Tonsillectomy for PFAPA syndrome (a rare cause of recurrent fever, mouth ulcers, sore throat and swollen neck glands)

Review question

This review compared the clinical effectiveness and safety of removing the palatine tonsils (tonsillectomy), with and without removal of the adenoids, against non-surgical management of children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. We searched for and included any randomised controlled trials published up to October 2013.

Background

PFAPA syndrome is a rare cause of regular, repeated episodes of fever, sore throat and swollen neck glands in children. It is a diagnosis that needs confirmation by paediatricians working in centres with expertise in this condition and most children who suffer from repeated sore throats and tonsillitis will not have it.

Study characteristics

We found two small randomised controlled trials, with a low risk of bias, comparing tonsillectomy or adenotonsillectomy against non-surgical interventions (total of 67 participants, with data from 65 analysed). One study (39 participants) used the adenotonsillectomy procedure in the intervention group and followed up patients for 18 months. This study applied stringent criteria for diagnosing PFAPA when recruiting patients. The other trial (28 participants) only removed the tonsils and followed up patients for up to six months. Less stringent recruitment criteria were applied and it was possible that patients with other types of recurrent sore throats might have been recruited and included in the trial. Neither study masked participants and investigators to the type of treatment received. Participants in the control groups of both studies received standard medical treatment.

Key results

The two trials showed that children with PFAPA are likely to benefit from tonsillectomy. The results showed that children who had surgery were about four times more likely to be free of PFAPA symptoms from the point of surgery until the end of the follow-up periods for these studies. There was an overall decrease in the number or frequency of PFAPA episodes experienced by the children in the surgery group. While the average child in the control arm had an average of one episode every two months, this was reduced to less than one-tenth of that; i.e. about one episode every two years among children who had surgery. In addition, the length of each episode was also shortened by an average of 1.8 days (reduced from an average of 3.5 days to 1.7 days per episode) for children who had surgery.

Courses of corticosteroids can be used to treat episodes of symptoms in children with PFAPA. One trial reported that the proportion of children given a course of corticosteroids was lower in children who received surgery.

The trials reported no complications of surgery. However, these studies might be too small to detect important but rarer types of complications such as bleeding from the surgery. Other outcomes such as quality of life, absence from school or quality of life were not reported.

Quality of evidence

The quality of the evidence is moderate (that is, further research is likely to have an important impact on our confidence in the estimates of effects and may change these estimates). The studies are very small. Studies with larger numbers of patients are required to estimate the effects more precisely. There is also some uncertainly about whether the effects observed in these studies can be replicated in most children with PFAPA for two reasons. It is unclear whether some children who did not have PFAPA had been included in the study that applied less stringent inclusion criteria for PFAPA diagnosis. Secondly, it is uncertain whether the treatment received in the control arms of the studies was adequate and represented current practice.

Authors' conclusions: 

The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

Read the full abstract...
Background: 

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane review first published in 2010.

Objectives: 

To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) in children with PFAPA.

Search strategy: 

We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2013.

Selection criteria: 

Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA.

Data collection and analysis: 

Two authors independently assessed trial quality and extracted data. We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results: 

Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias.

One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months.

Combining the trial results suggests that patients with PFAPA experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution).

There was a large overall reduction in the average number of episodes over the total length of follow-up in these studies (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years. The severity, as indicated by the length of PFAPA symptoms during these episodes, was also reduced. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group. The proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92).

Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Other outcomes such as quality of life, number of days with pain after surgery and absence from school were not measured or reported.

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