with no history of thyroid disease. This indicates that such immune events might boost the activation of pre-existing TPO specific T and B cells. Clinical follow up of thyroiditis patients during and months after COVID-19 infection/vaccination is essential.
Keywords: COVID-19, COVID-19 vaccination, SARS-CoV-2, Anti- thyroid peroxidase (TPO) antibodies, Thyroid disease
Introduction
Infectious agents are well known to trigger autoimmune flares in humans and animals [1]. Among these, autoimmune thyroiditis has been particularly attributed to viral infections, especially those targeting the respiratory tract [2]. Following the emergence of Coronavirus disease-19 (COVID-19), several studies reported thyroid dysfunctions of potential autoimmune etiology after SARS-CoV-2 infection and/or vaccination [3].
Evidence linking SARS-CoV-2 to autoimmune thyroiditis, however, remains inconsistent. Increased anti-thyroid peroxidase antibodies (anti-TPO) have been observed in hospitalized patients compared with pre-pandemic and healthy controls [4], and rising anti-TPO titers 3–6 months post-COVID-19 suggest new-onset or persistent subclinical hypothyroidism [5]. Conversely, other studies found no significant differences in thyroid function or anti-TPO levels between convalescent patients and healthy controls, although thyroid volume was reduced in convalescents [6, 7].
Findings regarding vaccine-induced thyroid autoimmunity are similarly conflicting. Lui et al. (2022) reported a moderate increase in anti-TPO levels, particularly following mRNA-based vaccination, without clinically significant thyroid dysfunction [8]. In contrast, recipients of inactivated virus vaccines showed no changes in anti-TPO titers pre- and post-vaccination, suggesting minimal autoimmune impact [9]. A review of 83 post-vaccination thyroiditis cases found that most involved subacute thyroiditis (SAT) or Graves’ disease, primarily after mRNA vaccination [10].
COVID-19–related autoimmune thyroiditis likely results from molecular mimicry between SARS-CoV-2 and thyroid antigens such as TPO [11–13] and activation of autoreactive T and B cells by infection or vaccination [14]. Another suggested mechanism is through direct viral injury to thyroid follicular cells expressing viral entry receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), potentially promoting thyroid damage and autoimmunity [15, 16].
Few studies have assessed COVID-19 infection and/or vaccination in individuals with pre-existing thyroid disease, and none have examined the cumulative impact of immune events from both exposures on autoimmune thyroiditis development. Defining each infection or vaccine dose as an immune event, this study investigates the role of SARS-CoV-2 in inducing autoimmune thyroiditis across participants with varying infection and/or vaccination histories, including those with established thyroid disease, children, and pre-COVID controls.
Materials and methods
Participants, setting, sample collection and ethical consideration
This study used a cross-sectional design and convenience sampling methodology. The 544 serum samples used here were collected for various purposes of previously published studies. These were grouped into 6 different groups as detailed below. All samples, demographic and clinical data were collected after obtaining consents from participants or, in the case of children, their guardians. Ethical approval for each study is listed in the grouping below. All samples were stored at − 20⸰C until further use.
Group 1 (G1)
75 participants naturally infected with COVID-19, not vaccinated, and with no history of thyroid disease. Infection was confirmed by real time polymerase chain reaction (RT-PCR). Samples, demographic and clinical data were collected from participants recruited at Prince Hamza Hospital (PHH) inpatient or outpatient departments between May 2020 and August 2021 [17, 18]. The study adhered to the guidelines of the Declaration of Helsinki and was approved by the institutional review board (IRB) committee at the Hashemite University (No. 88 6/7/2020/2021) and PHH.
Group 2 (G2)
122 participants fully vaccinated, with no reported infection of COVID-19, and no history of thyroid disease. Participants are Jordanian adults who received two doses of either Sinopharm or Pfizer-BioNTech vaccines. Samples, demographic and clinical data were collected 2 weeks post the second vaccine dose between March and April 2021 [19] The study adhered to the guidelines of the Declaration of Helsinki and was approved by the IRB committee at the Hashemite University (No. 6/7/2020/2021).
Group 3 (G3)
97 participants both infected and vaccinated, with no history of thyroid disease. Participants are adult Jordanians recruited at PHH between July and October 2022. Samples, demographic and clinical data were collected from participants after a mean of 413.4 days (± 135.3 days) from receiving the last vaccine dose. Participants had at least one PCR confirmed COVID-19 infection, and received a minimum one dose of either Sinopharm, Pfizer-BioNTech or AstraZeneca vaccines. This study adhered to the guidelines of the Declaration of Helsinki and was approved by the IRB committee at the Hashemite University (No.22/4/2021/2022) and PHH [20].
Group 4 (G4)
35 participants, approximately half (51.4%) with reported natural infection, all vaccinated, with pre-established thyroid disease. COVID-19 infection was confirmed by RT-PCR. Participants received at least one dose of either Sinopharm, Pfizer-BioNTech or AstraZeneca vaccines. Samples, demographic and clinical data were collected from participants recruited at PHH between July and October 2022. Samples and data were collected after 431.14 ± 128.43 days of receiving the last vaccine dose. This study adhered to the guidelines of the Declaration of Helsinki and was approved by the IRB committee at the Hashemite University (No.22/4/2021/2022) and PHH [20].
Group 5 (G5)
69 random Jordanian children with or without reported history of COVID-19 infection, and no vaccination. Infection history was based on parents’ report of either PCR confirmation or symptoms. Children voluntarily participated in the study, after their guardians’ agreement. Samples, Socio-demographic and previous history of COVID-19 infection data were collected for each child at health centers in Central Jordan between July and November 2022. The study adhered to the guidelines of the Declaration of Helsinki and was approved by the IRB committee at the Hashemite University (No.22/4/2021/2022) and PHH [21].
Group 6 (G6)
In a cross-sectional study, from June to September 2018, 146 university students were interviewed and asked about fast-food consumption and other dietary habits. Participants’ samples, socio-demographic characteristics and clinical data were collected from participants who agreed to participate. Samples from this group were collected pre-COVID-19 and thus have no history of COVID-19 infection or vaccination. The study adhered to the guidelines of the Declaration of Helsinki and was approved by the IRB committee at Yarmouk University in Northern Jordan (No. 15/2017) [22, 23].
Anti-spike IgG measurement
Samples of groups 1, 2, 3, 4 and 5 were previously tested for the presence of anti-spike protein (anti-S) antibodies [18–21] using an Enzyme Linked Fluorescent Assay (VIDAS®, Biomerieux inc., Hazelwood, MO, USA). The ratio between relative fluorescence value measured in the sample and that obtained for the calibrator (humanized recombinant anti-S antibody) was calculated and used as index for result interpretation. An index of 1 or more was considered positive and that of less than 1 was considered negative. A standard equation that complies with the World Health Organization standards was used to convert readings into binding antibody units per milliliter (BAU/mL).
Anti-nucleocapsid IgG measurement
Samples of groups 1, 2, 3, 4 and 5 were previously tested for the presence of anti-nucleocapsid (anti-N) antibodies [17, 18, 20, 21]. IgG and IgM against Coronavirus Nucleocapsid were detected using COVID-19 IgG/IgM Duo for quantitative analysis (NanoEntek/Korea). The protocol was run according to manufacturer instructions. System readings > 1.00 U/mL were considered positive.
Anti-TPO measurement
Anti-TPO antibody quantification was performed using two-step immune-enzymatic test by BS-200 chemistry analyzer (Mindray, China) in this study. The analyzer automatically calculates each sample’s analyte concentration on the master calibration curve read from the barcode and a 4-Parameter Logistic Curve Fitting (4PLC) with RLUs from anti-TPO calibrators of predetermined concentration values. System readings > 9.00 IU/mL were considered positive.
TSH, FT3 and FT4 measurement
Only anti-TPO positive samples were analyzed for thyroid functions, given availability of samples. Testing included the measurement of TSH, FT3 and FT4 hormone levels.
A Mindray automated chemiluminescence immunoassay analyzer CL-9000i (Mindray, China) was used to determine serum TSH, FT3, and FT4 levels, using reagents provided by Shenzhen Mindray Biomedical Electronics Co., Ltd. (Mindray, China). The analyzer measured each sample’s analyte concentration using the master calibration curve read from the barcode and a 4-Parameter Logistic Curve Fitting (4PLC) employing relative light units (RLUs) from three-level calibrators of defined concentration values. Analyzer results were revealed in µIU/mL, pg/mL, and pmol/L for TSH, FT3, and FT4 respectively. The normal reference range used for TSH according to manufacturer and laboratory reference standards was as follow: 6 days-3 months 0.7–11.0, 4–12 months 0.73–8.35, ˃1 year-˂6 years 0.7–5.97, 4–19 years 0.4–6.2, 20–54 years 0.27–4.2, 55–100 years 0.5–8.9). The reference normal range for FT3 was 11–19 years 2.56–5.01, 20–39 years 2.38–4.37, 40–69 years 2.43–3.98. The normal reference range for FT4 was 6.44-19-8.02.
Statistical analysis
Analysis was performed using the Statistical Package for the Social Sciences (SPSS, version 21.0 Chicago, IL, USA). Descriptive statistics were presented as frequency and percentage or mean and standard deviation (SD). Significant difference between frequencies was assessed using the Chi-square test or Fisher’s exact test while significant differences between means was assessed using Student’s t-test or one-way ANOVA followed by LSD post-hoc test. Correlations between continuous variables were analyzed using the Pearson bivariate correlation test with correlation coefficient values (R). Multivariate linear model was used for analysis. Multiple linear regression model was used to predict the relative effect of different independent variables on the continuous dependent variable (the main outcome: anti-TPO titer). The contribution of each independent variable was measured using Beta coefficient and P-value. A P-value ≤ 0.05 was considered to indicate statistical significance.
Results
Demographic and COVID-19 history of population study
Table 1 enlists the 544 participants of this study. As shown in groups’ details above, these participants were previously recruited for various purposes. Hence, data collected for different groups are variable and sometimes not available or not applicable (NA).
Table 1.
Demographic, clinical, and COVID-19 infection and vaccination data of study population
| Group number | G1 | G2 | G3 | G4 | G5 | G6 | P-value | |
|---|---|---|---|---|---|---|---|---|
| Group description | Category | COVID-19 infection only N (%) |
COVID-19 vaccination only N (%) | COVID-19 vaccination and infection N (%) | Thyroid disease N (%) | Pediatric control N (%) |
Pre-COVID-19 control N (%) |
|
| Number of cases | 75 | 122 | 97 | 35 | 69 | 146 | - | |
| Age | Mean ± SD | 38.43 ± 15.69 | 43.93 ± 13.20 | 43.51 ± 11.64 | 46.86 ± 11.57 | 7.38 ± 4.88 | 24.95 ± 8.99 | 0.000 |
| Gender | Male | 40 (53.3) | 68 (55.7) | 45 (46.4) | 3 (8.6) | 37 (53.6) | 93 (63.7) | 0.000 |
| Female | 35 (46.7) | 54 (44.3) | 52 (53.6) | 32 (91.4) | 32 (46.4) | 53 (36.3) | ||
| Admission type | Outpatients | 34 (45.3) | 122 (100) | 87 (89.7) | 35 (100) | NA | NA | 0.000 |
| Inpatients | 41 (54.7) | 0 (0) | 10 (10.3) | 0 (0) | ||||
| Body Mass Index | Underweight < 18.5 | 2 (2.7) | 5 (4.1) | 3 (3.1) | 0 (0) | NA | NA | 0.270 |
| Normal 18.5–24.9 | 19 (25.3) | 39 (32.0) | 27 (27.8) | 10 (28.6) | ||||
| Overweight 25-29.9 | 30 (40.0) | 42 (34.4) | 46 (47.4) | 11 (31.4) | ||||
| Obese ≥ 30 | 24 (32.0) | 36 (29.5) | 21 (21.6) | 14 (40.0) | ||||
| Chronic diseases * | Yes | 16 (21.3) | 68 (55.7) | 51 (52.6) | 35 (100) | NA | NA | 0.000 |
| No | 59 (78.7) | 54 (44.3) | 46 (47.4) | 0 (0) | ||||
| Thyroid diseases | Yes | 0 (0) | 0 (0) | 0 (0) | 35 (100) | NA | NA | 0.000 |
| No | 75 (100) | 122 (100) | 97 (100) | 0 (0) | ||||
| Smoking | Yes | 30 (40.0) | 50 (41.0) | 36 (37.1) | 5 (14.3) | 0 (0) | NA | 0.000 |
| No | 45 (60.00 | 72 (59.0) | 61 (62.9) | 30 (85.7) | 69 (100) | |||
| Pregnancy | Yes | 1 (1.3) | 2 (1.6) | 2 (2.1) | 1 (2.9) | NA | NA | 0.734 |
| No | 74 (98.7) | 120 (98.4) | 95 (97.9) | 34 (97.1) | ||||
| COVID-19 infection | Yes | 75 (100) | 0 (0) | 97 (100) | 18 (51.4) | 28 (40.6) | 0 (0) | 0.000 |
| No | 0 (0) | 122 (100) | 0 (0) | 17 (48.6) | 41 (59.4) | 146 (100) | ||
| COVID-19 symptoms | Yes | 32 (42.7) | 0 (0) | 28 (28.9) | 10 (28.6) | 28 (40.6) | NA | 0.000 |
| No | 43 (57.3) | 122 (100) | 69 (71.1) | 25 (71.4) | 41 (59.4) | |||
| COVID-19 PCR | Positive | 75 (100) | 0 (0) | 86 (88.7) | 14 (40.0) | 13 (18.8) | NA | 0.000 |
| Negative | 0 (0) | 122 (100) | 11 (11.3) | 21 (60.0) | 56 (81.2) | |||
| COVID-19 vaccination | Yes | 0 (0) | 122 (100) | 97 (100) | 35 (100) | 0 (0) | 0 (0) | 0.000 |
| No | 75 (100) | 0 (0) | 0 (0) | 0 (0) | 69 (100) | 146 (100) | ||
| Duration from last COVID-19 disease/vaccination to sampling (days) | Mean ± SD | 93.49 ± 117.40 | 425.0 ± 130.30 | 414.90 ± 131.21 | 431.14 ± 128.43 | 377.0 ± 138.52 | NA | 0.000 |
NA: not available or not applicable. *Chronic diseases: all chronic medical illness except thyroid diseases (Diabetes Mellitus, hypertension, hyperlipidemia, cardiac diseases, asthma, and others)
Variations in age and gender distribution were found among groups. Groups 1–4 are mostly middle-aged participants (means of 38 to 46 years), whereas control group 6 constitutes of young university students. Heterogeneity in gender is very profound in group 4 whose participants are mostly females (91.4%), followed by group 6 with a predominance of males (63.7%). Except for group 1, with more than half inpatient participants (54.7%), all other participants were recruited from outpatient clinics/labs (groups 2–5) of from general population (G6). Most patients of group 1 suffered from “other than thyroid” chronic diseases (78.7%). All G4 patients suffered from other chronic illnesses, along with their thyroid disease. Chronic diseases include diabetes mellitus, hypertension, hyperlipidemia, cardiac diseases, asthma, and others. Groups 1–3 had significantly more smoking participants compared to group 4, probably because group 4 participants are mostly females. Group heterogeneity was also reflected in reported COVID-19 infection, COVID-19 symptoms, and COVID-19 PCR results. Similarly, COVID-19 vaccination and duration from last COVID-19 disease/vaccination to sampling (days) were significantly different between groups. This is clearly expected due to the design of study groups as G1 have COVID-19 infection with no COVID-19 vaccination, G2 have COVID-19 vaccination only with no COVID-19 infection, G3 have COVID-19 vaccination and infection, G4 half reported natural infection and all vaccinated, while G5 pediatric control and G6 pre-COVID-19 control have no history of COVID-19 infection and no COVID-19 vaccination (Table 1).
Anti-TPO response is significantly higher in pre-established thyroid disease group followed by infected/vaccinated group
A significant difference in mean anti-TPO titers and positivity rates was observed among groups (Table 2; Fig. 1A). Participants with pre-existing thyroid disease (G4) and those both infected and vaccinated (G3) showed significantly higher anti-TPO titers than pediatric (G5) (P = 0.007 and 0.004, respectively) and pre-COVID-19 controls (G6) (P = 0.014 and 0.007, respectively). Although mean anti-TPO titers were higher in the infection-only (G1) and vaccination-only (G2) groups than in controls, the differences were not significant; the G2–G5 comparison approached significance (P = 0.061). These findings indicate that combined infection and vaccination significantly increase anti-TPO titers.
Table 2.
Laboratory data of study population. Anti-S IgG, anti-N IgG, anti-TPO, TSH, FT3, and FT4
| Group number | G1 | G2 | G3 | G4 | G5 | G6 | P-value | |
|---|---|---|---|---|---|---|---|---|
| Group description | COVID-19 infection N (%) | COVID-19 vaccination only N (%) | COVID-19 vaccination and infection N (%) | Thyroid disease N (%) | Pediatric control N (%) | Pre-COVID-19 control N (%) | ||
| Anti-S COVID-19 IgG results | Positive | 39 (52.0) | 115 (94.3) | 95 (97.9) | 34 (97.1) | 55 (79.7) | NA | 0.000 |
| Negative | 36 (48.0) | 6 (4.9) | 1 (1.0) | 0 (0) | 14 (20.3) | |||
| Not done | 0 (0) | 1 (0.8) | 1 (1.0) | 1 (2.9) | 0 (0) | |||
| Anti-S COVID-19 IgG titer BAU/mL | Mean ± SD | 98.89 ± 146.05 | 400.56 ± 219.27 | 453.88 ± 201.081 | 396.09 ± 217.57 | 181.68 ± 182.21 | NA | 0.000 |
| Anti-N COVID-19 IgG results | Positive | 30 (40.0) | 84 (68.9) | 81 (83.5) | 28 (80.0) | 45 (65.2) | NA | 0.095 |
| Negative | 45 (60.0) | 32 (26.2) | 13 (13.4) | 7 (20.0) | 24 (34.8) | |||
| Not done | 0 (0) | 6 (4.9) | 3 (3.1) | 0 (0) | 0 (0) | |||
| Anti-N COVID-19 IgG titer ng/mL | Mean ± SD | 12.72 ± 6.89 | 8.55 ± 7.55 | 10.57 ± 6.86 | 9.69 ± 8.03 | 6.27 ± 6.55 | NA | 0.142 |
| Anti-TPO results | Positive | 9 (12.0) | 19 (15.6) | 17 (17.5) | 15 (42.9) | 1 (1.4) | 16 (11.0) | 0.000 |
| Negative | 66 (88.0) | 103 (84.4) | 80 (82.5) | 20 (57.1) | 68 (98.6) | 130 (89.0) | ||
| Anti-TPO titer IU/mL | Mean ± SD | 31.54 ± 161.62 | 48.04 ± 175.23 | 74.22 ± 213.90 | 91.45 ± 198.62 | 4.80 ± 19.28 | 20.16 ± 89.35 | 0.009 |
| TSH titer µIU/mL | Mean ± SD | 2.11 ± 1.28 | 4.27 ± 2.77 | 4.44 ± 5.61 | 2.48 ± 2.03 | 1.71 | NA | 0.346 |
| TSH results | Low | 1 (11.1) | 0 (0.0) | 0 (0.0) | 2 (14.3) | 0 (0.0) | NA | 0.344 |
| Normal | 8 (88.9) | 10 (62.5) | 12 (75.0) | 9 (64.3) | 1 (100.0) | |||
| High | 0 (0.0) | 6 (37.5) | 4 (25.0) | 3 (21.4) | 0 (0.0) | |||
| FT3 titer pg/mL | Mean ± SD | 4.50 ± 2.39 | 3.29 ± 1.10 | 3.32 ± 0.91 | 5.64 ± 5.41 | 4.30 | NA | 0.218 |
| FT3 results | Low | 0 (0.0) | 0 (0.0) | 1 (7.1) | 1 (9.1) | 0 (0.0) | NA | 0.519 |
| Normal | 7 (77.8) | 16 (94.1) | 11 (78.6) | 7 (63.6) | 1 (100.0) | |||
| High | 2 (22.2) | 1 (5.9) | 2 (14.3) | 3 (27.3) | 0 (0.0) | |||
| FT4 titer pmol/L | Mean ± SD | 15.56 ± 8.67 | 11.10 ± 3.65 | 11.58 ± 2.04 | 19.27 ± 22.69 | 17.00 | NA | 0.371 |
| FT4 results | Low | 0 (0.0) | 1 (6.2) | 0 (0.0) | 2 (14.3) | 0 (0.0) | NA | 0.101 |
| Normal | 7 (77.8) | 14 (87.5) | 16 (100.0) | 9 (64.0) | 1 (100.0) | |||
| High | 2 (22.2) | 1 (6.2) | 0 (0.0) | 3 (21.4) | 0 (0.0) |
TPO: Thyroid peroxidase, TSH: thyroid stimulating hormone, FT3: free triiodothyronine (T3), FT4: free thyroxine (T4), NA: not available or not applicable
Fig. 1.
(A) Mean anti-TPO titers in different participant groups. (B) The effect of number of immune events on anti-TPO seropositivity rates in G3 and G4. *: P < 0.05, **: P < 0.01, ***: P < 0.0001, ns: not significant. G1: infected only participants, G2: vaccinated only participants, G3: combined infection/vaccination participants, G4: combined infection/vaccination participants with pre-established thyroid disease, G5: pediatric controls mostly infected but not vaccinated, G6: pre-pandemic controls neither infected nor vaccinated
Similarly, anti-TPO positivity was significantly higher in the thyroid disease (42.9%) and infection/vaccination (17.5%) groups compared with pediatric (1.4%) and pre-COVID-19 controls (11.0%) (P < 0.05).
Number of immune events (infection and/or vaccination) significantly correlates with anti-TPO positivity rates
As shown in Fig. 1B, G4 participants with four or more anti–COVID-19 immune events had significantly higher anti-TPO seropositivity than those with three or fewer events (P < 0.0001). Participants with three immune events also showed higher seropositivity than those with two or fewer events. A similar trend was observed in G3 participants, though it did not reach statistical significance.
Anti-TPO titers and TSH levels correlate moderately among G3 and strongly among G4 participants
As shown in Fig. 2, anti-TPO titers correlated positively but weakly with TSH levels among all anti-TPO–positive participants (R = 0.27). This correlation was stronger in G3 (R = 0.47) and strongest in G4 (R = 0.64). In contrast, negative correlations were observed in G1 and G2 participants.
Fig. 2.
The correlation between anti-TPO titers and TSH levels in (A) all anti-TPO positive participants, (B) G3 (combined infection/vaccination participants) and (C) G4 (combined infection/vaccination participants with pre-established thyroid disease)
Among anti-TPO positive participants, TSH, T3 and T4 measures did not show significant differences among groups
No significant differences were observed among groups in mean TSH titers or the frequency of abnormal TSH (Table 2), although G3 had the highest mean TSH. Only G4 and G1 included participants with abnormally low TSH, while G2 had the highest proportion with abnormally high TSH.
For T3, mean titers and abnormal T3 frequency did not differ significantly among groups. Descriptively, G4 had the highest mean T3 and the largest proportion of participants with abnormally high T3, whereas only G4 and G3 included participants with abnormally low T3.
Similarly, no significant differences were found in mean T4 titers or abnormal T4 frequency. G4 had the highest mean T4, while G1 had the highest proportion with abnormally high T4. Abnormally low T4 was observed only in G2 and G4.
Anti COVID-19 IgG response does not correlate with anti-TPO response
The significant inter-group differences in anti-S positivity rates and mean titers (Table 2) were reported previously [17, 18, 20, 21]. Notably, anti-S antibody presence and levels did not correlate with anti-TPO antibodies (P = 0.140, Table 4). Similarly, anti-N responses showed no correlation with anti-TPO positivity or titers.
Table 4.
Correlation between anti-TPO titer and other continuous variables among total study participants (N = 544)
| Factor | Number | Pearson’s correlation coefficient (R) | P-value |
|---|---|---|---|
| Age | 544 | 0.129 | 0.003 |
| Duration days | 357 | 0.080 | 0.131 |
| TSH | 56 | 0.270 | 0.036 |
| FT3 | 53 | − 0.214 | 0.124 |
| FT4 | 56 | − 0.103 | 0.448 |
| Anti-S COVID-19 IgG titer | 395 | 0.074 | 0.140 |
| Anti-N COVID-19 IgG titer | 245 | − 0.011 | 0.859 |
Factors affecting mean anti-TPO titers among groups
The number of COVID-19 vaccine doses was significantly associated with anti-TPO titers, with participants receiving three doses showing the highest mean response (P = 0.007, Table 3). Age showed a weak but significant positive correlation with anti-TPO titers (R = 0.129, P = 0.003), as did TSH levels (R = 0.27, P = 0.036, Table 4). No other variables showed significant correlations.
Table 3.
Factors affecting anti-TPO titer mean according to different categories among total study participants (N = 544)
| Factor | Category | Number | TPO titer Mean ± SD |
P-value |
|---|---|---|---|---|
| Gender | Male | 286 | 35.81 ± 153.15 | 0.479 |
| Female | 258 | 45.20 ± 155.69 | ||
| Body Mass Index | Underweight < 1 | 8 | 18.00 ± 26.85 | 0.242 |
| Normal 18.5–24.9 | 76 | 58.53 ± 186.45 | ||
| Overweight 25-29.9 | 99 | 92.48 ± 252.92 | ||
| Obese ≥ 30 | 71 | 35.41 ± 82.53 | ||
| Chronic diseases | Yes | 116 | 70.91 ± 219.32 | 0.083 |
| No | 282 | 38.06 ± 146.95 | ||
| Smoking | Yes | 91 | 53.98 ± 192.20 | 0.866 |
| No | 232 | 50.35 ± 166.53 | ||
| COVID-19 number of infections | zero | 326 | 30.41 ± 125.40 | 0.104 |
| one | 183 | 49.99 ± 178.66 | ||
| Two | 35 | 81.17 ± 236.33 | ||
| COVID-19 vaccines/number of doses | zero | 290 | 19.45 ± 104.26 | 0.007 |
| one | 7 | 11.00 ± 26.90 | ||
| Two | 195 | 65.11 ± 191.82 | ||
| Three | 52 | 67.10 ± 214.79 | ||
| COVID-19 vaccine type | Sinopharm | 221 | 50.70 ± 147.23 | 0.680 |
| Pfizer-BioNTech | 293 | 72.38 ± 224.58 | ||
| AstraZeneca | 36 | 45.75 ± 104.68 |
Multiple linear regression identified two factors significantly associated with anti-TPO titers: the interval between the last COVID infection or vaccination and blood draw, and the number of COVID-19 infections (P = 0.036 and 0.026, respectively, Table 5). These findings suggest potentially delayed effects of infection or vaccination and further support a link between COVID-19 and autoimmune thyroiditis.
Table 5.
Multiple linear regression analysis of factors affecting anti-TPO titer
| Factor | Beta coefficient | P-value |
|---|---|---|
| Age | -0.028 | 0.906 |
| Gender | -0.216 | 0.413 |
| BMI | -0.402 | 0.770 |
| Duration days | 0.469 | 0.036 |
| Smoking | 0.146 | 0.574 |
| Chronic diseases | -0.443 | 0.079 |
| COVID-19 infection | 0.601 | 0.026 |
| COVID-19 vaccines | 0.064 | 0.072 |
| TSH | 0.042 | 0.851 |
| FT3 | -0.289 | 0.298 |
| FT4 | -0.015 | 0.954 |
| Anti-S COVID-19 IgG titer | 0.011 | 0.964 |
| Anti-N COVID-19 IgG titer | -0.230 | 0.335 |
Discussion
Our major finding is: Along with combined COVID-19 infection and vaccination, significantly highest anti-TPO titers and seropositivity rates showed in participants with pre-established thyroid disease. Combined infection/vaccination participants with no previous history of thyroid disease also showed significantly higher anti-TPO titers compared to vaccinated only, infected only, and control pediatric and pre-COVID groups.
The very few studies published on the status of thyroid disease post infection and/or vaccination in patients with pre- established thyroiditis support our results. Those studies are based on case reports, and not on prevalence investigations. In a systematic review, Tutal et al. (2022) reported that out of 19 patients with post-COVID autoimmune thyroiditis and elevated anti-TPO titers, 9 (47.4%) had known previous thyroid disorders with stable remission [24]. Interestingly, a series of case reports reported changes in the type and/or severity of the primary autoimmune thyroid disease after COVID-19 infection [25].
Our pre-pandemic control group (group 6), showed an anti-TPO seropositivity of 11% (mean titer of 20.16 ± 89.35). Although most of the participants in this group were young adults and males, the anti-TPO response found here is very comparable to the 14.9% national prevalence rate of the Jordanian population in 2017 [26].
The positive correlation between age and autoimmune thyroiditis is an international staple [27, 28]. Our study found age to be a significant factor correlating positively with mean anti-TPO titers. On the other hand, although females are generally known to be more prone to thyroiditis and autoimmunity [27, 28], gender did not show correlation with anti-TPO titers among our groups. Still, > 90% of our pre-establish thyroiditis group consists of female participants.
The fact that COVID-19 infection and vaccination can cause de novo establishment of thyroid disease is contradictory in the literature. Our results show significantly higher anti-TPO titers in the combined COVID-19 infection/vaccination with no pre-established thyroid disease group compared to control pediatric and pre-pandemic groups. Even the infection alone and vaccination alone groups showed higher anti-TPO titers, although not statistically significant. This could indicate a role of SARS-CoV-2 infection or vaccination in inducing autoimmune thyroiditis.
Although significant intergroup differences were observed in age, gender, chronic comorbidities, and COVID-19 infection and vaccination history (Table 1), only age, number of vaccine doses, pre-existing thyroid disease, and cumulative immune events (infection and/or vaccination) demonstrated a significant association with anti-TPO titers (Tables 3 and 4; Figs. 1 and 2). Multiple linear regression analysis (Table 5) further identified the duration since the last COVID-19 infection or vaccination and the number of infections as significant predictors of anti-TPO titers. While analyses presented in Tables 1, 2, 3 and 4; Figs. 1 and 2 are univariate or bivariate and supported by descriptive data, the regression model in Table 5 evaluates the relative contribution and strength of association of each independent variable with the dependent variable (anti-TPO titer).
Multiple cases were reported to develop new-onset Hashimoto’s and Grave’s thyroiditis after COVID-19 infection with positive anti-TPO antibodies [29–32]. Overall, our results show a weak positive correlation between TSH levels and anti-TPO titers, which could indicate the induction of thyroid disease. This correlation was not confirmed with relevant FT3 and FT4 abnormal levels. Whether this could be a transient state of thyroiditis that can self-resolve or not remains a question. Another probability is that the type of thyroiditis could be of the sub-acute type. Interestingly, COVID-19 has been reported to be linked to subacute thyroiditis rather than autoimmune thyroiditis, with negative anti-TPO antibodies, in some cases and is associated with elevated C reactive protein [33, 34]. Supporting our results, a study has shown elevated anti-TPO titers after COVID-19 vaccination with no significant effect on TSH levels. However, in contrary to our study, significant changes were noted in FT3 and FT4 levels post vaccination with no significant changes in anti-TPO antibody seropositivity. This implies that participants most likely to develop post-vaccine thyroiditis are those with pre-existing thyroid illnesses [8]. Other studies have also backed up our findings where subjects with no known thyroidal illnesses had higher anti-TPO antibody titers three months after COVID 19 infection [35]. In another study, TPO antibody seropositivity was concordant with our results where COVID-19 patients had a higher prevalence of positive anti-TPO titers in comparison to controls who weren’t infected [4].
Interestingly, COVID-19 specific anti-S and N titers showed no correlation with anti-TPO titers among all our participants’ groups. No previous studies directly investigated the relation between anti-COVID antibodies and the development of autoimmune thyroiditis. Based on molecular mimicry, we find it difficult to explain the lack of correlation between the magnitude of the anti-virus humoral response and the development of anti-TPO antibodies. A good explanation could be the lack of genetic susceptibility. The generation of auto-antibodies due to the presence of shared epitopes between self-antigens and virus is dependent on factors such as HLA type of the host [10].
Many studies proved that strong inflammation correlates with symptom severity of COVID-19 [17, 18]. We have not collected inflammatory measures of our participants; however, we did ask our participants whether their viral illness lead to hospitalization or not. We found no correlation between anti-TPO positivity/titers, and the status of being inpatients or outpatients at the time of sample collection.
To our knowledge, no studies reported the effect of number of doses of COVID-19 vaccination, or the effect of combined COVID-19 infection and vaccination, on anti-TPO positivity and titers. As previously stated, evidence of elevated anti-TPO titers was reported in infection and vaccination groups separately, potentially justifying why our co-infection/vaccinated participants had amongst the highest anti-TPO responses. Our results show that anti-TPO titers correlate significantly with number of infections and vaccine doses. We have also demonstrated how the accumulation of immune events (infection and vaccination) caused and increase in anti-TPO seropositivity, especially in the thyroid disease group. The presence of pre-established thyroid disease could indicate the presence of anti-TPO specific T and B cells that could get activated with each infection and or vaccination, whether due to molecular mimicry in the context of a susceptible genetic background, bystander activation by the inflammatory response induced by infection/vaccination, epitope spread, or due to virus induced thyroid injury. Activation of persistent viruses (other than SARS-CoV-2) proved to augment autoimmunity through the several forementioned mechanisms [36].
Our results show that elevated anti-TPO titers appeared more frequently later after infection and/or vaccination. In agreement with the literature [8, 35], anti-TPO titers correlated positively with sampling timing; days after the last infection/vaccination. Interestingly, very recent speculations that long COVID-19 is an autoimmune disorder either activated from a pre-established condition or induced by the virus after infection have been published [37]. Long COVID-19 is a serious condition of symptoms lasting chronically for weeks, months or even years post-SARS-CoV-2 infection [38]. A recent study by Matula et al. (2024) reported a much higher anti-TPO response > 1.5 years post-infection among a group of healthcare workers with long COVID symptoms (79%) compared to convalescent controls (18.5%) [39]. Interestingly, only 3 out of the 19 anti-TPO positive long COVID participants showed abnormal TSH titers, and 11/19 proved to have a prior history of elevated anti-TPO. In another study, Alphan et al. (2023) reported a notable positive link between the post-recovery period after infection, anti-TPO titers and the emergence or persistence of subclinical hypothyroidism [5]. Based on our results and the above, we recommend monitoring thyroid disease including autoimmune measures in long COVID patients and in patients with pre-established thyroid disease. Further investigations are required to clarify the etiological link between elevated anti-TPO titers and long COVID.
Limitations
This study was limited by many ways: 1- Sample number variation among groups. 2- Low number of samples per group; especially G4. 3- Variations in demographic and clinical data collected among groups. 2-Lack of follow up data, especially for anti-TPO positive participants mainly because of lack of cooperation. 4- Lack of information on long-COVID-19 symptoms. 5- Lack of information/testing on inflammatory markers of participants.
Conclusions
COVID-19 infection and vaccination have been proposed as triggers of autoimmune thyroiditis, with elevated anti-TPO antibodies as a hallmark. Our findings support this association to some extent, emphasizing the importance of monitoring individuals with elevated anti-TPO titers for potential long COVID manifestations, which may be reflected by persistently moderate anti-spike IgG levels long after infection. While new-onset thyroid autoimmunity following COVID-19 cannot be excluded, our analysis indicates that only age, number of vaccine doses, pre-existing thyroid disease, and cumulative immune events significantly influence anti-TPO titers. Multiple linear regression further identified the duration since the last infection or vaccination and the number of COVID-19 infections as significant predictors. Additionally, a potential contribution of other viral infections, such as influenza, to thyroid autoimmunity cannot be ruled out.
Acknowledgements
NA.
Abbreviations
- TPO
Thyroid Peroxidase
- COVID-19
Coronavirus disease-19
- anti-TPO
Anti-thyroid peroxidase antibodies
- SAT
Subacute thyroiditis
- ACE2
Angiotensin converting enzyme 2
- TMPRSS2
Transmembrane serine protease 2
- RT-PCR
Real time polymerase chain reaction
- PHH
Prince Hamza Hospital
- anti-S
Anti-spike protein
- anti-N
Anti-nucleocapsid
- TSH
Thyroid stimulating hormone
- FT3
Free triiodothyronine
- FT4
Free thyroxine
Author contributions
A. Q.: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review and editingM.T.: Conceptualization, Formal analysis, Methodology, Resources, Visualization, Writing – original draft, Writing – review and editingM.M. A.: Conceptualization, Formal analysis, Resources, Visualization, Writing – review and editingO.J.: Investigation, Writing – original draftS. T.: Investigation, Methodology, Writing – original draftA.S.: Data curation, Investigation, Methodology, Resources, Supervision, Writing – original draft, Writing – review and editingR. A.: Investigation, Writing – original draftM.K.: Investigation, Writing – original draft.
Funding
This research was funded by the Deanship of Scientific Research, The Hashemite University, Zarqa, Jordan (Research fund serial Number 751, research fund project number 52, year of funding 2022).
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study adhered to the guidelines of the Declaration of Helsinki and was approved by the institutional review board (IRB) committee at the Hashemite University (No. 88 6/7/2020/2021) and PHH. IRB committee at the Hashemite University (No.22/4/2021/2022) and PHH (Al-Shudifat et al., 2023). IRB committee at the Hashemite University (No.22/4/2021/2022) and PHH. IRB committee at Yarmouk University in Northern Jordan (No. 15/2017).
Consent for publication
Not applicable.
Informed consent
Informed consent to participate was obtained from all of the participants in the study.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.