Marshall syndrome

Among the diseases that are characterized by seemingly unprovoked attacks of fever is Marshall syndrome, which appears in children over several years (on average from 4.5 to 8 years).

The pathology, described in an article in The Journal of Pediatrics almost 30 years ago by four American pediatricians, was named after the first of its co-authors, Gary Marshall, a doctor at the Children's Hospital in Philadelphia.

In English-language medical terminology, Marshall syndrome is called PFAPA syndrome – periodic fever with aphthous stomatitis, pharyngitis and cervical lymphadenitis, that is, inflammation of the lymph nodes in the neck.

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Epidemiology

The exact prevalence of this syndrome in the general population is unknown; Marshall syndrome occurs slightly more often in boys than in girls (55-70% of cases).

The first manifestation is usually noted between the ages of two and five (approximately three and a half years), although it may occur earlier. The manifestations of the syndrome (attacks) in most patients last for five to seven years and spontaneously cease by the age of ten or in adolescence.

Studies have not revealed any racial or ethnic characteristics of the syndrome; the number of familial cases is insignificant.

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Causes Marshall syndrome

For a long time, febrile fever with symptoms of inflammation in the throat, mouth and neck that periodically occurs in children was considered an idiopathic condition. Then, the causes of Marshall syndrome began to be associated with hereditary genetic mutations, but a specific gene has not yet been definitively identified. However, pediatricians take into account the family history and the tendency of blood relatives to inflammations of this localization and fever: according to some data, a positive family history is detected in 45-62% of patients. And such a predisposition is seen as a real risk factor for the manifestation of PFAPA syndrome.

The genetic causes of Marshall syndrome known in modern clinical pediatrics are rooted in the uncharacteristic activation of both forms of immune response during infections – innate and adaptive, as well as in changes in the nature or kinetics of the immune response. However, the pathogenesis of Marshall syndrome has not been fully elucidated, since two versions are considered: activation of immunity during recurrent infections and disruption of the immune response mechanisms themselves. The first version is clearly untenable, since recent microbiological studies have shown contradictory serological results and lack of response to antibiotic treatment.

As for problems with the immune response mechanism, there is a connection with defects in innate immunity proteins. During each outbreak of this syndrome, the number of activated T cells or antibodies (immunoglobulins) in the blood does not increase, and the level of eosinophils and lymphocytes is often reduced. On the other hand, during these same periods, there is an activation of the production of interleukin IL-1β (which plays an important role in initiating fever and inflammation), as well as inflammatory cytokines (gamma interferon, tumor necrosis factor TNF-α, interleukins IL-6 and IL-18). And this may be a consequence of excessive expression of the CXCL9 and CXCL10 genes on chromosome 4.

The main mystery of PFAPA syndrome is that the inflammatory response has no infectious triggers, and what causes gene expression is unknown. Officially, Marshall syndrome is a disease of unknown etiology and uncertain pathogenesis (according to ICD-10 class 18 - symptoms and deviations from the norm not classified in other classes; code - R50-R610). And if earlier it was classified as a sporadic disease, now there are grounds confirmed by research to consider it recurrent, that is, periodic.

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Symptoms Marshall syndrome

The first signs of attacks in Marshall syndrome – which, according to clinical observations, occur every 3-8 weeks – are sudden fever with peaks of body temperature increase up to +38.8-40.5°C and chills.

There may also be prodromal symptoms of Marshall syndrome, which manifest themselves approximately one day before the increase in temperature in the form of general malaise and headache. Then inflammation of the oral mucosa with small, slightly painful aphthous ulcers appears (on average in 55% of patients). Sore throat (sometimes with exudation) has the appearance of pharyngitis - inflammation of the mucous membrane of the pharynx. Painful swelling of the lymph nodes in the neck is noted, as in lymphadenitis. It should be borne in mind that the entire complex of symptoms is observed in 43-48% of cases.

There are no other symptoms, such as rhinitis, cough, severe abdominal pain or diarrhea, with Marshall syndrome. Fever can last from three to four days to a week, after which the temperature also returns to normal, and all symptoms disappear.

At the same time, children are completely healthy in the periods between fever attacks and have no deviations in general development. According to clinical studies, there are no consequences or complications of PFAPA syndrome (or none have been identified at this time).

Diagnostics Marshall syndrome

Today, Marshall syndrome is diagnosed based on a typical clinical picture. Tests are limited to a general blood test.

To alleviate parental concerns, avoid unnecessary and costly testing, and prevent potentially dangerous treatments, there are diagnostic criteria for PFAPA syndrome:

• the presence of more than three recorded regular cases of fever lasting no more than five days, occurring at equal intervals;
• the presence of pharyngitis with minor lymphadenopathy in the neck area and/or aphthous ulcers on the oral mucosa;
• absence of developmental abnormalities and normal health status between episodes of illness;
• rapid resolution of symptoms after a single dose of corticosteroids.

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Differential diagnosis

Differential diagnosis of this syndrome includes other diseases with periodic fevers: familial Mediterranean fever, autoimmune Behcet's disease, cyclic neutropenia (with a three-week cycle and extensive damage to gum tissue), juvenile rheumatoid arthritis (Still's disease). Upper respiratory tract infections and bacterial pharyngitis, tonsillitis, lymphadenitis, and aphthous stomatitis should be excluded.

It is important to differentiate Marshall syndrome from congenital hyper-immunoglobulin D syndrome (mevalonate kinase deficiency syndrome) in children in the first year of life, in which periodic attacks of fever - in addition to the symptoms inherent in PFAPA syndrome - are accompanied by abdominal pain, enlarged spleen, vomiting, diarrhea, pain and swelling of the joints; from a very early age, such children experience developmental delay and deterioration of vision.

Treatment Marshall syndrome

Pediatricians have not yet come to a consensus on what the treatment for Marshall syndrome should be.

The main drug therapy is symptomatic and consists of single doses of glucocorticoids. Thus, betamethasone or prednisolone is prescribed for fever relief in Marshall syndrome. Prednisolone in tablets is taken orally immediately at the onset of fever - at a rate of 1-2 mg per kilogram of the child's body weight (the maximum dose is 60 mg); betamethasone - 0.1-0.2 mg / kg.

GCS with immunosuppressive action are contraindicated in severe diabetes mellitus, hypercorticism, gastritis, kidney inflammation, in the period after vaccination, in weakened children. The most common side effect of prednisolone treatment is anxiety and sleep disturbance, so it should be taken several hours before bedtime. On the third or fourth day of the attack, the dose can be reduced to 0.3-0.5 mg/kg (once a day).

Clinical experience shows that antipyretic drugs, in particular non-steroidal anti-inflammatory drugs, help only to reduce fever, and are ineffective in combating other symptoms. When treating this syndrome symptomatically, it is important to assess the risks associated with possible side effects. So, before using even lozenges for a sore throat, you should consult a doctor. In particular, it is recommended to choose those that do not contain antibiotics, since antibacterial agents do not give any result in Marshall syndrome.

Children with Marshall syndrome require vitamins, especially calciferol (vitamin D), which – in addition to its role in calcium homeostasis and bone metabolism – may act as an immunoregulatory factor.

Prevention

Given the etiology of Marshall syndrome, as well as the lack of an algorithm for its treatment, its prevention is not covered in domestic and foreign medical literature.

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Forecast

The prognosis for this pathological condition is considered favorable, since over time, Marshall syndrome passes without consequences.

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