First defined by De Quervain, subacute thyroiditis is a self-limited inflammatory disorder of the thyroid gland. The disease is most prevalent in females, usually characterized by a sudden onset of neck pain and thyrotoxicosis. Clinically the disease has several characteristics typical of viral infections including a typical viral prodrome with myalgias, malaise and fatigue. Recurrent subacute thyroiditis has been reported [
2]. The follicles are often infiltrated, resulting in disrupted basement membrane and rupture of the follicles. The thyroid injury in subacute thyroiditis is thought to be the result of cytolytic T-cell recognition of viral and cell antigens present in an appropriate complex [
3].
I-A/Epidemiological evidence
The first descriptions showed a tendency for the disease to follow upper respiratory tract infections or sore throats, which explained why a viral infection has most often been implicated as the cause. Clusters of the disease have been reported during outbreaks of viral infection [
4]. Onset of the disease are observed between June and September and this seasonal distribution is almost identical to that of established infections due to some enteroviruses (Echovirus, Coxsackievirus A and B), suggesting that enterovirus infections might be responsible for a large proportion of cases [
5,
6].
An association between subacute thyroiditis and HLA B35 is noted in all ethnic groups tested [
7] and two-thirds of patients manifest HLA-B35. Familial occurrence of subacute thyroiditis [
8] and recurrence during the course of time [
9] are associated with HLA B35. Thus, the onset of subacute thyroiditis is genetically influenced and it appears that subacute thyroiditis might occur through a susceptibility to viral infection in genetically predisposed individuals. HLA-B35 has been reported to be correlated with chronic active hepatitis, with hepatitis B [
10], with rapid progression of AIDS [
11] and with the T lymphocyte responses against human parvovirus B19 [
12]. Recently, the medical records of 852 patients with subacute thyroiditis have been studied. The significant seasonal clusters of subacute thyroiditis during summer to early autumn was confirmed. According to the authors, "the history of patients showed no obvious association with virus infection". Unfortunately, no data on infections are available in the paper [
2].
I-B/Virological data
Virus-like particles were first demonstrated in the follicular epithelium of a patient suffering from subacute thyroiditis. Judging from the size, it was thought to be influenza or mumps virus [
13], which was concordant with an increased frequency of antibodies to the influenza B virus in patients with thyrotoxicosis [
14]. The same year, in five out of 28 patients with subacute thyroiditis, a cytopathic virus was isolated by coculturing patient samples with susceptible cell lines[
15]. The agent was later studied by electron microscopy and classified as a paramyxovirus [
16]. Subsequently, the agent was reanalyzed by immunofluorescence and electron microscopy and was reclassified as a foamy virus [
17]. However, the implication of foamy virus has not been confirmed: a more comprehensive study using different techniques demonstrated no association between foamy-virus infection and thyroiditis in 19 patients [
18]. Moreover the expression of HFV gag proteins had not been found by indirect immunofluorescence [
19]. As part of a larger study investigating the prevalence of foamy-virus infection in humans, 59 patients with thyroid disorders, including 28 with Quervain's thyroiditis, were analyzed by different techniques including PCR. Again, there was no prevalence of foamy virus infection [
20]. The origin of the foamy-virus-like agent in the original publications remains unclear, but because the more comprehensive study was unable to detect foamy-virus infection in de Quervain patients, it is highly unlikely that it is a causative agent of this condition [
21].
Some cases could be due to the mumps virus. Subacute thyroiditis has occurred in epidemic form: patients with subacute thyroiditis diagnosed during a mumps epidemic were found to have circulating anti-mumps antibodies even without clinical evidence of mumps [
22]. High titers of mumps antibodies have been found in some patients with subacute thyroiditis, and occasionally parotitis or orchitis, usual in mumps, were associated with thyroiditis [
23]. In favor of thyroid infection is the fact that in two patients out of 11 with subacute thyroiditis diagnosed during a mumps epidemic, the mumps virus was cultured from thyroid tissue obtained at biopsy [
22].
Enteroviruses have been suspected. Patients with subacute thyroiditis, who had no clinical evidence of viral disease, demonstrated increases by at least four times in viral antibodies. These viral antibodies included antibodies to mumps virus, but also coxsackie, adenovirus and influenzae. Coxsackie viral antibodies were the most commonly found, and the changes in their titers most closely approximated the course of the disease [
24]. In a case report, thyroiditis was attributed to enterovirus: IgM and IgG were found at a quadruple titer against coxsackievirus B4 whereas no other antibodies were found against other coxsackies, echoviruses or mumps [
25]. In 27 consecutive patients with subacute thyroiditis, antibody tests, virus isolation and antigen detection were negative. Enterovirus RNA was not detected by RT-PCR neither in blood samples nor in the thyroid tissue in the fine-needle aspiration samples. Common respiratory viruses were also screened. There was no evidence of viral infections, except one patient who had acute CMV infection[
26].
Case reports have implicated – CMV in an infant with acute infection and – EBV in an adult female because of positivity for Epstein-Barr virus-specific antibodies and in a 3-year-old girl suffering from infectious mononucleosis because of the presence of EBV DNA both in plasma and leukocytes [
27‐
29]. However, when thyroid specimens of nine patients obtained by fine-needle aspiration biopsy were examined, no EBV or CMV DNA was detected [
30]. Serum virus-specific antibodies to measles, rubella, mumps, type I herpes, chicken pox, human parvovirus B19 and CMV were found in 10 patients during the course of illness. In spite of the presence of IgG to each virus in more than 70% of patients, changes in the IgG titers were observed for those to measles, rubella, chicken pox or CMV in 4 patients [
30]. In an adult female, subacute thyroiditis was diagnosed one month after acute infection suggesting that rubella virus could also be implicated [
31].
Viral antibody titers to common respiratory tract viruses are often elevated. Since the titers fall promptly and are not increased during recurrence [
9] and since multiple viral antibodies may appear in the same patient, the elevation could be an anamnestic response due to the inflammatory condition [
32].
Although the search for a viral cause is usually unrewarding, it appears that the thyroid could respond with thyroiditis after invasion by a variety of different viruses and that no single agent is likely to be causative in the syndrome of subacute thyroiditis.