Onset of Marshall syndrome in adulthood

Marshall syndrome in adults

In most cases, periodic fever is diagnosed in children aged 1 to 5 years. However, some medical studies show that adults also face a similar disease. Characteristic clinical signs appear. Among sick people, men are more common (50-70%).

The disease often occurs in adults aged 40-50 years. Periodic fever has been a problem for 4-8 years.

Marshall syndrome in adults is manifested by the following symptoms:

• the respiratory tract is affected, but there are no obvious manifestations of the infectious disease;
• aphthous stomatitis develops;

• cervical lymphadenitis appears;
• tonsillitis, pharyngitis develops;
• muscle pain appears;
• sore throat bothers you;
• during the next attack, pain appears in the joints;
• coughing is periodically disturbing;
• there is general weakness in the body;
• body temperature periodically rises with chills;
• there is pain in the throat area;
• Nasal congestion occurs.

In some situations, attacks occur without significant symptoms. In most cases, the criteria for assessing the patient's condition are established for young children, so adults may exhibit different signs.

Episodic fever occurs and is present for 1-7 days, then resolves on its own. A few months later, patients are diagnosed with a repeat episode.

Onset of Marshall syndrome in adulthood

Marshall syndrome (GS Marshall), or PFAPA syndrome (Periodic Fever, Aphtousis stomattis, Pharingitis, cervical Adenitis), ‒ periodic fever, aphthous stomatitis, pharyngitis, adenitis ‒‒ was first described in 1987 [1]. The symptom complex of the disease includes fever up to 40° C with chills, a febrile attack lasts about 5 days, and then the temperature decreases on its own. The disease is cyclical, with intervals between attacks from 2 to 12 weeks. [2]. The onset of the disease is usually observed at 5 years of age [3], but in rare cases the disease begins at the age of 40–50 years. The average duration between the first and last episodes is 3 years 7 months. ±3.5 years. In most cases, episodes recur within 4–8 years [4]. The etiology of Marshall syndrome is unknown. The possible role of activation of latent viral infection in the occurrence of the disease was discussed. An autoimmune mechanism for the development of the disease is possible (this is indicated by the rapid effect of the use of corticosteroids (GCS)). The effectiveness of tonsillectomy in children in stopping febrile attacks suggests a possible role for streptococcal infection [3]. Marshall syndrome is not formally included in the group of periodic syndromes, since its hereditary predisposition has not been proven. However, PFAPA syndrome is usually considered in this group of diseases. Criteria for the diagnosis of PFAPA syndrome (Thomas et al., 1999) [5]: - periodic febrile fever; - onset of the disease at an early age (up to 5 years); - symptoms of respiratory tract damage in the absence of infection; - aphthous stomatitis; - cervical lymphadenitis; - pharyngitis/tonsillitis; - cyclic neutropenia is excluded; - presence of symptom-free intervals; - normal growth and development. The criteria were developed for children, so in rare cases of this syndrome occurring in adults, not all of them are applicable.

Clinical case

In July 2020, patient B., 56 years old, was admitted to the rheumatology department of City Clinical Hospital No. 4 with complaints of muscle pain, periodic pain and sore throat, coughing, weakness, fatigue, periodic fever up to febrile levels with chills, lasting for 1–7 days, passing on its own, episodes of stomatitis, the appearance of a purple spot on the right shin. It is known from the anamnesis that the first increase in temperature to febrile levels, accompanied by lymphadenopathy and sore throat, was observed in 1996 and was regarded as a manifestation of streptococcal infection (possibly rheumatism). In 2009 (at the age of 50) she suffered an episode of sore throat, enlarged cervical and submandibular lymph nodes, fever up to 40° C, accompanied by chills, and symptoms of stomatitis. The attack lasted about a day, the patient received antibacterial therapy. A few months later, an episode of febrile fever recurred, and antibiotic therapy was again prescribed. Subsequently, she noted periodic chills. In June 2014, a sore throat and febrile fever reappeared for 24 hours, but the temperature returned to normal on its own. Since then, the patient has had There were episodes of fever accompanied by weakness, myalgia, sore throat, dry mouth, and nasal congestion. The duration of attacks is about 3–6 days with further normalization of temperature. The last febrile episode was observed in May 2020. In September 2014, the patient developed a hyperemic spot on the anterior surface of the left leg, regarded as erysipelas. A few days later, a similar spot appeared on the back surface of the right leg with epithelial detachment; the resulting bladder was opened on an outpatient basis and the serous fluid was evacuated. Since this time, no dynamics of the spot have been observed (Fig. 1).

The patient was repeatedly examined for fever in infectious diseases hospitals; no evidence of infectious diseases was obtained; antibacterial therapy was administered. In July 2020, she was examined in the cardiology department with suspicion of infective endocarditis, but no evidence of endocarditis was received either; a biopsy of the damaged area on the lower leg revealed nonspecific changes, regarded as hyperpigmentation. Urine tests revealed leukocyturia, for which the patient received antibiotic therapy. A blood test revealed an increase in the ASL-O titer to 1223 IU/ml, and bicillin therapy was prescribed (4 injections of bicillin-5 1.5 million units intramuscularly). Concomitant diseases: congenital heart disease - ventricular septal defect; Pulmonary artery stenosis – diagnosed in childhood. In 2010, there was a head injury, and since then there has been an increase in blood pressure. In the rheumatology department of City Clinical Hospital No. 4, an examination was carried out to clarify the genesis of febrile attacks. Endoscopy: antral erosive gastritis was detected; colonoscopy: atrophic colitis, chronic internal hemorrhoids in remission; Ultrasound of the abdominal cavity and kidneys: hepatomegaly, diffuse changes in the liver such as fatty hepatosis, condition after cholecystectomy, diffuse changes in the pancreas, left kidney cyst; Ultrasound of the thyroid gland: diffuse changes in the thyroid gland, enlargement of the jugular lymph nodes; Echo-CG: confirmed congenital heart disease (ventricular septal defect with left-to-right shunting, pulmonary stenosis, pulmonary hypertension with a pressure gradient on the pulmonary artery of 38 mm Hg). A computed tomography scan of the chest was performed: a CT picture of single small pleuropulmonary adhesions against the background of emphysematous swellings in the middle lobe of the right lung. Mediastinal lymph nodes are within normal values. CT scan of the abdominal cavity: left kidney cyst, fatty hepatosis. MRI of the brain revealed no pathology. Clinical blood tests and urine tests (including Nechiporenko tests) revealed no pathology. Blood and urine cultures: no growth. Biochemical blood test: CRP level - 0.42 mg/l, ferritin - 171.2 μg/l. The persistent high level of ASL-O (1000 IU/ml) was noteworthy. Blood tests for other infections (malaria, herpes virus, yersinia, borrelia, brucella, salmonella) are negative. Immunological blood test without pathology. The patient also underwent an immunochemical study of serum and urine proteins (indicators are within normal limits, no monoclonal secretion was detected) and a bone marrow study (bone marrow punctate is hypercellular, polymorphic composition, granulocytopoiesis is within normal limits. Erythropoiesis is normoblastic, slightly activated). Immunophenotypic characteristics of bone marrow cells: lymphocytes of aberrant immunophenotype were not identified; the percentage of subpopulations of T- and NK-lymphocytes is reduced. Thus, the main symptoms that the patient had were pain in the throat, joints, and attacks of fever accompanied by chills. In combination with high titers of ASL-O and previous erysipelas, these symptoms could indicate a streptococcal infection. However, the frequency of fever attacks (until May 2020), the lack of effect of antibacterial therapy, lymphadenopathy and episodes of stomatitis gave reason to suspect one of the periodic syndromes - Marshall syndrome, or PFAPA syndrome. The patient's symptoms met most of the criteria for Marshall syndrome (except the second and last criteria, which apply only to children). The only doubt that was raised was that since May 2020, no attacks of febrile fever were observed. The following treatment tactics were chosen. Resumption of bicillin therapy (taking into account the possible explanation of fever by streptococcal infection, as well as the etiological factor of PFAPA syndrome). If the attacks decrease or stop, continue bicillin therapy. In case of ineffectiveness, prescribe the H2-histamine receptor blocker cimetidine (the literature describes the possible positive effect of this drug in Marshall syndrome [6]) and try to stop the attack with large doses of GCS (according to the literature, the use of large doses of GCS in Marshall syndrome can have a positive effect and improve the prognosis, namely, to make attacks more rare and prevent their occurrence [7]). Since August 2020, the patient has been receiving bicillin-5 1.5 million units intramuscularly once a week. Fever attacks have not recurred for 13 months. I feel satisfactory. The disease lasted about 7 years. Perhaps we can talk about the patient’s recovery; in this case, bicillin therapy in an adult patient was analogous to tonsillectomy in children and led to the cessation of febrile attacks. Interestingly, the patient remains with an elevated ASL-O titer, so treatment with bicillin-5 continues. The demonstrated clinical case confirms that, despite the extremely rare occurrence of PFAPA syndrome in adulthood, Still's disease should not be excluded from the doctor's differential diagnostic search.

Symptoms in children

Marshall syndrome in children does not cause external changes; the child is no different from his peers.

Patients develop clinical symptoms of the pathological condition:

In most cases, the high temperature lasts 4-5 days, then subsides. The child feels well, there are no symptoms of an infectious or viral disease. Associated symptoms also disappear.

After some time (2-12 weeks), the temperature rises again. The results of a comprehensive examination will show the course of a mild inflammatory process. It is important for parents to take their child to the hospital to establish an accurate diagnosis and undergo treatment.

Causes

Even with modern developments in medicine, Marshall syndrome has not been studied properly. The causes of this pathology have not yet been precisely determined, so it is almost impossible to prevent the disease.

With this disease, the child’s body temperature periodically rises to 40 degrees, fever and inflammation of the pharynx, tonsils and oral cavity are observed . The disease manifests itself periodically and a person can say exactly when the next attack will occur. However, it is not possible to prevent such attacks, since doctors resort only to symptomatic treatment. Any therapy prescribed for Marshall syndrome is aimed at relieving the symptoms of the disease, but is not able to prevent subsequent attacks.

There is an assumption that the disease occurs due to certain autoimmune disorders.

Although the causes of this pathology are still unknown, doctors identify several factors that may contribute to the development of the disease.

Latent infection

Hidden viral infection. There is a whole list of latent viral infections that do not manifest themselves for a long time. Such viruses penetrate the body and accumulate in particularly sensitive organs. But these infections usually do not appear periodically, since the development of the disease is provoked by reduced immunity or unfavorable environmental conditions.

Similar viral infections include herpes. Many people are carriers of this virus, but the disease manifests itself only under certain conditions. Provoking factors can be hypothermia, decreased immunity or another infection.

Chronic tonsillitis

Young children often suffer from sore throat. If not treated properly, the disease quickly becomes chronic. The bacteria that inhabit the tonsils of a sick child release many toxic substances that lead to intoxication of the body. High temperature, inflammation of the mucous membranes and fever may be the immune system's response to inflammation.

Exacerbations of chronic tonsillitis in preschool children are sometimes very difficult. There is a high temperature, stomatitis and purulent plaque on the tonsils.

Malfunction of the autoimmune system

The most likely cause of Marshall syndrome in children is called autoimmune failure. Diseases of this group can be blocked for some time, but cannot be cured. In this case, the immune system, for unknown reasons, begins to perceive its cells as foreign and fights against them. This leads to a persistent increase in temperature and severe inflammation. Interestingly, there are no visible reasons for such a reaction of the body.

The frequency of attacks may vary. In some children, seizures occur after 3 weeks, in others after two months.

Reasons for appearance

Doctors cannot say exactly what causes a fever in a child. As a response of the small organism, adaptive and innate immunity are activated. Doctors are inclined to believe that Marshall syndrome in children is caused by autoimmune disorders.

The following possible reasons are identified:

According to some reports, Marshall syndrome is activated by streptococcal infection.
Doctors suggest that in some situations Marshall syndrome occurs as a result of mutation of certain genes that a person has. Genetic analysis is performed to confirm.

In each case, certain clinical symptoms appear, with which it is important to promptly go to the hospital and undergo examination. At risk are children whose close relatives have suffered a similar disease (45-60%). Marshall syndrome is more often diagnosed in boys.

Causes of Marshall syndrome

The etiology remains unknown. Today, PFAPA syndrome is considered as a polygenic or multifactorial disease, in which genetic and environmental factors and possible features of the body’s response to infection play a modifying role. In 7-10% of patients, mutations of the MEFV gene are detected, which is involved in the formation of the pyrin protein by granulocytes, monocytes, dendritic cells, fibroblasts of the skin, peritoneum and synovial membrane. Its putative function is to reduce the inflammatory response by inhibiting neutrophil activation and chemotaxis. Mutations in TNFRSF1A, MVK, and the gene encoding the NLRP3 protein are detected.

The cytokine profile in this pathology allows us to note an increase in serum levels of interleukin-1β (IL-1β), TNFα, IL-6, IL12p70, including in the period between attacks, which indicates a constantly ongoing subclinical inflammation. A specific infectious agent has not been isolated, some studies indicate the possible involvement of Epstein-Barr viruses, herpes simplex types 1, 2 and cytomegalovirus, as well as rare bacterial agents: Mycobacterium chelonae, Plasmodium, Borrelia, Brucella (brucella). Some of the patients studied showed vitamin D deficiency.

Diagnostics

The child must undergo a comprehensive examination to establish the cause of the development of pathological processes and the correct diagnosis. The pediatrician will conduct an examination, prescribe a diagnosis and, based on the results obtained, draw up a treatment regimen.

For Marshall syndrome, the child is prescribed the following diagnostic measures:

Additional diagnostics include instrumental examination:

It is important to establish the exact cause of the pathological condition and differentiate the disease, since many disorders are accompanied by fever (chronic somatic diseases, colds, cyclic neuropenia, damage to the upper respiratory tract).

Taking into account the results of a comprehensive examination, the patient may additionally need consultation with other specialized doctors (otolaryngologist, dentist, immunologist, geneticist, rheumatologist).

During a comprehensive diagnosis, the doctor pays attention to the following features:

• there is a clear alternation of periods of fever and remission;
• exacerbation lasts 2-7 days;
• the disease is not amenable to antibiotic therapy;
• The distinctive features of the pathological condition are noted.

The symptoms of Marshall syndrome in children disappear after a course of treatment with corticosteroids.

Prevention

Doctors cannot say for sure which factor provokes the development of pathological processes.

Therefore, as a preventative measure, it is recommended to adhere to general precautions:

1. Teach your child to lead a healthy and active lifestyle.
2. Temper the body, strengthen the immune system.
3. Eat properly and rationally, give preference to fortified foods.
4. Play sports and be physically active.

In winter and during periods of viral and bacterial epidemics, children with Marshall syndrome should be given vitamin D3. Pediatricians do not advise parents to carry out treatment on their own, since many drugs cause side effects. There is a high probability of complicating the child’s condition, so it is important to go to the hospital and get qualified advice.

Treatment methods

Marshall syndrome in children requires complex therapy after examination. Medicines are prescribed, which are recommended to be taken strictly according to the prescribed regimen, in order to avoid side effects or complications.

The attending physician selects tactics based on the patient’s condition and the results of comprehensive diagnostics. In severe situations, surgery is performed.

Medications

The medications are selected by the pediatrician, based on the results of a comprehensive examination and the condition of the little patient. It is important to strictly adhere to the prescriptions to reduce the likelihood of side effects.

Marshall syndrome in children involves the use of the following drugs:

Additionally, with Marshall syndrome, children are prescribed vitamin complexes to increase the body's defenses. Antibiotics are used if the diagnosis of secondary infection of the body is confirmed.

There is also a certain group of drugs that doctors use for Marshall syndrome:

Medicines cause various side effects, so you should not take them on your own without a doctor’s prescription. It is also important to adhere to the established scheme, which was selected by a specialist.

Other methods

Marshall syndrome in children cannot always be cured with medications. The lack of positive dynamics after drug therapy or when complications arise in the patient requires surgical intervention.

The child is indicated for tonsillectomy. In most cases, after removal of the tonsils, the child no longer worries about fever. But surgical treatment is resorted to in emergency situations when the effectiveness of drug therapy is completely absent.

There are children who have complete intolerance to medicinal components, so surgical intervention is also prescribed.

Tonsillectomy is not performed during an exacerbation of a febrile condition. Surgical intervention helps in 70% of cases to prevent the secondary appearance of the syndrome.

Treatment of Marshall syndrome

Treatment methods are still a matter of debate. Antibiotic therapy, the use of antiviral and antihistamine drugs are not effective; NSAIDs have only a short-term antipyretic effect. To date, the following have been successfully used to treat PFAPA syndrome:

• Corticosteroids . One or two doses of prednisolone (1-2 mg/kg), betamethasone (0.1-0.2 mg/kg) can abruptly stop attacks of fever within a few hours. Other associated symptoms take longer to resolve. Steroids are used only during attacks; the indicated dosages do not cause toxic effects. Glucocorticoid therapy can shorten the interval between attacks, but does not prevent relapses.
• Colchicine. May be effective in preventing frequent episodes of fever; it does not affect the course of the febrile period. A side effect is gastrointestinal disorders (in 20% of cases). There have been several studies of this drug, most of them in Israel, where a large proportion of patients carry pathogenic variants of MEFV.
• Cimetidine . In small group studies, approximately a quarter of patients (24-27%) had complete resolution of fever episodes while taking it, and another 24-32% reported partial effectiveness with a reduction in the frequency or severity of attacks.
• Anakinra . Currently, recombinant interleukin-1β receptor antagonists (anakinra) are being considered as experimental therapy, and studies of this group of drugs are being conducted. All patients demonstrated clinical improvement and a decrease in the level of cytokines in the blood.
• Tonsillectomy. It is a radical method that leads to complete recovery. Surgery should be performed only in cases of intolerance or ineffectiveness of standard drug therapy due to certain risks of invasive intervention (bleeding, complications of anesthesia).

Daily life of children with Marshall syndrome

The child's quality of life may be affected by occasional fever. Until an accurate diagnosis is established, parents will also worry. Regular episodes of Marshall syndrome should not affect your child's school attendance. Despite chronic illnesses, children need to study and receive an education.

It is important to create the most suitable conditions for patients with similar diseases, so that they not only have time to master the school curriculum, but also communicate with their peers.

The same goes for sports activities. Physical activity is good for children's health in moderation. One of the main goals of therapy for Marshall syndrome is to allow the patient to lead a normal life.

Dietary nutrition provides a rational and fortified menu, which includes foods high in calcium and essential microelements. A growing body absolutely needs vitamins. It is recommended to exclude unhealthy dishes and products from the diet (fast food, carbonated sweet drinks, processed foods).

As for vaccination, there are no special prohibitions. Vaccinations must be done according to plan, but in the case of children with Marshall syndrome, the attending physician should be warned about the existing disease. The child may need individual recommendations on an individual basis.

Attention to your health is also necessary if you are planning a pregnancy or using contraceptives. This rule of daily life applies more to adults who have been diagnosed with Marshall syndrome, which is extremely rare.

During pregnancy, the female body goes through hormonal changes, so it is important to carefully monitor your condition and constantly be under the supervision of your doctor. Treatment when the next attack of fever occurs must be strictly tailored to it in order to exclude a negative effect on the development of the fetus.

Possible complications

Marshall syndrome in children does not cause complications. In adolescence, the disease disappears on its own, and the child outgrows it. Negative consequences of the syndrome arise as a result of the addition of a secondary infection at the time of the appearance of clinical signs.

A complication of Marshall's syndrome is also purulent mediastinitis, a retropharyngeal abscess. Many children are forced to stay at home and miss classes during the next attack, but this is not critical; knowledge can be acquired independently.

In most cases, Marshall syndrome occurs in a child before the age of 4-8 years. Then the disease goes away on its own and complications appear only in rare situations. Children who have had this disease have a positive prognosis. There are not only no repeated relapses, but also no consequences. The child continues to develop normally psychologically, neurologically and physically.

Clinical picture

Marshall syndrome in children occurs with a number of characteristic symptoms. But even knowing the peculiarities of the course of the disease, it is sometimes very difficult for doctors to differentiate the pathology from other diseases or autoimmune disorders. To make a diagnosis, the doctor carefully collects anamnesis, highlighting the characteristic signs of the disease.

• Fever. There is a certain periodicity in the development of a febrile state. Periods of remission can last from 2 to 7 weeks. Attacks occur approximately once a month, but sometimes this time period is shorter. The fever can last for about 5 days, after which everything goes away without a trace. As the disease progresses, the intervals between attacks of fever tend to increase.
• Temperature. Marshall syndrome is characterized by a very high temperature. Temperatures can reach 41 degrees. This is accompanied by unbearable headache, impaired consciousness, delirium and chills. This temperature is difficult to reduce with antipyretic drugs. If you manage to knock it down a little, then for a short time.
• Sore throat. With Marshall's disease, pharyngitis often occurs. This disease is accompanied by severe sore throat, which increases significantly when swallowing, dry mouth and coughing. The patient develops a persistent feeling of a foreign body in the throat. All symptoms of pharyngitis usually disappear without a trace simultaneously with the attack.
• Stomatitis. The disease often occurs with stomatitis. At the same time, painful ulcers appear on the oral mucosa, and the body temperature rises greatly. Stomatitis may be a consequence of immune disorders.
• Enlarged lymph nodes. With Marshall syndrome, the submandibular lymph nodes are severely inflamed. Their increase can be seen even with the naked eye. When you feel the nodes, you can note their pain and compactness.
• Severe abdominal pain. A similar symptom with this autoimmune disease occurs in approximately half of sick children.
• Pain in joints and head. These signs are always present with high temperature and fever.