SUMMARY
PFAPA syndrome is a disease of unknown etiology, characterized by sudden onset of high fever, aphthous stomatitis, pharyngitis and cervical lymphadenopathy attacks, and is recurrent. This syndrome, which is generally more common in children under the age of five and in males, has a benign course. Sequelae does not develop in the long term. Although the clinical picture is well defined, the lack of laboratory findings specific to the disease makes diagnosis difficult. Treatment includes steroids and in some cases tonsillectomy.
PFAPA syndrome is a clinical entity of unknown etiology, characterized by recurrent high fever attacks accompanied by periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. It was first described by Marshall et al. in 1987. Later, in 1989, this picture was named after the initials of the English words "Periodic Fever", "Apthous Stomatitis", "Pharyngitis", "Adenitis", which gave its name to the syndrome (1).
Familial Mediterranean in the differential diagnosis of fever of unknown cause in children. Periodic fever syndromes, including fever, should be taken into consideration. Since there are no specific laboratory tests for PFAPA syndrome, it is diagnosed clinically after other possible causes of fever, such as infection, are excluded.
It manifests itself with upper respiratory tract infection findings, aphthous stomatitis and high fever (38-41o C) attacks that last an average of 5 days (3-6 days) and recur every 3-6 weeks (2-4). Since fever attacks are usually seen regularly, the family can often predict when the next attack will occur (5).
PATHOPHYSIOLOGY
Viral and autoimmune mechanisms in etiology. Although it has been suggested, the exact cause is not fully known (1,4,6). Cytokine regulation disorders are suspected in the mechanism of the disease. The increase in TNF-alpha, IFN-gamma and IL-6 levels during attacks reflects the inflammatory state (1,5). Found locally increased in the tissue in the pathogenesis of oral lesions Cytokines such as IL-2, IL-6 and IL-10 may play a role (7). It has been suggested that in PFAPA syndrome there may be an unexpected excessive response in the immunological response to the antigens or epitopes of the infectious agents ( 6 ). We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (± 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset.Values were compared to age-matched, healthy controls. In studies conducted with Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-y serum concentrations compared to symptom-free periods and to controls, with IL-1β , TNF-a and IL-12p70 levels being significantly higher than in controls. Production of IFN-γ and IL-2 was found to be significantly higher than in healthy children. During the asymptomatic period, serum concentrations of IL-1β, IL-6, TNF-a and IL-12p70 were significantly increased compared to controls. During the asymptomatic period, serum IL-1β, IL-6, TNF-alpha, and IL-12p70 were significantly increased compared to controls. Intracellular TNF-a synthesis was not elevated at any time point. Serum levels of anti-inflammatory cytokines such as IL-4 and IL-10 were found to be low compared to the control group. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response. This observed increase in pro-inflammatory cytokines even between febrile attacks suggests that there is a dysregulation of the immune system in PFAPA syndrome due to the continuous release of pro-inflammatory cytokines and a reduced anti-inflammatory response (8). Revue / Journal TitleSince steroids can relieve fever attacks, it supports the claim that the disease occurs as a result of the inflammatory process. All genetic studies conducted to identify the gene that is likely to cause the disease have been inconclusive. Only in a study conducted in Israel, it was reported that heterozygous mutations in the MEFV gene were observed at a high rate in patients with PFAPA (9).
An important data about children with PFAPA is that there is no familial transmission. medical bibliography Although sibling cases have been reported rarely, a complete familial transmission has not been demonstrated (10).
CLINICAL
In PFAPA syndrome, fever is present in every episode, but the other three findings are pharyngitis. , aphthous stomatitis and cervical lymphadenopathy may not be seen in the same episode. It has been reported in the literature that the most common finding other than fever is cervical lymphadenopathy (88%), followed by pharyngitis (72%) and aphthous stomatitis (70%). Fever attacks occur suddenly. It is often unresponsive to antipyretic and antibiotic treatments. Fever is usually above 39 oC. Although there may be short-term decreases, it generally remains high. One of the most important findings of PFAPA disease is that although the fever is high, the general condition of the child is mostly undeteriorated. This finding is very useful in making the differential diagnosis of the disease and infections. Fever subsides spontaneously after an average of 3-5 days. Fever rapidly decreases and disappears within 3-4 hours following the application of corticosteroids, which are the only temporary treatment method for the disease. Fever remains at normal levels until the next attack (5). During the attack, painful and large lymphadenopathies located in a chain on both sides of the neck are observed in all patients. Lymphadenopathies begin just below the chin and spread along the anterior cervical chain. The presence of lymphadenopathy in other parts of the body other than the cervical region is not a feature of this syndrome (11-12). Most patients have a typical picture of cryptic tonsillitis. Tonsils are often hypertrophic. There is a distinct pattern of pharyngitis on the pharynx. Throat culture and rapid streptococcal tests taken from the patients are negative. Tonsillitis in patients is unresponsive to antibiotic treatments, and the crypts disappear rapidly after corticosteroid treatment (11-12). Aphthous ulcer is the most frequently overlooked finding. It is a minor aphthous ulcer, is usually mildly painful and heals without leaving a scar (4). The aphthous lesion appears as an oval, white or yellow oral ulcer with an inflamed red border in the non-keratinized mucosa (13). Other symptoms include headache, abdominal pain, nausea, vomiting, sweating, chills, cranial neuritis and rarely arthralgia may occur. While musculoskeletal complaints such as arthralgia or myalgia are observed in children with PFAPA, no signs of arthritis are observed (14). Hepatosplenomegaly may also be observed in some patients. The other main feature is that the patient is completely healthy between attacks (9).
Although the frequency of PFAPA syndrome is unknown, it is thought to be more common than thought. Based on current evidence, no geographic or ethnic factors associated with this syndrome have been identified. Recurrent fever attacks can last for years, but as the child grows, these attacks become less frequent (5-10). Most cases are under the age of five and are more common in males (15). Although the syndrome is chronic in some children, it usually resolves spontaneously within 4 to 8 years. To date, no long-term sequelae due to PFAPA syndrome have been reported, and these patients have normal growth and development curves compatible with their age (4-6). The disease can sometimes be carried into adulthood and similar clinical findings may occur in adults (16).
The clinical findings detected in the largest series published so far (the study of Thomas and Padeh et al.) are summarized in Table 1.
LABORATORY
There are no specific laboratory parameters specific to the disease. While there is a slightly increased leukocyte count (typically < 13000 mm3) and erythrocyte sedimentation rate (usually < 60 mm / hour) during the attack, these tests return to normal between attacks (5). The increase in CRP levels during febrile episodes in children with PFAPA syndrome indicates that inflammatory mechanisms are involved in the process (17). Most of the patients have negative throat cultures for streptococcus, which is suspected to be due to tonsillitis (18). A slight increase in serum IgD and IgE levels may be observed. In addition, Igs, IgG subgroups, antinuclear antibody, C3, lymphocyte CD4/CD8 ratio, Epstein-Barr virus and adenovirus serology should be studied for differential diagnosis.
DIFFERENTIAL DIAGNOSIS
PFAPA ‘ Since there are no specific symptoms specific to PFAPA and it often shows clinical findings similar to other syndromes, there is debate as to whether PFAPA is truly a separate clinical condition. Diagnosis of PFAPA should be based on a careful history and detailed examination. Close follow-up will help identify other existing symptoms of a serious disease at an early stage.
Fever is an important finding of childhood and can be seen most frequently during viral upper respiratory tract infections (2). Neoplastic and rheumatological diseases (Behçet's Disease, Juvenile Rheumatoid Arthritis) in cases where fever recurs and infections are excluded in the differential diagnosis; It should be remembered that congenital or acquired immunodeficiency diseases (hypogammaglobulinemia, IgG subgroup deficiency, hyper IgM syndrome, hyper IgE syndrome, cyclic neutropenia and AIDS) and various endocrine or metabolic disorders may also cause this condition.
Periodical fever syndromes should be considered in cases where fever recurs at certain intervals and the cause is not understood. In general, in periodic fever syndromes, the common finding is that there are at least seven days between recurrent febrile periods and at least three febrile periods occur within a six-month period. During the fever-free intervals, the patient is completely asymptomatic. The clinical picture is characterized by systemic inflammation attacks.(3) . Conditions that cause periodic fever include PFAPA syndrome, HyperIg D syndrome (HIDS), Tumor necrosis factor-associated periodic syndrome (TRAPS), Familial Mediterranean Fever (FMF), Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS). neutropenia can be considered (19).
TREATMENT
In children with PFAPA, during the 3-4 day attack period, high fever and other clinical findings are unresponsive to antibiotic treatment. The high fever level in patients is not affected by antipyretic treatments (paracetamol, ibuprofen, acetyl salicylic acid). Spontaneous recovery is usually seen within five days (3-5). However, glucocorticoids are quite effective in controlling symptoms. A single dose of prednisolone to be given at any time during the attack.
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