Periodic fever syndrome

In 1987, 12 cases of a peculiar syndrome were described, which manifested itself as periodic fever, accompanied by pharyngitis, aphthous stomatitis, and cervical adenopathy. In English-speaking countries, it began to be designated by the initial letters of this complex of manifestations (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) - PFAPA syndrome. French-language articles often call this disease Marshall syndrome.

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Epidemiology

This disease is more often observed in boys (approximately 60%). The syndrome generally begins to manifest itself at about 3-5 years (average: 2.8-5.1 years). However, there are also frequent cases of the disease developing in 2-year-old children - for example, among the 8 patients studied, 6 had fever attacks at the age of 2 years. There was also a case in an 8-year-old girl, when 7 months before contacting doctors, she developed symptoms of the disease.

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Causes of intermittent fever syndrome

The causes of periodic fever syndrome are not yet fully understood.

Currently, scientists are discussing several of the most likely causes of the development of this disease:

• Activation of latent infections in the body (this is possible when certain factors coincide - due to a decrease in immunological reactivity, the dormant virus in the human body “wakes up” with the development of fever and other symptoms of the syndrome);
• a bacterial infection of the tonsils, palate or throat that has become chronic - the products of microbial activity begin to affect the immune system, which causes an attack of fever;
• autoimmune nature of the development of pathology - the patient's immune system perceives the cells of its own body as foreign, which provokes an increase in temperature.

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Symptoms of intermittent fever syndrome

Periodic fever syndrome is characterized by a clearly defined periodicity of febrile attacks - they recur regularly (usually every 3-7 weeks).

In rarer cases, the intervals last 2 weeks or more than 7. Research indicates that, on average, the intervals between attacks initially last 28.2 days, and the patient experiences 11.5 attacks per year. There is also information about longer breaks - in 30 cases they lasted within 3.2 +/- 2.4 months, while French researchers gave a period of 66 days. There are also observations in which the intervals last on average about 1 month, and occasionally 2-3 months. Such differences in the duration of free intervals are most likely due to the fact that over time they begin to lengthen.

On average, the period between the first and last attack is 3 years and 7 months (error +/- 3.5 years). Attacks are usually repeated over a period of 4-8 years. It should be noted that after the attacks disappear, no residual changes remain in patients, and no disturbances occur in the development or growth of such children.

The temperature during an attack is usually 39.5 ⁰ -40 ⁰, and sometimes even reaches 40.5 ⁰. Antipyretic drugs help only for a short period of time. Before the temperature rises, the patient often experiences a short prodromal period in the form of malaise with general disorders - a feeling of being exhausted, severe irritability. A quarter of children experience chills, 60% have a headache, and another 11-49% experience arthralgia. The appearance of abdominal pain, mostly mild, is noted in half of the patients, and another 1/5 of them experience vomiting.

The set of symptoms by which this pathology was named is not observed in all patients. Most often in such cases, cervical adenopathy is detected (88%). In this case, the cervical lymph nodes enlarge (sometimes up to 4-5 cm in size), they are doughy to the touch and slightly sensitive. The enlarged lymph nodes become noticeable, and after the attack they quickly decrease and disappear - literally in a few days. Other groups of lymph nodes remain unchanged.

Pharyngitis is also observed quite often - it is diagnosed in 70-77% of cases, and it should be noted that in some cases the patient has predominantly weak catarrhal forms, while in others there are superpositions along with effusion.

Aphthous stomatitis occurs less frequently – the frequency of such manifestations is 33-70%.

An attack of fever usually lasts for 3-5 days.

During febrile attacks, leukocytosis may occur in moderate forms (approximately 11-15x10 ⁹ ), and the ESR level increases to 30-40 mm/h, as does the CRP level (up to 100 mg/l). Such shifts stabilize quite quickly.

Adult periodic fever syndrome

This syndrome usually develops only in children, but in some cases it can also be diagnosed in adults.

Complications and consequences

Possible complications of this syndrome include:

• A complete blood count shows neutropenia (a decrease in the number of leukocytes (white blood cells) in the blood);
• Frequent bouts of diarrhea;
• Rashes appear on the skin;
• Joints become inflamed (arthritis develops);
• Manifestations of neurological disorders (convulsions, severe headaches, fainting, etc.).

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Diagnostics of intermittent fever syndrome

Periodic fever syndrome is usually diagnosed as follows:

• The doctor analyzes the patient's complaints and medical history - finds out when the fever attacks appeared, whether they have a certain periodicity (if so, what it is). They also determine whether the patient has aphthous stomatitis, cervical lymphadenopathy or pharyngitis. Another important symptom is whether signs of the disease appear in the intervals between attacks;
• Next, the patient is examined - the doctor determines the enlargement of the lymph nodes (either by palpation or by appearance (when they increase to a size of 4-5 cm)), as well as the palatine tonsils. The patient has a reddened throat, and whitish ulcers sometimes appear on the oral mucosa;
• The patient's blood is taken for a general analysis - to determine the level of leukocytes, as well as ESR. In addition, a shift to the left side of the leukocyte formula is detected. These symptoms indicate that there is an inflammatory process in the body;
• A biochemical blood test is also performed to determine an increase in the CRP index, and in addition to this, fibrinogen - this sign is a signal of the onset of inflammation. An increase in these indicators indicates the development of an acute inflammatory reaction of the body;
• Examination by an otolaryngologist and an allergist-immunologist (for children - pediatric specialists in these fields).

There are also cases of familial forms of this syndrome - for example, two children from one family showed signs of the disease. But it has not yet been possible to find a genetic disorder that is specific to periodic fever syndrome.

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Differential diagnosis

Periodic fever syndrome must be distinguished from chronic tonsillitis, which occurs with frequent periods of exacerbation, and other diseases such as juvenile idiopathic arthritis, Behcet's disease, cyclic neutropenia, familial Mediterranean fever, familial Hibernian fever, and hyperglobulinemia D syndrome.

In addition, it must be differentiated from cyclic hematopoiesis, which, in addition to being the cause of the development of periodic fever, can also be an independent disease.

Differential diagnosis of this syndrome with the so-called Armenian disease can be quite difficult.

Another rare disease has similar symptoms – periodic syndrome, which is associated with TNF, in medical practice it is designated by the abbreviation TRAPS. This pathology has an autosomal recessive nature – it occurs due to the fact that the gene of the conductor 1 TNF undergoes mutation.

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Treatment of intermittent fever syndrome

The treatment of periodic fever syndrome has many unsolved questions and discussions. The use of antibiotics (penicillins, cephalosporins, macrolides and sulfonamides), nonsteroidal anti-inflammatory drugs (paracetamol, ibuprofen), acyclovir, acetylsalicylic acid and colchicine has proven to be of little use other than shortening the duration of fever. In contrast, the use of oral steroids (prednisolone or prednisolone) causes a sharp resolution of febrile episodes, although it does not prevent the development of relapses.

The use of ibuprofen, paracetamol, and colchicine during treatment cannot provide a lasting result. It was determined that relapses of the syndrome disappear after tonsillectomy (in 77% of cases), but a retrospective analysis performed in France showed that this procedure was effective in only 17% of all cases.

There is an option with the use of cimetidine - such a proposal is based on the fact that this drug can block the activity of H2 conductors on T-suppressors, and in addition to this, stimulate the production of IL10 and inhibit IL12. Such properties help stabilize the balance between T-helpers (type 1 and 2). This treatment option allowed to increase the period of remission in ¾ of patients with a small number of tests, but with large numbers this information was not confirmed.

Studies show that the use of steroids (e.g. prednisolone at a single dose of 2 mg/kg or over 2-3 days in decreasing doses) quickly stabilizes the temperature, but they are not able to eliminate relapses. There is an opinion that the effect of steroids can shorten the duration of the remission period, but they are still the most commonly chosen drug for periodic fever syndrome.

Prevention

Since there is currently no precise information about the causes of the development of PFARA syndrome, there is no set of methods for preventing this disease.

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Forecast

Periodic fever syndrome is a non-infectious pathology in which acute attacks of fever develop with high periodicity. With the correct diagnosis, the prognosis is favorable - it is possible to quickly cope with acute attacks, and in the case of a benign disease, the child may not even need tonsillectomy.