Etiology and outcome of PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis) syndrome among patients operated with tonsillectomy in childhood

Abstract Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a syndrome characterized by regular, high-fever episodes with healthy periods in between. In a classic phenotype of the syndrome, the fevers begin in childhood before the age of five, and fever flares are accompanied by aphthous stomatitis, pharyngitis, and/or cervical adenitis. The etiology of the syndrome is unknown, but tonsillectomy (TE) has been shown to be an effective treatment for the disease. The purposes of this study were as follows: (1) to assess the long-term outcome of PFAPA patients treated by TE with either the classic or incomplete phenotype (later onset of the disease and/or missing oropharyngeal symptoms), (2) to compare the health and growth of PFAPA patients with healthy controls, and (3) to compare the histological and microbiological findings of the tonsils of PFAPA patients with controls via conventional and modern sequencing technologies. In this approximately 9-year follow up, 97% (n = 56) of patients with the classic phenotype and all patients (n = 50) with the incomplete phenotype achieved a prompt and constant response after TE. There were no differences in either the length of fever episodes or flares between patients with both the classic and incomplete phenotypes. The health and growth of 119 PFAPA patients was compared to that of sex- and age-matched controls (n = 230), and no differences in prevalence of chronic diseases or growth were found between the groups. Infections, oral thrush, and pollen allergy were more common in the history of the PFAPA patients than in the controls. Microbiological and histological findings of the tonsils of PFAPA patients (n = 31) were compared with the findings of the controls (n = 24) who had undergone TE for other reasons. Biofilm formation and Candida albicans were more frequently found among PFAPA patients than the controls, but Staphylococcus aureus, varicella zoster, and herpes simplex viruses were more common in the controls. While comparing the bacterial microbiota between the groups, we found significant differences in the presence and relative abundance of many bacteria. For example, Cyanobacteria were more common and abundant in the case samples than in the controls. Because the long-term outcome after TE was excellent, both in classic and incomplete PFAPA patients; a new diagnostic criteria for the syndrome is proposed. The microbes of the tonsils in PFAPA patients differ from that of the controls, which may play an important role in triggering the inflammatory processes that lead to symptoms of PFAPA.Tiivistelmä Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrooma, on oireyhtymä, jossa potilaat kärsivät hyvin säännöllisesti ilmaantuvista, toistuvista kuumejaksoista, joiden välillä potilaat ovat terveitä. Klassisessa tautimuodossa kuumeilut alkavat lapsuudessa ennen viiden vuoden ikää ja kuumevaiheeseen liittyy liitännäisoireita: suun limakalvojen rakkuloita, nielutulehdusta ja/tai kaulan imusolmukkeiden suurentumista. Oireyhtymän syytä ei tiedetä, mutta nielurisaleikkaus (TE) on osoittautunut tehokkaaksi hoidoksi. Tutkimuksen tarkoituksena oli (1) arvioida PFAPA potilaiden vointia pitkäaikaisseurannassa TE:n jälkeen ja vertailla taudinkuvaa niiden PFAPA potilaiden välillä, joilla oli klassinen PFAPA tai epätyypillinen PFAPA. (2) Lisäksi tutkimme myös TE:lla hoidettujen PFAPA potilaiden sairastuvuutta, yleistä terveydentilaa ja kasvua vertaamalla näitä sukupuoli- ja ikävakioituihin kontrolleihin ja (3) selvitimme mikrobiologisia ja histologisia löydöksiä PFAPA potilaiden nielurisoissa verrattuna muista syistä TE:ssa käyneiden lasten nielurisoihin. Tässä noin yhdeksän vuoden seurannassa TE:n jälkeen oli täysin parantunut 97% (n = 56) potilaista, joilla oli klassinen PFAPA, ja kaikki (n = 50) potilaat, joilla oli epätyypillinen PFAPA (tauti oli alkanut viiden ikävuoden jälkeen ja/tai klassiset liitännäisoireet puuttuivat). Kuumeprofiilit eivät muilta osin eronneet ennen nielurisaleikkausta näissä ryhmissä. PFAPA potilaiden (n = 119) kasvu ja yleinen terveydentila eivät eronneet väestökontrolleista (n = 230). Krooniset ja autoimmuunisairaudet olivat yhtä harvinaisia molemmissa ryhmissä. Potilaat raportoivat sairastaneensa enemmän infektioita ja sammasta lapsuudessa ja heillä oli enemmän siitepölyallergioita. PFAPA potilaiden (n = 31) ja muista syistä TE:ssa käyneiden lasten (n = 24) nielurisojen mikrobiologiaa ja histologiaa tutkittiin ja vertailtiin. Biofilmimuodostusta nielurisan pinnalla ja Candida albicansia löytyi enemmän tapauksilta kuin kontrolleilta, kun taas Staphylococcus aureusta, varicella zoster- ja herpes simplex -viruksia tavattiin enemmän kontrolleilla. Myös mikrobiomi erosi ryhmien välillä, esimerkiksi syanobakteerit olivat yleisempiä PFAPA risoissa kuin kontrolleilla. Klassisten ja epätyypillisten PFAPA potilaiden terveydentila TE:n jälkeen oli pitkäaikaisseurannassamme erinomainen ja siksi ehdotamme, että PFAPA –syndrooman diagnostisia kriteereitä tulisi muuttaa. Nielurisojen mikrobisto on erilainen kontrolleihin verrattuna ja tällä voi olla merkitystä PFAPA syndrooman inflammatorisessa prosessissa

PFAPA-jaksokuume on lapsen tavallisin kuumeoireyhtymä

Tiivistelmä PFAPA-jaksokuume (periodic fever, aphthous stomatitis, pharyngitis, adenitis) on pienten lasten tavallisin kuumeoireyhtymä. Tyypillistä sairaudelle ovat säännöllisesti 2–6 viikon välein ilmenevät 3–5 vuorokautta kestävät korkeakuumeiset jaksot. Noin puolella lapsista oirekuvaa hallitsee pelkkä kuume ilman varmistettuja suun, nielun tai kaulan imusolmukkeiden oireita. Oireyhtymää voi esiintyä myös yli viisivuotiailla lapsilla. Todennäköiseen diagnoosiin riittää viisi hyvin säännöllisesti ilmaantunutta kuumejaksoa, joille ei ole muuta selitystä. Kuumeen syytä ei tunneta, mutta nielurisojen poisto lopettaa tehokkaasti kuumejaksot riippumatta nieluoireiden esiintymisestä. Oireita lievittävänä hoitona voidaan käyttää suun kautta otettavaa glukokortikoidivalmistetta, joka ei kuitenkaan lopeta kuumejaksoja. Suomessa muiden geneettisten kuumeoireyhtymien diagnostiikkaa tarvitaan harvoin. PFAPA-jaksokuumetta sairastaneiden lasten pitkäaikaisennuste on hyvä.Abstract PFAPA (periodic fever, aphtous stomatitis, pharyngitis, adenitis) is the most common periodic febrile syndrome in young children. The most typical feature is a clockwork periodicity of high fever every 2 to 6 weeks for 3 to 5 days. Half of children have fever as the only symptoms and do not experience classic oral or cervical symptoms. PFAPA symptoms most often start in children younger than 5 years of age but PFAPA occurs also in older children. Probable diagnosis can be made after five regularly recurring febrile episodes without other explanation. Etiology for fever flares is still unknown. Tonsillectomy is an effective treatment for PFAPA. Corticosteroids relieve acute symptoms but do not prevent recurrent febrile episodes. In ethnic Finnish population, other genetic febrile syndromes are rare. The long-term prognosis after childhood PFAPA is excellent

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome:relapse and tonsillar regrowth after childhood tonsillectomy

Abstract Objectives/Hypothesis: Tonsillectomy is an effective treatment for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, but the role of adenoidectomy, as well as later tonsillar regrowth, is unclear. To find out if the volume of lymphoid tissue is pivotal to the efficacy, we analyzed the association between the relapse of the symptoms of PFAPA syndrome and regrowth of tonsillar tissue after tonsillectomy or adenotonsillectomy. Study Design: Prospective cohort study of operated PFAPA pateints. Methods: We invited all patients that had undergone tonsillectomy or adenotonsillectomy due to PFAPA syndrome at the Oulu University Hospital, Oulu, Finland, between the years 1990 and 2007, at the age of ≤12 years, to a follow-up visit, after an average period of 9.8 years after their diagnoses. Out of the 132 invited, 94 (71%) participated in the follow-up study. Results: At the follow-up study visit, 5 (5%) of the 94 PFAPA syndrome cases experienced recurrent fevers. The regrowth of palatine tonsillar tissue was seen in four of them (80%) as compared to 19/89 (21%) of symptom-free patients (P = 0.006). Two of the patients with clear PFAPA relapse at the time of the study visit were reoperated with clear effect on the symptoms. At the time of the study visit, 59/63 (94%) of the patients who had undergone adenotonsillectomy and 30/31 of the patients (97%) who had undergone tonsillectomy earlier were free of fever flares (P = 0.99). Conclusion: Palatine tonsil regrowth was associated with PFAPA syndrome relapse after tonsillectomy. Reoperation might be a treatment option in these patients

Tonsil mycobiome in PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome:a case-control study

Abstract Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in children with unknown etiology, effectively treated with tonsillectomy. Earlier we have shown that tonsil microbiome is different in patients with PFAPA as compared to that in controls. Recently, fungal microbiome, mycobiome, has been linked to the pathogenesis of inflammatory diseases. We now investigated the role of mycobiome of tonsils in PFAPA. Random forest classification, a machine learning approach, was used for the analysis of mycobiome data. We examined tonsils from 30 children with PFAPA and 22 control children undergoing tonsillectomy for non-infectious reasons. We identified 103 amplicon sequence variants, mainly from two fungal phyla, Ascomycota and Basidiomycota. The mean relative abundance of Candida albicans in the tonsil mycobiome was 11% (95% CI: 19 to 27%) in cases and 3.4 % (95% CI: -0.8% to 8%) in controls, p =0.104. Mycobiome data showed no statistical difference in differentiating between PFAPA cases and controls compared to a random chance classifier (area under the curve (AUC) = 0.47, SD = 0.05, p = 0.809). In conclusion, in this controlled study, tonsillar mycobiome in children with PFAPA syndrome did not differ from that of the controls

Endoscopic sinus surgery (ESS) to change quality of life for adults with recurrent rhinosinusitis:study protocol for a randomized controlled trial

Abstract Background: Endoscopic sinus surgery (ESS) has been used for decades to treat recurrent acute rhinosinusitis episodes (RARS) in adults. RARS results in infectious symptoms, antibiotic courses, sick leaves, and impaired quality of life. Theoretically, the ESS procedure, through improving the drainage of the paranasal sinuses, decreases the symptoms and enhances the quality of life of the RARS patients. Whether this is true has not been reported in a randomized trial yet. Methods: We conduct a single-center, non-blinded, randomized, 6-month, parallel group superiority clinical study including 80 adult participants referred to surgical treatment for RARS. The participants will either have ESS or conservative medical treatment (control group). The primary outcome will be the difference between the mean disease-specific Sinonasal Outcome Test 22 (quality of life questionnaire) change scores (from baseline to 6 months) of ESS and control group. Discussion: This study will add significant new information to the effect and harms of ESS procedure in the treatment of adults with RARS. Trial registration: ClinicalTrials.govNCT04241016. Registered on 17 January 2020

Impact of Particle Size Reduction and Carbohydrate-Hydrolyzing Enzyme Treatment on Protein Recovery from Rapeseed (Brassica rapa L.) Press Cake

The aims were to assess how particle size reduction and carbohydrate-hydrolyzing enzyme treatment influence protein recovery from rapeseed cold-pressed cake and to determine the effect of these pretreatments in protein extraction procedures varying in ionic strength, pH, and total solid content. Defatted press cake (median particle size 600 µm) was milled to 21-164 µm and 7 µm median particle sizes by pin disc milling and air-flow milling, respectively. The milled press cake samples were treated with a carbohydrate-hydrolyzing enzyme preparation, after which proteins were extracted in saline (pH 6) or alkaline (pH 12) buffer at 5 % solid content, or in water at 20 % solid content. Particle size reduction of the press cake did not influence enzyme action or protein yield, suggesting that protein release from the press cake is not physically limited by cell walls or internal cell structures. As an exception, protein release from the aleuronic cells appeared to be hindered by intact cell walls. Enzyme treatment improved protein recovery, more substantially when the extraction was carried out in water at 20 % solid content than in saline or alkaline conditions at 5 % solid content. The enzyme mediated its positive effect most probably by reducing the water holding capacity of the press cake, thereby facilitating solid-liquid separation, and releasing anionic compounds which improved protein solubility through electrostatic stabilization. The results suggest that carbohydrate-hydrolyzing enzymes are beneficial for rapeseed protein extraction at reduced water content or when no salt or alkali is added to increase protein solubility