Marshall syndrome

MARSHALL’S SYNDROME (PFAPA syndrome):

IDENTIFICATION OF ETIOLOGICAL ORIGIN.

A MYSTERY FOR 35 YEARS. 

Markov I.S.¹ʾ², Kramaryov S.O.³, Markov A.I.¹ˉ³, Yevtushenko V.V.³ 

Vitacell clinic¹, Markov clinic²,

National Medical University of the name Bogomolets O.O.³ (Kyiv, Ukraine),

Department of Pediatric Infections (chair – Prof.Kramaryov S.O.)

Summary.

The aim of the study was to define the etiological origin of Marshall's syndrome or PFAPA-syndrome and in particular recurrent fever, which was called febrile attack^© (FA), which is the main sign of this pathological state.

The study design was clinical-diagnostic and included the search for ways to diagnose and treat Marshall's syndrome, the main clinical feature of which was a sudden high recurrent returning fever of unknown origin. The studies were prospective-retrospective and were longitudinal with long-term periodic observation for a certain part of the same patients during 1-10 years after diagnosis and appropriate treatment. Due to the effectiveness of the obtained results the study had direct character, because it undoubtedly led to the recovery of the patient with the improvement of his/her general state and quality of life. Conditions: the studies were two-center and conducted in outpatient conditions on the basis of 2 clinics, specialized in the field of chronic infectious diseases with a full range of laboratory studies. Participants of the research were all children from infancy up to 14 years of age who were consulted at the clinics in 2009-2020 with complaints of temperature disorders, including sudden high fever of unknown origin accompanied by other clinical symptoms, typical of Marshall's syndrome.

Results. During 2009-2020, 721 children with clinically dominant sudden high-grade short-term usually returning fever, called as febrile attack^© (FA), there were supervised, including 205/721 (28.4%) children under 3 years of age, 263/721 (36.5%) - aged 3 to 7 years and 253/721 (35.1%) - aged 7 to 14 years. The etiological diagnosis of this pathological state in children before going to the clinic remained uncertain and usually took place under the false mask of other diagnoses. In 14 cases, children were pre-diagnosed with Marshall's syndrome. In all 721 (100%) patients with FA and with complete or partial clinical picture of Marshall's syndrome there were detected two foci of chronic bacterial infection: in the kidneys and in the nasopharynx. Herewith almost for 3/4 of cases (531/721 or 73.6% of patients) there was diagnosed locally asymptomatic Nephrodysbacteriosis^© without clinical, generally laboratory (including almost normal general urine analysis) and instrumental signs of inflammatory process in the kidneys. In the results of bacteriological examination of warm urine (three times, 3 consecutive days) there were revealed urinary cultures of different strains of bacteria - totally 1123 strains that provoked the development of Chronic Bacterial Intoxication Syndrome^© (CBIS), including sudden fever or FA, confirmed by toxicological blood examination based on the diagnostic system Toxicon. The main causes of sudden fever or FA and other symptoms of general intoxication, associated with Nephrodysbacteriosis, were enterococci (most often - Enterococcus faecalis) - 453/1123 or 40.3% of strains isolated from 62.8% of sick children, Escherichia coli - 248/1123 or 22.1% of strains (isolated in 34.4% of patients) and pathogenic staphylococci (mostly Staphylococcus aureus) - 206/1123 (18.4%) of strains isolated from 28.6% of patients. In the results of bacteriological examination of smears from the nose, pharynx, mouth and plaques of stomatitis, from mucus of nose and sputum there were revealed in the vast majority of children (670/721 or 92.9%) pathogenic staphylococci (St. aureus - in 535/721 or 74,2% of cases, St. haemolyticus - in 135/721 or 18.7%), which completely dominated in this nasopharyngeal microbiome. Separately/simultaneously with staphylococci there were also isolated Streptococci: mainly Streptococcus pyogenes - in 168/721 (23.3%) children, less often - Streptococcus pneumonia (in 71/721 or 9.8%). On the basis of toxicological blood examination in the vast majority of appropriately examined children (in 77/96 or 80.2%) there was found severe toxemia, in 16/96 (16.7%) - moderate and only in 3/96 (3,1%) - mild. All 721 children with febrile attacks and other manifestations of Marshall's syndrome were treated with bacterial autovaccines. 622/721 or 86.3% of children were considered to have received treatment, the consequences of which could be considered as established. After the first cycle of vaccination, which consisted of 2-3 courses, sudden fever had stopped in 461/622 (74.1%) children, including in more than half of the cases (322/622 or 51.8%) – already after the first course. Else in another 133/622 (21.4%) cases, FA attacks along with other clinical symptoms had disappeared after the second cycle of vaccination consisted of 2-3 additional courses. Only in 28/622 (4.5%) cases for complete recovery there was required the third cycle of vaccination. There were no complications or side effects of allergic or anaphylactic nature due to treatment with bacterial autovaccines.

Conclusions. It’s established that Marshall's syndrome (or PFAPA-syndrome) has an associated bacterial-toxic origin and etiologically is linked with two foci of chronic bacterial infection: in the kidneys, mainly due to enterococci, Escherichia coli and staphylococci (usually - locally asymptomatic), called as Nephrodysbacteriosis^© with the development of CBIS^© with severe bacterial endotoxicosis with symptoms of toxic origin, in particular with recurrent fever or FA, that was confirmed by appropriate toxicological studies of blood, and in the nasopharynx (mostly - staphylococcal etiology, less often - with streptococcal-mixed) that causes local purulent-inflammatory symptoms. An effective method of treating patients with sudden recurrent fever and other manifestations of bacterial-toxic origin (Marshall’s syndrome) was the use of bacterial autovaccines: in 51.8% of cases attacks of fever discontinued already after the first course, in general after 1-3 cycles - in 100%.

Additional information as below, namely “Known”, “New”, “Key words” – to be accepted or not by the editors [authors].  

Known: the existence of such a pathological state as Marshall's syndrome or PFAPA-syndrome of unknown genesis, which are assosiated with recurrent fever and usually with such a complex of symptoms as stomatitis, pharyngitis and cervical lymphadenopathy and for which for 35 years there was not found any certain explanation of their separate or common etiological origin.

New: for the first time in clinical practice, it has been determined and laboratory confirmed (by the results of bacteriological and toxicological examinations) that Marshall's syndrome or PFAPA-syndrome has an associated bacterial-toxic origin and is linked to two foci of chronic bacterial infection: in the kidneys which is called Nephrodysbacteriosis^© and produces symptoms of toxic origin of a general character, including recurrent fever or febrile attack, and in the nasopharynx (mainly due to staphylococci) which causes local purulent-inflammatory symptoms. For the first time, it has been used an effective method of treating Marshall's syndrome with bacterial vaccines made from autostrains of bacteria, isolated from urine and nasopharynx.

Key words: febrile attack^©, Marshall's syndrome or PFAPA-syndrome, Nephrodysbacteriosis^©, Chronic Bacterial Intoxication Syndrome^© (CBIS), bacterial autovaccines.

During the last time, scientific publications in the field of clinical medicine are noticeably oversaturated with figures, graphs, materials of statistical processing of research results, mathematical modeling, algorithms and treatment protocols. It seems that a little else and the doctor himself will be no more needed: his functions will be taken over by a trained service operator without medical education or even a computer. Under these undoubtedly important but secondary factors, “their majesty clinic”, epidemiological anamnesis and medical history of disease, and sometimes even the patient himself with his personal complaints and hopes for a better life are being often lost. Patients with unidentified or etiologically uncertain diagnoses of chronic diseases of infectious origin (there are many of them today, which do not fit into existing protocols and schemes) sometimes can not "reach" and find their doctor, wandering around the medical offices of specialists of different profile. Unfortunately, today doctors have forgotten to listen to the patient. Therefore the treatment itself is often symptomatic and palliative. Although it is known that what is correctly diagnosed, it is well treated. Therefore, it seems to us that our this publication will give more hope to the recovery for patients with a previously etiologically uncertain diagnosis of one of the most widespread syndromes of chronic disease in children and sometimes adults, as well as will enable their doctors to obtain a more positive clinical outcome in their treatment.

In 1987, Gary Scott Marshall and colleagues published in the journal “Pediatrics” the first description of 12 clinical observations of a peculiar syndrome - recurrent fever accompanied by aphthous stomatitis, pharyngitis and cervical lymphadenitis [1], which was called Marshall's syndrome. According to the first letters of the symptomocomplex (Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis/cervical adenopathy), this disease also has another name – PFAPA-syndrome [2]. In the following years, there were descriptions of dozens of similar cases given by other authors, therefore to talk about the rarity of the syndrome is unlikely. Most researchers believe that this disease is much more widespread than it was previously thought.

Until recently, Marshall's syndrome remained a chronic disease of unknown etiology, which occures mainly in children, more often in boys. The main characteristic of the syndrome is repeated sudden attacks of high body temperature (38-41°C), which take place periodically with intervals of 3 to 7 weeks. These episodes are often, but not necessarily, accompanied by aphthous stomatitis, pharyngitis and cervical lymphadenitis. The complete set of features, that gave the name of the syndrome, is observed in less than half of the cases [3]. The diagnostic criteria for the disease include the above mentioned clinical symptoms, as well as the time when the disease started at an early age (under 5 years), the presence of asymptomatic intervals, the complete absence of symptoms between attacks of the disease, normal growth and development of a child.

Typical manifestations of Marshall's syndrome include a clear periodicity of attacks. In almost half of the cases, the parents of a sick child can predict in advance the day when the next attack will begin. Spontaneous termination of febrile fever is observed in 3-6 days. According to available data, PFAPA syndrome does not lead to additional diseases or complications and usually disappears when children get older [4]. However, in some cases in adults, the disease may not disappear on its own or may return again after many years [5]. According to the authors, the ability of a single dose of corticosteroids to stop the attack of PFAPA indicates on the involvement in the development of the disease rather pro-inflammatory cytokines than infection. PFAPA-syndrome is considered to be the most widespread form of intermittent fever in children. And although genetic causes have not been identified, this syndrome is now more often grouped with hereditary fever syndromes: it usually begins in early childhood (at the age of 2–5 years) and is more widespread in boys.

There have not been found any diagnostic laboratory tests for identification of PFAPA-syndrome. Indicators of acute phase (C-reactive protein, erythrocyte sedimentation rate) increase during the febrile episode, but not between episodes. In the acute period, in blood analyses moderate leukocytosis (more than 12x10⁹/l) simultaneously with neutropenia is often revealed. All indicators return to normal in the period between attacks. During bacteriological examination of cultures from the throat it may be revealed beta-hemolytic streptococcus group A (BHSA), but these patients do not respond to treatment with penicillins. On this basis, it was noted that patients with PFAPA-syndrome are carriers of BHSA, and the existing local symptoms are a manifestation of BHSA-tonsillopharyngitis. That is, previously also there have been attempts to explain the origin of pharyngitis and stomatitis by a focus of chronic bacterial infection in the nasopharynx. However, the etiology of the rapid rise of temperature, which had no obvious clinical signs of infectious origin and which there was difficult to link with BHSA and local manifestations of inflammation and persistence of streptococci in the nasopharynx, remained uncertain.

The diagnosis is made on the basis of medical history of disease and clinical data. The main hallmark of Marshall's syndrome, which dominates in the clinical picture, is periodical high fever, which begins suddenly on the background of complete health and may be accompanied by chills. The temperature ranges from 38.5 to 41ºC for 2-7 days, then drops sharply to normal. Before the fever, the child may experience irritability, mood swings, the child may complain of malaise, sore throat. Ulcers/cankers of aphthous stomatitis in the mouth appear in 40-80% of patients, pharyngitis in 65-100%, and cervical lymphadenopathy in 60-100%. Often patients have also other symptoms, such as abdominal pain (40-65%), joint pain (11-42%), vomiting (18-41%) and headache (18-65%). Diarrhea, cough, runny nose and rash are less often. In adulthood, episodes rarely have the same interval between attacks, and during the attack itself it’s rarely diagnosed pharyngitis, herewith chest pain, headache, arthralgia, myalgia, ocular symptoms and rash appear more often. Thus, today one can say that the main symptoms, which, in fact, gave the terminological name of PFAPA-syndrome, are not mandatory for this disease and the only ones: Marshall's syndrome has else many other clinical manifestations, the origin of which also remained unclear.

Attacks of the disease usually cease on their own in 3-7 days. Medicines treatment is prescribed to reduce the severity of attacks [6]. A single dose of corticosteroids (usually prednisolone) at a dose of 1-2 mg/kg (maximum dosage - 60 mg) at the beginning of the disease usually stops the attack within a few hours and reduces the severity of attacks. The main disadvantage of such therapy is the possible reduction of asymptomatic intervals between attacks, which occurs in 19-50% of patients [7]. After discontinuation of glucocorticoid therapy (GT), the frequency of episodes usually returns to initial level. The prescription of antibiotics and antipyretics has almost no positive clinical effect. Based on the literature data and researchers’ own observations, many researchers believe that there is not only the difficulty of diagnosing this syndrome, but also long-term irrational treatment, which remains without the desired positive clinical outcome [8, 9]. As an alternative to medicines treatment, there were attempts to use tonsillectomy and removal of adenoids, but such radical steps have also rarely led to a satisfactory clinical outcome - fever attacks continued [6, 10]. 

In recent decades, human hereditary autoinflammatory diseases/syndromes (AID) arouse scientific and practical interest for clinicians. All known AIDs combine recurrent character of fever and systemic inflammation simultaneously with other clinical symptoms, which differ by certain permanence. According to modern data, AIDs are classified as primary immunodeficient states caused by genetic disorders of the interaction of inflammation regulators, and occur in the absence of the pathogen. Many AIDs, manifesting in childhood, have a severe course and a serious prognosis. The exception is one of the most widespread variants of AID in children - PFAPA-syndrome or Marshall's syndrome, since it has a favorable prognosis usually with complete recovery of the child. It is just the regularity and stereotype of febrile attacks of PFAPA, according to researchers of this syndrome, may indicate on a violation of immune regulation as a potential mechanism of the development of this auto-inflammatory disorder.  

Many researchers of PFAPA-syndrome believe that the trigger for this disease with an unknown type of inheritance and an uncertain specific mutant gene is, however, just genetically determined dysregulation of innate immunity, associated with excessive production of inflammation mediators such as proinflammatory cytokines IL-1, TNFα, IL-6, IL-12p70 and others [11, 12]. The cytokine profile of these inflammatory mediators, increased in the blood serum both in periods of exacerbation and in remission state, indicates, according to the authors, on the presence of a constant focus of subclinical inflammation in patients with Marshall's syndrome. However, still there have not been identified features of autoimmune aggression (autoantibodies, autoreactive T-lymphocytes) in patients. Specific biological markers of PFAPA-syndrome have also not been identified, therefore the diagnostics is largely based on knowledge of the main clinical symptoms of the disease, described in detail by G.S.Marshall back in 1987-1989, and on the assessment of high clinical efficacy. Taking into account the frequent coincidence of the debut and subsequent manifestation of Marshall’s syndrome with the time of beginning of children's visits to organized children's collectives, it becomes clear why PFAPA-patients are usually observed for many years in the group of children which often sick (COS) and unreasonably are subjected to long-term and almost ineffective load with medicines. Thus, now the origin, diagnostic methods and effective treatment of patients with Marshall’s Syndrome/PFAPA remain an unresolved issue. 

Today, it is difficult to say whether Marshall’s syndrome can be attributed to AID over time, whether it will be proven that it has genetic origin and/or is associated with dysregulation of innate immunity by excessive production of inflammation mediators. But it seems to us that in 35 years after the first mention of this disease, finally the answer to the question of its etiological origin has been found and there have been clarified the causes of sudden recurrent fever and other symptoms, combined in the clinical picture of PFAPA-syndrome or Marshall's syndrome. In our opinion, there have been found clear diagnostic methods and there has been proven the high efficiency of its treatment. And as it’s often the case, everything turned out to be much simpler and clearer, almost like in Krylov's well-known story from 1808: "And the casket simply opened." However, let's start from the beginning.  

Firstly, there has been found the origin of the etiologically indeterminate sudden high-grade short-term fever, usually recurrent, which is the main feature of Marshall's syndrome. During 2009-2020, we monitored and treated more than 5,000 patients diagnosed with Chronic Bacterial Intoxication Syndrome^©, which had developed on the background of Nephrodysbacteriosis^©. The diagnostic term Chronic Bacterial Intoxication Syndrome^© (CBIS), Nephrodysbacteriosis^© and other new terms, related to this diagnosis, began to be used since February 2009, when for the first time there were diagnosticated these diagnoses [13]. But their complete understanding, interpretation and formulation took place throughout all this period of observations. Officially these diagnostically new terms were registered in 2020 [14]. The group of statistical processing of the observation results according to the method of random sampling included 4,500 immunocompetent (with the absence of HIV/AIDS) persons with CBIS, who were first reported in February 2021 [15]. Among 4,500 people with CBIS, there were 3999/4500 (88.9%) patients with temperature disorders, including 1952/3999 (48.8%) - children from infancy to 14 years. There were 1206/1952 (61.8%) children with prolonged subfebrile, 721/1952 (36.9%) with sudden temporary fever and 25/1952 (1.3%) with long-term febrile fever at 38-40°С and above, about which we have previously reported [16, 17]. Then it was for the first time detected and proven by the results of bacteriological and toxicological examination, as well as of appropriate effective treatment, that temperature disorders, including sudden recurrent fever, which was called febrile attack^© (FA), have a toxic origin and are linked with the development Nephrodysbacteriosis/CBIS. 

Moreover, we also reported about a new view on the “Clinical image of a child which often sick” [18, 19]. As our long-term practical observations have proven, the clinical image of a Child which Often Sick (COS) currently consists of three interrelated clinical states which are still usually separated each from other. The First clinical image included children with symptoms of acute often repeating recurrent respiratory disease (RRD). The Second clinical image with the conditional patients’ name "COS with purulent-inflammatory diseases" included 1595 children with dominant chronic and often recurrent purulent-inflammatory diseases of the nasopharynx and bronchopulmonary system. The Third clinical image with the conditional patients’ name "COS with dominant toxic manifestations" included 1952 children with dominant temperature disorders of toxic origin and with other clinical manifestations of CBIS. 

It was noteworthy that purulent-inflammatory processes in the mouth in more than 1/3 of children with the Second clinical image in all age groups of COS were accompanied by almost constantly recurrent painful stomatitis (554/1595 or 34.7%) with focal or almost total lesions of mucous membranes, by chronic tonsillitis (1048/1595 or 65.7%) usually with recurrent anginas and by chronic recurrent pharyngitis (503/1595 or 31.5%). Moreover, almost all children in this group (1570/1595 or 98.4%) had enlarged lymph nodes of the nasopharyngeal ring. On the other hand, in 142/721 (19.7%) COS with the Third clinical image, the next relapse of FA was usually combined with aphthous or aphthous-ulcerative stomatitis and enlargement of the submandibular and cervical lymph nodes. 

Such a strange coincidence of symptoms in a new etiologically determined generalized clinical image of COS could hardly be explained by a simple coincidence: sudden recurrent high fever, stomatitis, pharyngitis and enlargement of cervical lymph nodes [18, 19]. Doesn't it resemble anything? Yes, and for us too. Therefore, it is time to move to a new view on the etiological origin of Marshall’s syndrome or PFAPA-syndrome.     

Materials and methods. 

In this report, we will analyze the clinical state and results of laboratory examinations of 721 children which were under our observation during 2009-2020 with clinically dominant sudden recurrent high-grade short-term fever, called as febrile attacks^©, including 205/721 (28.4%) children aged under 3 years, 263/721 (36.5%) - aged 3 to 7 years and 253/721 (35.1%) - aged 7 to 14 years. There were 414/721 (57.4%) boys and 307/721 (42.6%) girls. Despite the different duration of the disease (from several months to many years), the true etiological diagnosis of this pathological state in children before going to the clinic remained uncertain and passed under the false mask of completely other diagnoses. In 14 cases, children were pre-diagnosed with Marshall's syndrome. 

All patients were examined by bacteriologically cultural method using appropriate nutrient media (chief of the bacteriological department of the Markov Clinic’s laboratory – L.P.Vustich, scientific consultant – L.G.Vasylenko). In all cases, there were performed bacteriological tests of smears from the nose and throat and of urine, according to clinical indicators additionally - from the mouth, tongue, foci of stomatitis on the mucous membranes, gums, nasal mucus, sputum, secretions from the ear, skin, conjunctiva. Bacteriological confirmation of diagnoses Nephrodysbacteriosis^© and CBIS^© was performed routinely by culturing morning warm urine three times (three consecutive days) that was usually carried out at home using appropriate devices Diaslide^© DS-101 and DS-105 (Novamed, Israel) with nutrient media CLED agar, McConkey agar and chromogenic agar UriSelect. In case of growth of cultures of microorganisms, they were transferred to Petri dishes with nutrient media such as meat-peptone agar (MPA) with the addition of 5% blood, Endo medium, Saburo agar, Mueller-Hinton agar and some others to continue the standard procedure for identification of isolated cultures. Urine for bacteriological examination was obtained by natural way without the use of invasive method of bladder catheterization. Moreover, 115/721 (15.9%) children with FA (mainly during temperature increase in the first 2-3 days of a febrile attack) underwent blood culturing for sterility on two nutrient media: on the "Double medium", consisting of beveled in vials 100 ml nutrient agar and 100 ml of 10% glucose bouillon (prepared on nutrient bouillon) and on medium for control of sterility (thioglycol medium).

Control groups of bacteriological examination of nasal and throat smears, as well as warm urine (three times, 3 days in a row) consisted of 205 clinically healthy infants (from 3 to 12 months), who were brought to the clinic for routine preventive vaccination (group 1), and 70 healthy adults (women - 30 or 42.9%, men - 40 or 57.1%) aged from 20 to 65 years (group 2).  

Toxicological examination of blood was performed by the method of complex toxicometry using the diagnostic system "Toxicon" (20) on the basis of the City Burn Center (Kyiv City Clinical Hospital No.2, Ukraine) and Children's Hospital "Okhmatdyt" (Kyiv, Ukraine). During 2012-2020 toxicological examination was performed for 96 children aged from 3 to 14 years, who were often ill and had temperature disorders, with appropriate statistical processing of the results. There were studied parameters of toxemia to determine the characteristics of "toxic proteomes". Separately there were considered general cytolytic and autoimmune activity of toxic proteomes, as well as depending on the clinically dominant toxic effects on organs and systems and depending on the dominant etiological pathogen [21]. Arithmetic mean (M) and standard deviation (SD) were used for descriptive statistics of quantitative indicators. The distribution of qualitative characteristics is presented in percent (%). T-test and dispersion analysis (ANOVA) were used to compare scores between groups. The Xi-square criterion was used to compare the distributions of qualitative features. Software product for statistical analysis - STATA 12. Advisory assistance in the formation of the primary database and statistical analysis was received at the Department of Medical Statistics of the National Medical Academy of Postgraduate Education named P.L.Shupyk, Kyiv, Ukraine (Associate Professor O.B.Tonkovid).    

There were also performed generally clinical examinations, which included general analyzes of blood, urine, feces, etc., according to clinical indicators - biochemical examination (biochemical analyzer Beckman Coulter AU480, USA) of liver and kidney samples, protein fractions and rheumatoid tests, glucose and glycated hemoglobin, exchage of lipids, vitamins, trace elements, etc. Almost all patients pursuant to plans of differential diagnosis underwent ELISA and PCR-studies (real-time) for herpes viruses (HSV 1/2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8), according to clinical and epidemiological indicators – for Borrelia, HIV and other viral and bacterial infections. Almost all patients underwent examination of immune status to determine: cell chain links by the method of flow cytometry with immunophenotyping of cells of peripheral blood (flow cytofluorimeter CytoFLEX, Beckman Coulter, USA), total immunoglobulins IgA, IgM, IgG, complement systems C3 and C4, phagocytosis and circulating immune complexes. According to clinical indicators, there were additionally studied markers of autoimmune diseases, autoimmune hepatitis, allergies (general and specific IgE), hormones (first of all - the thyroid gland), there was performed microscopic examination of sputum and nasal secretions. According to clinical indicators, patients underwent instrumental examination: ultrasound, X-ray, MRT and/or CT, ECG, EEG, etc.  

Terminology.   

The new diagnostic terms used in this article are interpreted as follows.

Nephrodysbacteriosis^© is a locally asymptomatic (without signs of inflammation process) long-term focus of chronic bacterial infection in the kidneys, which is usually formed by ascending way and at the beginning leads to the development of distant from kidneys features of chronic bacterial intoxication syndrome and almost always precedes the debut of the clinically manifest pyelonephritis. 

Chronic Bacterial Intoxication Syndrome^© (CBIS) is a pathological state caused by endotoxicosis that develops on the background of the focus of chronic bacterial infection in the kidneys (Nephrodysbacteriosis and/or pyelonephritis) and causes clinically multivector manifestations of toxic lesion of different organs and systems of the organism, namely: generally toxic, as well as mainly neurotropic, psychotropic, dermatotropic, arthromyotropic, ophthalmotropic and possibly others.

Febrile attack^© (FA) - a sudden fever of toxic origin with an unexpected rapid and usually short-term (from several hours to 5-7 days) increase of temperature from 38°C to 40°C and above in a clinically healthy child or adult and almost monosymptomatic in general plan (without the development of local symptoms of inflammation in the nasopharynx, bronchi, lungs, intestines, kidneys, etc.), which occurs as one of the dominant clinical manifestations of CBIS^©, which developed on the background of Nephrodysbacteriosis^©.

FA as a rule appears without harbingers and discontinues fairly quickly regardless of the prescribed treatment without undesirable visible clinical consequences, but usually returns just so quickly after a certain or indefinite time. About such a temperature it could be said that it comes without a declaration of war and discontinues without a declaration of capitulation. Outwardly, it seems that this fever came from nowhere and went into nowhere. The temperature during FA is usually completely independent of the efforts of parents and doctors: usually poorly exposed to antipyretic medicines, rarely responds to antibiotics and usually decreases rapidly after detoxification therapy.

Pain attack^© - in patients with Nephrodysbacteriosis^© and Chronic Bacterial Intoxication Syndrome^© (including - on the background of a febrile attack^©) it’s rapid development of pain feelings of various locations (type trigeminitis, solaritis, intercostal neuralgia, headache, cardialgia, pain in the joints and spine, muscle pain, pelvic pain, etc.) with paroxysmal and often intolerable character, usually without the development of pain-related local inflammatory processes and more often with prolonged recurrent course.

Results and discussion. 

Since the main clinical feature of Marshall's syndrome, in fact - his business card, is a sudden short-term recurrent high-grade fever, it becomes clear why for the basis for clinical analysis of the overall picture of the disease in such children there was chosen just this symptom, which was called febrile attack^©.

Clinic. FAs of toxic origin, which were associated with the formation of locally asymptomatic focus of chronic bacterial infection in the kidneys, we observed during 2009-2020 in 721 children who are often sick, namely: at the age under 3 years - in 205/721 (28.4%), in preschool age from 3 to 7 years - in 263/721 (36.5%) ) and at school age - in 253/721 (35.1%). There were 414/721 (57.4%) boys and 307/721 (42.6%) girls. It should also be noted that among 253 schoolchildren who came under supervision at school age, in 143/721 (19.8%) cases the first disorders of the temperature regime, first of all – FA, began to be noted at an early and preschool age. That is, totally in 611/721 (84.7%) children, FA began to appear for the first time at the age before 7 years, that corresponded to one of the main clinical criteria for the diagnosis of Marshall’s syndrome.

In these cases, as some say "on an equal footing" without any warnings and reports from the outwardly healthy organism of a child, the temperature critically quickly reached usually 39-40°C or even higher. The main distinction between the usual increase in temperature in a child, who habitually got sick, and FA was the mismatch of mild catarrhal manifestations and symptoms of purulent-inflammatory process of any location, first of all in the nasopharynx, mouth, ears and bronchopulmonary system, to the height of the temperature reaction. That is, there is a high temperature, but there aren’t local symptoms of inflammation. In the morning the child could feel good, run, play, take an interest in the surrounding world, but in 2-3 hours the child was "burning" and had a temperature of 39-41°C.

In most cases (443/721 or 61.4%), FA was short-term and lasted mostly from a few hours to 1-2 days, else in a third of cases (240/721 or 33.3%) - from 3 to 5 days and only in 38/721 or 5.3% of cases - up to 5-7 days. The increase in temperature during FA, especially within only a few hours, resembled the known from the literature one-day or ephemeral fever (febris ephemera or febriculara). But in contradistinction to ephemeral fever, in 544/721 (75.5%) cases FA returned, usually repeating within 1-2 months at various, including equal intervals, sometimes less often - only a few times a year. So, relapses of FA, repeated every 3-7 weeks, much prevailed - in 341/544 (62.7%) children, else in 1/3 of cases (179/544 or 32.9%) relapses were every 8-12 weeks and only in 24/544 (4.4%) children temperature attacks were much less frequent and occurred only 2-3 times a year. In cases, when FA returned every 3-7 weeks, parents of almost a third of children (101/341 or 29.6%) really (as for Marshall's syndrome) could name the day of the next attack (more often - on the 28th-30th days), which they awaited in anxious fear. In almost 2/3 of cases (450/721 or 62.4%) FA either occurred in children with prolonged long-term (possibly intermittent) subfebrile, or left behind a subfebrile temperature more often of prolonged character.

The type of fever in patients with FA, which were under supervision, was different, but in 417/721 (57.8%) cases it prevailed the temperature of remitting or weakening character (febris remittens) with a change within 1°C during a day, which, however, almost did not decrease to normal. Else in 234/721 (32.5%) patients the fever had an intermittent character (febris intermittis) with a decrease in temperature during the day to normal and with a new increase. Usually, such fluctuations in temperature almost did not depend on the treatment prescribed to children, and occurred according to some unknown and incomprehensible scheme. Other types of fever had limited or single character and occurred in 70/721 (9.7%) cases.

Clinically, FA was almost always accompanied by other symptoms which were considered as concomitant or additional and which could hardly explain the origin of FA. But they usually formed a stable clinical picture of the disease, which completely or to some extent resembled the classic Marshall’s syndrome. The following table 1 shows additional clinical symptoms, which more or less often appeared together with FA and reflected the clinical image of a child which often sick (COS) with dominant chronic and often recurrent purulent-inflammatory diseases of the nasopharynx and with manifestations of chronic bacterial intoxication syndrome, first of all - with temperature disorders with febrile attacks, which had all signs of a sudden recurrent high fever.

Table 1.

Additional clinical manifestations of disease in children (n=721)

with febrile attacks  

(sudden recurrent high fever)

As one can see in the Table 1, the main and almost "recognizable" features of Marshall's syndrome, such as enlarged lymph nodes of cervical group, stomatitis and pharyngitis were quite often in patients with febrile attacks. So, regardless of age, almost all children with FA (99.2%) had enlarged lymph nodes of the external lymphopharyngeal ring, accessible for palpation: first of all – anterior- and posterior-cervical, submandibular, often - occipital, parotid. The degree of lymph nodes enlargement was different: more often I degree (from 0.5 to 1.5cm in diameter) and II (from 1.5 to 2.5cm) - respectively in 417/715 (58.3%) and 270/715 (37.8%) cases. Herewith, the lymph nodes remained mobile, unconnected each other and almost intact or slightly painful to the touch. In 35-47% of cases, depending on age, children were simultaneously diagnosed with pharyngitis, less often – with stomatitis (11-27%). Much more often (56-81% depending on age) in children there was found concomitant chronic tonsillitis, which often during FA also acquired features of exacerbation. Adenoids were found in 160/721 (or 22.4%; depending on age - 14.2-30.8%) children.

In 27/721 (3.7%) children mainly of preschool and school age with chronic tonsillitis and in 70/721 (9.7%) children with adenoids on the previous stages of observation and treatment due to recurrent high temperature, there was performed tonsillectomy and/or adenoidectomy, which did not affect the course of the disease by no means - attacks of short-term fever continued. This reaffirmed our view that the guillotine cannot be a cure for chronic bacterial infections. Almost a third of children (23-36%) complained of headache, 20-27% - abdominal pain, 32-41% experienced sore throat, 19-23% - in the joints, 7.5% of school-age children - in muscles. It should be noted that in general the pain syndrome of different location was a quite typical feature in children with FA and sometimes acquired a dominant intolerable character with a recurrent paroxysmal course that resembled a pain attack^© of unknown origin, as in our following observation (example 1).   

Example 1. 

In the spring of 2015, in the Vitacell Clinic came the father and grandfather of a beautiful boy, let's call him Andriychyk, 7 years old, which the day before was once again discharged from the surgical department, where he spent 3 days on suspicion of acute appendicitis. This was already the seventh hospitalization with suspicion of appendicitis during the last 4 months. Fortunately for the child, due to the uncertain clinical picture of these acute abdominal pain attacks, repeating 2-3 times a month already within the last year, mostly – simultaneously with a sharp increase in temperature to 39°C and above, maximally localizing each time around the navel, none hospitalization did not end with surgery. Although the surgeons' patience almost terminated and the boy had already been premedicated several times. According to relatives, Andriy was already well known to surgeons in various profile departments of Kyiv, since he was probably the same number of times discharged to home after an examination in the admission department and a general blood analysis, which usually remained almost "calm", although for some reason it showed constant lymphocytosis and neutropenia instead of expected neutrophilia. The last time the boy was admitted to the same surgical department, in which almost 15 years ago the senior co-author of this article managed after consultation to prevent unnecessary appendectomy in several children with Yersinia mesadenitis, which to a great extent also imitated acute appendicitis, but quickly discontinued together with pain syndrome after prescription of Laevomycetinum (Chloramphenicolum). The chief of the department was the same as 15 years ago, and after listening to the story of the wanderings of this suffering child, he had advised to find the same infectious diseases specialist to be consulted.

During the consultation at the clinic it was revealed the following. In his early childhood, Andriy was a sick child with a problematic nasopharynx, from which St.aureus was more than once isolated, and very often he received antibiotics. From about the age of 3 years, parents began to notice frequent (almost every month) unexpected sudden increase in temperature (as it became clear during the consultation at the clinic - typical febrile attacks) without local features of purulent-inflammatory process and with moderate catarrhal manifestations in the nasopharynx with concomitant symptoms of chronic pharyngitis, tonsillitis, recurrent stomatitis. In a few days, everything quickly discontinued, leaving behind almost constant subfebrile, increased sweating, decreased hemoglobin (up to 105 g/l), intoxication shadows under the eyes, increased irritability and uncontrollability of the child. Later the child began to complain of intermittent joint pain, and since 6 years it appeared severe, sometimes intolerable abdominal pain, which recurred every 2-3 weeks and was usually accompanied by a rapid and high increase in temperature. Since 3 years in the urine there were periodically detected minor proteinuria, leukocyturia and bacteriuria, but they remained without attention. Taking into consideration the above mentioned, the boy was diagnosed with Nephrodysbacteriosis and CBIS with dominant febrile attacks and recurrent abdominal pain of the solaritis type, which had a course of pain attack. The diagnosis was confirmed by isolation of 3 urine cultures of Enterococcus faecalis. A bacterial autovaccine was prepared, and there was performed immunization with a course of 10 injections. Already during vaccination and for the next 5 years of follow-up observation, there were no more FA and attacks of abdominal pain.

The clinical course of FA was often accompanied by such manifestations of chronic intoxication (CBIS) as weakness and increased fatigue (17-35%), drowsiness (18.6% - mostly in school-age children), irritability, mood swings and emotional excitability, uncontrollability of behavior (11-17%), increased sweating (34-42%), sometimes vomiting not related to food poisoning (8-18%). Quite typical in children with FA there were intoxication shadows and puffiness under the eyes (67-93%), which remained in the inter-relapse periods during temporary normalization of temperature, itching of the skin and mucous membranes (12-19%), various skin rashes (bacterial toxicoderma), which were noticed in 34.3% of children (from 28 to 39% depending on age). Thus, as shown in Table 1, only about 25% of symptoms were linked with inflammatory process in the nasopharynx. The vast majority of clinical manifestations that accompanied FA, as well as FA itself, were not directly etiologically or pathogenetically related to chronic pharyngitis, tonsillitis, recurrent stomatitis and enlargement of cervical lymph nodes, because they were of other origin.

Changes in the general blood analyses in children with FA, associated with Nephrodysbacteriosis/CBIS, were not specific, but rather typical. In more than a third of cases (275/721 or 38.1%) there was detected a slight leukocytosis with an increase in the level of leukocytes above 10-12×10⁹/l (depending on the age norm in the child), which only in single cases was accompanied by neutrophilic shift of leukocyte formula to the left, typical for purulent-inflammatory processes. But not much less often on the contrary there was detected leukopenia with a decrease in the level of leukocytes below 4.0×10⁹/l - in 154/721 or 21.4% of children. The dominant feature in the general analysis of blood (in 638/721 or 88.5% of cases) was relative and absolute lymphocytosis - from moderate above by 5-10% up to a real increase in lymphocytes in 2-2.5 times the age norm that was usually explained by "endured viral infection", and sometimes even by the appearance of a small number of atypical mononuclear cells (usually up to 5%). With a significant increase in the level of lymphocytes there was a corresponding secondary decrease in the level of granulocytes, first of all – neutrophils blood elements. Neutropenia in patients with FA on the background of Nephrodysbacteriosis and CBIS had always secondary dependant character and was usually the result of primary lymphocytosis.

Quite typical there was also more frequently the stable decrease in level of hemoglobin and erythrocytes (in 35-40% of cases) and platelets (in 10-15% of cases), which had no clear explanation of origin and could remain for years, despite intensive modern treatment of anemia more than once. Herewith, sometimes leukopenia with neutropenia and thrombocytopenia could be significantly pronounced and could reach almost critical levels. Prescription more than once in such cases of the most modern medicines to improve leukopoiesis and thrombocytopoiesis usually gave temporary and limited result. Another manifestation of Nephrodysbacteriosis and of the impact of chronic intoxication on the general blood analysis could be an increase in ESR: from 20-25 mm/h to 40-45 mm/h, which could also last for years. Herewith, other indicators of blood analysis could remain within norm.

In the periods between attacks of temperature, a rather limited number of symptoms could remain: enlargement of the cervical lymph nodes, increased sweating, unstable subfebrile temperature, intoxication shadows under the eyes, sometimes - weakness, increased fatigue; in the blood analysis - lymphocytosis. Herewith, the general state of the children almost did not suffer, there were no visible predictors of the next attack. 

In adults, episodes of FA as a clinical manifestation of Marshall's syndrome do not have the same time interval between attacks, and during the attack itself, stomatitis is extremely rare, only sometimes – there are pharyngitis and/or enlarged cervical lymph nodes. As we reported earlier [15, 16], in 399 adults with FA, that were under our supervision, along with a sudden increase in temperature there were more often other manifestations of CBIS: mild chills or feeling of fever, pain syndrome with chest pain, headache, arthralgia, myalgia, spine pain, it bothered skin itching, rash, increased sweating, spasms peripheral blood vessels with freezing and paresthesias of the extremities, decreased vitality, phobias and panic attacks. In cases when FA that appeared in childhood remained in adulthood, attacks lost their typical time intervals between temperature attacks and became unpredictable, as in the following example 2.  

Example 2.

Patient M., 19 years old, went to the clinic on June 30, 2021 with complaints of long-term (from childhood) recurrent fever, recurrent sore throat, increased weakness, rapid fatigue after physical and sports activities (for several years he could not play sports and ballroom dancing), intermittent joint pain and chills, social passivity. From the distant anamnesis, according to the boy's mother, there had been clarified that from an early childhood (from the age of 2 years) he had attacks of high temperature, which were often accompanied by exacerbation of chronic tonsillitis with severe anginas, constant cervical lymphadenitis, recurrent stomatitis and pharyngitis. For several years, fever attacks were monthly and recurred almost every 28-30 days. The temperature almost did not respond to the prescription of antibiotics, poorly exposed to antipyretics and lasting usually from 2 to 5 days disappeared. Despite various diagnoses and almost constant treatment, usually with the use of antibiotics, the fever returned again and again. After starting school at the age of 7 years, colds and long-term runny nose became more frequent, chronic sinusitis developed, and recurrent anginas, stomatitis and pharyngitis remain. Fever attacks continued, but lost their constant periodicity, recurring only 5-7 times a year, and height - the temperature during the attack did not exceed more than 38°C. During the next increase in temperature and visiting the medical institution at the place of residence on June 12, 2021, for the first time there was diagnosed Marshall's syndrome and for 11 days (from June 12 to June 22) there was prescribed treatment with corticosteroid (CS) medicines in the maximum daily dosage of 90 mg/day. In 2-3 hours the temperature decreased, but finally returned to normal on the second day after the prescription of CS.

Examination in our clinic revealed 2 foci of chronic bacterial infection: in the nasopharynx (there were isolated 2 strains of Staphylococcus aureus and 1 strain Streptococcus pyogenes) and in the kidneys (2 urinary strains Enterococcus faecalis). There was diagnosed: -Nephrodysbacteriosis with latent formation of chronic sluggish pyelonephritis, -chronic bacterial intoxication syndrome with FA and subsequent episodes of temperature increase (up to 37.4-37.8°C), with excessive weakness and rapid fatigue, intermittent headache and joint pain, periodical chills, decreased tolerance to physical, sports and mental loads, social passivity, apathy, with cognitive disorders with impairment of memory, logical and associative thinking, with elements of difficult speech (word selection) and concentration of attention, with irritability, intoxication "shadows" under the eyes, secondary hypochromic anemia and -chronic staphylococcal-streptococcal infection of the nasopharynx with recurrent chronic tonsillitis, pharyngitis, stomatitis (in anamnesis), cervical lymphadenopathy and recurrent pyoderma of the face. Marshall’s syndrome (lasting 17 years). Concomitant diagnoses: state after multiple courses of treatment with antibiotics. Chronic EBV-infection in the stage of low replicative activity (healthy virus-excretion with saliva). There were found lymphocytosis (47%) and high level of ASLO (712.7 IU/ml), which is appropriate for Nephrodysbacteriosis and CBIS mainly of enterococcal origin [15]. While determining immune status there was revealed a minimal decrease of the content of cytotoxic cells (CD3+, CD56+) and natural killers (CD3-, CD56+) on the background of increased content of T-helpers (CD3+, CD4+, CD8-) and T-suppressors (CD3+, CD4-, CD8+). 

There was prescribed and carried out for 110 days consecutive treatment with three courses of bacterial autovaccines (monovalent staphylococcal with 12 injections, divalent Escherichia coli-enterococcal with the addition of 2 autostrains Ent.faecalis with 10 injections and polyvalent urovaccine with autostrains also with 10 injections). During the next 6 months of follow-up observation, the boy's state improved significantly: fever attacks did not recur more, weakness and rapid physical and mental fatigue almost discontinued, headache, joint pain and cognitive disorders stopped, he became socially active again and returned to his favorite ballroom dancing.      

Diagnostics. During bacteriological examination of warm urine of 721 sick children with FA and complete or partial clinical picture of Marshall's syndrome in all patients there were isolated urine cultures of various strains of bacteria. In 377/721 (52.3%) cases, there was isolated by 1 culture of bacteria, i.e. 377 strains. Else in 286/721 (39.7%) patients there were simultaneously isolated by 2 cultures of various bacteria, i.e. else 572 strains, and by 3 cultures from one portion of urine there were isolated much less often – only in 58/721 (8.0%) cases (174 strains). More than 3 strains from one bacteriological culturing were almost not isolated at all. Thus, in total there were isolated 1123 strains of various bacteria that were considered as diagnostic confirmation of the presence of the focus of chronic bacterial infection in the kidneys in all these 721 patients with febrile attacks.

Herewith, in almost 3/4 of cases (531/721 or 73.6% of patients) there was diagnosed locally asymptomatic Nephrodysbacteriosis without clinical, general laboratory (including almost normal general urine analysis) and instrumental features of inflammatory process in the kidneys. Else in 162/721 (22.5%) cases, there was diagnosed delayed latent formation of clinically asymptomatic chronic pyelonephritis with detected for the first time proteinuria, leukocyturia and cylindruria, about which the parents of the children did not even guess. In 28/721 (3.9%) patients there were detected etiological pathogens of chronic pyelonephritis in the stage of slightly pronounced clinical exacerbation. As we noted earlier [15], just the presence of a focus of chronic bacterial infection in the kidneys led to the development of CBIS with dominant temperature disorders of a toxic nature and with the development of febrile attacks.

Table 2 shows the results of bacteriological examination of warm urine of 721 children with a sudden high short-term recurrent fever, called febrile attack having toxic origin, and with other clinical symptoms, complex of which was appropriate to the diagnosis of Marshall’s syndrome.   

Table 2.

Results of bacteriological examination of warm urine of patients (n=721)

with febrile attacks on the background of Nephrodysbacteriosis/CBIS. 

As Table 2 shows, the main factor in the emergence of temperature disorders on the background of CBIS in the form of FA were enterococci, the level of isolation of which from the urine compared to other bacteria was significantly more: 453 from 1123 in total isolated strains or 40.3%. The undisputed leader among the isolated urine cultures of enterococci was Enterococcus faecalis: 398 strains or 35.4% of all isolated strains and 87.8% (398/453) from all isolated enterococci, much less often - Enterococcus faecium - 37 strains (3.3% and 5.1%, respectively) and Enterococcus durans - 18 strains (1.6% and 2.5%). But taking into account the double and sometimes even triple simultaneous isolation of various bacteria in one patient, it becomes clear that enterococci as the main etiological causative agent of CBIS with FA were isolated in more than half of cases (453/721 or 62.8% of the total number of sick children). Escherichia coli took the second place after enterococci - 22.1% or 248 strains (isolated in 34.4% of patients).

Thus, just these two bacteria - enterococci and Escherichia coli were the main dominant etiological factors in emergence of FA on the background of Nephrodysbacteriosis/CBIS and totalled almost 2/3 or 62.4% of all isolated strains of urinary cultures and were isolated from the urine in total in 97.2% of patients with this diagnosis.

Staphylococci totalled the next large group of bacteria isolated from the urine of patients with temperature disorders: in total 18.4% or 206/1123 strains isolated from 28.6% of patients. In this group of pathogens, the undisputed leader was Staphylococcus aureus: its number was 2/3 (139/206 or 67.5%) of all isolated staphylococci and exceeded 2 times the total number of strains of urinary cultures of Staphylococcus haemolyticus isolated from sick children (19.3% and 9.3%, respectively). Only in single cases (17/1123 strains or 1.5% were isolated from 2.4% of patients) as a urine culture there was isolated Streptococcus pyogenes. And although staphylococci in total pursuant to frequency of their detection were only the second after enterococci and Escherichia coli, it should be noted the following. The territory of the mucous membranes of the genitourinary organs in general and the kidneys in particular for staphylococci is not familiar and commonplace. Taking into consideration their predominantly airborne way of transmission, the first and main focus of these bacteria is primarily formed in the nasopharynx, tonsils and paranasal sinuses. From there, by various ways they go into the genitourinary organs where for certain time (more often in children) they may even dominate in the etiological structure of the focus of chronic bacterial infection in the kidneys (Nephrodysbacteriosis) with the development of CBIS with temperature disorders.

The next clinically significant etiological stage after staphylococci was occupied by Klebsiella - 6.73% or 76/1123 strains (mainly due to Klebsiella pneumonia), isolated in 10.5% of patients. Quite often there were also isolated Proteins - 3.6% or 40/1123 strains isolated from 7.1% of patients (Proteus mirabilis and Proteus vulgaris), less often - enterobacters (almost equally Enterobacter aerogenes and Enterobacter cloacae) - 2.7% or 31/1123 strains from 4.3% of patients and morganellas (Morganella morganii) - 1.33% or 15/1123 strains from 2.1% of patients. Another very small group of enterobacteria isolated from urine was composed of urinary cultures of acinetobacters, citrobacters and in very rare cases - Alcaligenes faecalis, hafnia, sera. There were also isolated 2/1123 (0.18%) strains of Pseudomonas aeruginosa from 2 children with a surgical urological anamnesis.

Separately it should be noted that bacteriological examination of warm urine only in less than 1/3 of cases (in 227/721 or 31.5% of children) was performed during the FA itself on the background of increased temperature. All other children were bacteriologically examined between relapses. Positive results with isolation of urinary cultures during the usual normal well-being of children, that confirmed the presence of Nephrodysbacteriosis, could indicate a persistent nature of the focus of chronic bacterial infection in the kidneys, which provoked subsequent attacks of FA.

It was of interest to determine the prevalence of Nephrodysbacteriosis among healthy individuals. For this purpose, two control groups were examined: healthy children and adults. Bacteriological examination of urine (three times, 3 days in a row) was performed in 205 clinically healthy infants (from 3 to 12 months) that totaled control group 1, who were brought to the clinic for routine preventive vaccination, and 70 healthy adults (women - 30 or 42.9%, men - 40 or 57.1%) aged 20 to 65 years (control group 2). Among children of control group 1, Nephrodysbacteriosis due to the isolation of various urine cultures was detected in 110/205 (53.7%) cases, that could be, on the one hand, considered as a kind of "diaper fee", and on the other hand - as confirmation of a fairly early asymptomatic formation of a focus of chronic bacterial infection in the kidneys, which subsequently acquired its clinical equivalents. Among adults in control group 2, the results of bacteriological examination of warm urine were positive only in 5/70 (7.1%) cases, that could emphasize that Nephrodysbacteriosis in adults was not a variant of the norm with clinically asymptomatic course. Such a high frequency of detection of Nephrodysbacteriosis in healthy children (in every second among the examined infants of the first year of life) evidences, firstly, about a significant prevalence of temporarily asymptomatic bacterial carriage in the kidneys, and secondly, that the basis of clinical manifestation of febrile attacks and other manifestations of CBIS, which compose the basis of Marshall's syndrome, is usually laid much before their clinical manifestation.

Detection of clinically locally asymptomatic Nephrodysbacteriosis as a persistent focus of chronic bacterial infection in the kidneys confirms the previously reported view that the cytokine profile of inflammatory mediators, increased in blood serum during both exacerbation and remission periods, is a feature of presence in patients with Marshall’s syndrome of a constant focus of subclinical inflammation [11, 12].

During bacteriological examination of smears from the nose, pharynx, mouth, plaques of stomatitis, mucus from the nose and sputum, in children which were under supervision with FA there was found the following: St.aureus was detected in total from smears of different locations and biomaterial in 535/721 (74.2%) cases, St.haemolyticus – else in 135/721 (18.7%). That is, in the vast majority of children (670/721 or 92.9%) there were found pathogenic staphylococci, which occupied a dominant position in this nasopharyngeal microbiome. Herewith, the frequency of detection of Staphylococcus aureus remained almost stable throughout the year and did not change significantly compared to spring-summer or autumn-winter periods. Separately/simultaneously with staphylococci there were also isolated Streptococci: mainly Streptococcus pyogenes - in 168/721 (23.3%) children, less often - Streptococcus pneumonia (in 71/721 or 9.8%). In a small number of cases, simultaneously with staphylococci and/or streptococci there were isolated conditionally pathogenic, pathogenic and saprophytic bacteria such as enterococci (mainly Enterococcus faecalis), Escherichia coli, Klebsiellas (usually Klebsiella pneumonia), Proteus (mainly Proteus mirabilis and Proteus vulgaris), enterobacters, in single cases - acinetobacters, citrobacters, Alcaligenes faecalis and Pseudomonas aeruginosa, as well as corynebacteria, Neisseria, diphtheroids and some other saprophytic bacteria.

In clinically healthy children of control group 1, Staphylococcus aureus was isolated from the nasopharynx in 131/205 children (63.9%), among healthy adults of the control group 2 - in 22/70 (31.4%). Such clinically asymptomatic widespread persistence of staphylococci could last from several months to many years and could not require appropriate treatment. And this is probably just that circumstance that produces a natural question in such cases: whether it is the norm, whether it is the pathology and whether it should be treated all carriers of staphylococcus, or whether no one should be treated, because everyone has it. And the answer, as usual, probably lies in the middle: it is necessary to treat those patients whose staphylococcus has clinical manifestations and shows its pathogenic properties and causes recurrent purulent-inflammatory diseases of the nasopharynx or any other location. When it is in a clinically asymptomatic state of commensal (healthy carrier) - it really may not need treatment. 

When culturing blood on sterility on two nutrient media for 115/721 (15.9%) children with FA (mainly during fever in the first 2-3 days of febrile attack) in all 115 cases, the blood remained sterile: there was no positive result of bacteriological culturing (i.e. bacteremia). This largely confirmed the fact that high fever in children with FA was not septic, but of some other nature. The toxic origin of FA was confirmed by toxicological examinations.

Toxicological examination of blood by the method of complex toxicometry using the diagnostic system "Toxicon" was performed on 96 children aged from 3 to 14 years, who were often sick, including with sudden short-term febrile fever by random sampling with appropriate statistical processing of results. During the toxicological examination of the blood, the following was found. In all 96 children with dominant toxic manifestations of CBIS, including with temperature disorders, in total all without exception indicators of cytolytic activity of toxic proteomes, which were tested, significantly exceeded the norm [21]. The difference was statistically high significant for all tested proteomes (p <0.001). Herewith, the cytolytic activity of some toxic proteomes, namely toxic proteomes of blood plasma, globulin-associated toxic proteomes, albumin-associated toxic proteomes with particles of size 10-200 nm and free-circulating toxic proteomes with particles of size ˂10 nm in children was statistically reliably higher (p<0.05). The autoimmune activity of the major toxic proteomes in children with CBIS was also statistically reliably higher (p<0.05). This concerned five proteomes such as globulin-associated toxic proteomes, free-circulating toxic proteomes, globulin-associated toxic proteomes with particles of size 10-200 nm, albumin-associated toxic proteomes with particles of size 10-200 nm and free-circulating toxic proteome with particles of size 10-200 nm. Taking into account such a high autoimmune orientation of toxic proteomes in patients with CBIS with temperature disorders, maybe it makes sense to carry out additional examination for detection of presence of Nephrodysbacteriosis/CBIS not only in a case of Marshall’s syndrome, but also in the case of other autoinflammatory diseases (AID) with recurrent fevers.

The vast majority of patients (77/96 or 80.2%) had severe toxemia, 16/96 (16.7%) - moderate and only 3/96 (3.1%) - mild. The form of intoxication was mostly compensated - in 87/96 (90.6%) patients, else in 9/96 (9.4%) - in the stage of generalization; there were not detected decompensated forms of intoxication in children. The toxin-bearing fraction of the most active toxic proteomes in the bloodstream in children was mainly represented by free-circulating (32/96 or 33.3%) and globulin-associated (30/96 or 31.25%) proteomes. Among toxic proteomes, it dominated molecules with a size of particles >200 nm, which were found in 72/96 (75.0%) children, and with a size 10-200 nm - in 22/96 (22.9%); else in 2/96 cases (2.1%) the sizes of proteomes were ˂10 nm. Only in almost half of the cases (47/96 or 48.9%) there was determined a strong connection of proteomes with the carrier fraction, but in more than half of the cases the connection was either fragile (14/96 or 14.6%), or in general absent (35/96 or 36.5%) that could explain the rapid dynamic change of the clinical state of a child during FA from clinically pronounced intoxication syndrome up to almost normal well-being. 

Physiological elimination of toxic proteomes in the organism of children took place mainly through the macrophage system of cells of mesenchymal origin (PEC) - in 73/96 or 76.0% of cases, much less often - through the liver (22/96 or 22.9%) and only in single cases (1/96 or 1.0%) - through the kidneys. In the vast majority of children with clinical manifestations of CBIS (93/96 or 96.9%, p˂0.001) there was determined a hyperergic type of reactogenicity of the systemic response to toxic proteomes.     

The similarities and differences between protein formations such as toxic proteomes and cytokines, which occur in patients with FA and with other clinical manifestations of Marshall's syndrome, have yet to be studied and clarified. There are in general known characteristics of proteomes as "a combination of proteins of the organism which are produced by a cell, tissue or by organism in a certain period of time" and cytokines as "small peptide information molecules." However, taking into consideration also the coincidental molecular weight not exceeding 30 kDa, these data may evidence a non-random determined ability of a single dose of corticosteroids to stop a febrile attack in patients with Marshall's syndrome thank to their impact not only on cytokines but possibly also on toxic proteomes.

Treatment. Treatment of all 721 children with febrile attacks was perfomed with bacterial autovaccines. Parents of some part of sick children (52/721 or 7.2%) after the first cycle of treatment no longer went to the clinic for a follow-up examination and disappeared from view, therefore they were not included in the group of statistical processing of treatment results. Also in the group of patients treated with autovaccines there were not included 47/721 or 6.5% of children who during immunization with bacterial vaccines under different circumstances simultaneously received antibiotics. Correspondingly, 99/721 or 13.7% of children were not included in the statistical processing of the obtained results. That is, the number of children who had received treatment, the consequences of which could be considered as determined and these consequences were not linked with the concomitant use of antibacterial medicines, was 622/721 or 86.3% of children.

As it was already noted in previous reports [15], there has been established a clear link between the emergence of Nephrodysbacteriosis and CBIS with temperature disorders, including FA, and previous use of antibiotics, which were unreasonably prescribed usually to "normalize the temperature". So, among children with FA, 570/721 or 79.1% of patients usually more than once received antibiotics before the emergence of sudden fever. Almost in 2/3 of children on the previous stages of treatment it could be stated syndrome of polypragmasia with prescription them more than 5 and often more than 10 medicines simultaneously. But all was in vain: the state of patients after prescribing so many medicines, "headed" mostly by antibiotics, either did not change at all, or improved for a short time up to the next attack of temperature. It was noteworthy the following clinical peculiarity of the treatment of children with FA using antibiotics: the periods of "light" intervals between the previous and the next courses of treatment due to relapse of fever during all time gradually decreased, like "shagreen skin" in the Honore de Balzac's novel "La Peau de Chagrin", losing its previous constant periodicity. It should also be noted that FAs usually almost did not respond to the use of antibiotics and were poorly exposed to antipyretic medicines that is understandable - because they had not purulent-inflammatory nature, but had toxic nature. Corticosteroid medicines were not additionally prescribed to children during FA attacks.  

Children with FA and other manifestations of Marshall's syndrome were treated with bacterial autovaccines in accordance with Local Protocols^©, approved by the Vitacell Clinic and the Markov Clinic and registered by the State Intellectual Property Service of Ukraine [22]. The production of thermally inactivated bacterial vaccines from autostrains of bacteria, isolated by cultural method, was performed in the bacteriological department of the Markov Clinic’s laboratory pursuant to an improved standard method according to the obtained Patent for a method of production and treatment with staphylococcal vaccine Staphylo-Primavac [23]. Bacterial autovaccines did not contain antibiotics and preservatives (phenol, formaldehyde, merthiolate, etc.). The shelf life of autovaccines at a temperature of +6+8°C is at least 6 months.

Schemes of treatment were always individual, but also had common features. One cycle consisted of 2-3 courses of immunization with bacterial vaccines. One course of immunization included 10 or 12 subcutaneous injections in increasing dosage over 19-21 days. An interval of 3 to 4 weeks was maintained between courses. The treatment cycle lasted generally from 70 to 110 days, depending on the number of courses. Intervals between treatment cycles, if necessary, were usually maintained during 3 months. The number of immunization cycles depended on the results obtained after previously performed treatment with autovaccines, namely on the presence/absence of clinical (first of all - relapses of FA), microscopic and bacteriological manifestations of Nephrodysbacteriosis/CBIS. Bacterial autovaccines were tried not to be administered directly during a fever attack, fearing a possible further increase in the child's temperature due to the simultaneous death of large numbers of bacteria and additional release of bacterial toxins with pyrogenic effect (by type of bacteremic (endotoxic) shock) into the blood.

The clinical effectiveness of the performed treatment occurred sufficiently high. So, already after the first vaccination cycle, which consisted of 2-3 courses, sudden fever has stopped in 461/622 (74.1%) children, including in more than half of cases (322/622 or 51.8%) - already after the first course. Else in 133/622 (21.4%) cases attacks of FA together with other clinical symptoms "retreated" after the second vaccination cycle with 2-3 additional courses. And only in 28/622 (4.5%) cases for a complete recovery it was necessary to provide a third cycle of vaccination with a total duration of treatment 12-15 months. There were no complications or side effects of an allergic or anaphylactic nature due to treatment with bacterial autovaccines which, as known, reduce the level of sensitization of the patient’s organism with causative agents of inflammation and usually lead to a significant decrease in the levels of IgE, which were increased before treatment. During follow-up observation, there were not detected neither return nor relapses of FA in most patients for 1-5 years, in some cases – for up to 10 years.

Thus, summarizing the above reported, it should be noted the following. Clinical manifestations of Marshall’s syndrome have bacterial-associated origin and are caused by the presence of two foci of chronic bacterial infection: in the kidneys and in the nasopharynx. Sudden high short-term recurrent fever or febrile attack and other general symptoms (weakness, rapid fatigue, drowsiness, increased sweating, pain syndrome, skin rash - bacterial toxicodermis, intoxication shadows under the eyes, etc.) are caused by the presence of a usually clinically locally asymptomatic focus of chronic bacterial infection in the kidneys (Nephrodysbacteriosis) and have toxic origin due to the development of Chronic Bacterial Intoxication Syndrome. The concomitant local symptoms of purulent-inflammatory nature (stomatitis, pharyngitis, enlarged cervical lymph nodes, chronic tonsillitis, etc.) are linked with chronic bacterial (mainly - staphylococcal and streptococcal-mixed) infection in the nasopharynx.

We did not find answers to the question why only in some cases (29.6%), FA as a major feature of Marshall’s syndrome has certain time dimensions and repeats with a certain interval usually every 28-30 days when parents expect the next attack of the disease as a punishment heavenly. But from our point of view, with the great probability, explanation has to be looked for not only in the peculiarities of dysregulation of the immune response of the child's organism or in the plane of hereditary auto-inflammatory diseases of a person with an unknown type of inheritance and an unknown mutant genome associated with excessive production of proinflammatory cytokines. More attention should be paid to the peculiarities of the life cycle of bacteria, which are indefinitely persisted in the kidneys, and to the pathological state itself that was called Nephrodysbacteriosis and underlies the emergence of FA and in general Marshall’s syndrome.

An indisputable feature of Marshall's syndrome is a sudden recurrent high fever. Because components of this syndrome such as stomatitis, pharyngitis and cervical lymphadenopathy are typical signs in children who are often sick [18, 19]. But without FA, it is no longer Marshall's syndrome. Therefore, from our point of view, all children with FA, regardless of the periodicity of fever attacks and concomitant clinical manifestations, can be considered as patients with Marshall's syndrome. Although in this case one of the main known signs of this syndrome is lost, that the syndrome allegedly occurs mainly in boys. According to our data, FA as the main component of Marshall's syndrome has no gender differences and occurs almost with equal frequency in children both male and female gender - 57.4% and 42.6% respectively, that is logical taking into consideration the determined etiological origin of this syndrome.

The question of an extended list of symptoms that may be included in the clinical picture of a disease such as Marshall's syndrome may be controversial. If to base on the regulated list of symptoms of PFAPA-syndrome, we have seen 142 children with this disease within the last 12 years. But if to take into account the determined etiological origin of the clinical manifestations of this pathological state, under our supervision there were 721 such children. From our point of view, it is just the sudden high short-term recurrent fever, to which Gary S.Marshall paid attention 35 years ago, having toxic origin as we have found, is the unifying commencement on which as if a necklace on a thread there are strung other symptoms - inflammation in the nasopharynx and general intoxication. Just therefore this disease should retain the name of Marshall's syndrome, because the term "PFAPA-syndrome" pursuant to the first letters of the previously determined symptom-complex (Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Aden) greatly limits the clinical view on this pathological state and its possible manifestations.   

Conclusions. 

1. Clinical manifestations of Marshall's syndrome (PFAPA-syndrome) have of associated bacterial-toxic origin, they are caused by two foci of chronic bacterial infection: in the kidneys and in the nasopharynx.

2. Sudden high short-term recurrent fever, called febrile attack^©, and other common symptoms (chills, weakness, rapid fatigue, drowsiness, increased sweating, pain syndrome, skin rash - bacterial toxicoderma, intoxication shadows under the eyes, etc.) are caused by the presence of usually clinically locally asymptomatic focus of chronic bacterial infection in the kidneys (Nephrodysbacteriosis^©) and have a toxic origin due to the development of Chronic Bacterial Intoxication Syndrome^© (CBIS). Local symptoms of purulent-inflammatory nature (stomatitis, pharyngitis, enlarged cervical lymph nodes, chronic tonsillitis, etc.) are linked with chronic bacterial mainly staphylococcal and less often - streptococcal infections in the nasopharynx.

3. Among 721 children with febrile attacks of toxic origin, which were under supervision, the full complex of manifestations of Marshall's syndrome was found in 142/721 (19.7%) cases. The clinical variety of symptoms in combination with sudden fever, as a leading feature of Marshall's syndrome, included also concomitant chronic tonsillitis (56-81% depending on age), which often during an FA attack also acquired features of exacerbation; 160/721 (or 22.4%; depending on age - 14.2-30.8%) children had adenoids. Almost a third of children (23-36%) complained of headache, 20-27% - abdominal pain, 32-41% experienced sore throat, 19-23% - in the joints, 7.5% of school-age children - in muscles. In general, pain syndrome of various locations was a fairly typical feature in children with FA and sometimes acquired dominant intolerable character with a recurrent attack-like course that resembled a pain attack^© of unknown origin.  

4. The clinical course of FA was often accompanied by such manifestations of chronic intoxication (CBIS) as weakness and increased fatigue (17-35%), drowsiness (18.6% - mostly in school-age children), irritability, mood swings and psychoemotional excitability, uncontrollability of behavior (11 -17%), increased sweating (34-42%), sometimes vomiting not related to food poisoning (8-18%). Quite typical in children with FA there were intoxication shadows and puffiness under the eyes (67-93%), which remained also in the inter-relapse periods during temporary normalization of temperature, itching of the skin and mucous membranes (12-19%), various skin rashes (bacterial toxicoderma), which were observed in 34.3% of children (from 28 to 39% depending on age).

5. Changes in the general blood analysis in children with FA, related to Nephrodysbacteriosis/CBIS, had not specific, but rather typical character. In more than a third of cases (275/721 or 38.1%), it was detected minor leukocytosis, which only in single cases was accompanied by neutrophilic shift of the leukocyte formula to the left. Not much less often on the contrary, leukopenia with a decrease in the level of leukocytes below 4.0×10⁹/l was detected in 154/721 or 21.4% of children. The dominant feature in the general blood analysis (in 638/721 or 88.5% of cases) was relative and absolute lymphocytosis, sometimes even with the appearance of a small number of atypical mononuclear cells (usually up to 5%). With a significant increase in the level of lymphocytes there was a corresponding secondary decrease in the level of granulocytes, first of all – neutrophilal blood elements. A quite typical there was also more often a stable decrease in the level of hemoglobin and erythrocytes (in 35-40% of cases), and in 10-15% of cases – of platelets, which could last for years, despite intensive more than once modern treatment. 

6. During bacteriological examination of warm urine of 721 sick children with FA and with complete or partial clinical picture of Marshall's syndrome, urine cultures of different strains of bacteria were revealed in all patients: in total 1123 strains, that was considered as diagnostic confirmation of the presence of a focus of chronic bacterial infection in the kidneys in all patients with febrile attacks. Herewith, in almost 3/4 of cases (in 531/721 or 73.6% of patients) it was diagnosed locally asymptomatic Nephrodysbacteriosis without clinical, generally laboratory (including almost normal general urine analysis) and instrumental signs of inflammatory process in the kidneys. It is just the presence of a focus of chronic bacterial infection in the kidneys led to the development of CBIS with dominant temperature disorders of a toxic nature with the emergence of FA attacks as the main clinical feature of Marshall’s syndrome.

7. The main factor in the occurrence of temperature disorders on the background of CBIS in the form of FA were enterococci (most often - Enterococcus faecalis), the level of isolation of which from the urine compared to other bacteria significantly prevailed and totaled 40.3% or 453 of 1123 in general isolated strains which were isolated in more than half of the cases (453/721 or 62.8%) of the total number of sick children. Escherichia coli took the second place after enterococci - 22.1% or 248 strains (isolated in 34.4% of patients), the third place - pathogenic staphylococci (first of all - Staphylococcus aureus): in total 18.4% or 206/1123 strains isolated from 28.6% of patients. During bacteriological examination of smears from the nose, pharynx, mouth and plaques of stomatitis, mucus from the nose and sputum in the vast majority of children (670/721 or 92.9%) there were revealed pathogenic staphylococci (St.aureus and St.haemolyticus). Much less often separately/simultaneously with staphylococci there were also isolated streptococci: mainly Streptococcus pyogenes - in 168/721 (23.3%) children, less often - Streptococcus pneumonia (in 71/721 or 9.8%).  

8. On the basis of toxicological examination of blood, in the vast majority of examined children (in 77/96 or 80.2%) it was found severe toxemia, in 16/96 (16.7%) - moderate and only in 3/96 (3.1 %) - mild. The form of intoxication was mostly compensated - in 87/96 (90.6%) patients, else in 9/96 (9.4%) - in the generalization stage; decompensated forms of intoxication in children were not detected. Among toxic proteomes, molecules dominated with a particles size >200 nm, which were found in 72/96 (75.0%) children, and with a particles size 10-200 nm - in 22/96 (22.9%); else in 2/96 cases (2.1%) the size of the proteomes was ˂10 nm. The strong connection of toxic proteomes with the carrier fraction was determined in less than half of the cases (47/96 or 48.9%); in other cases, the connection was fragile (14/96 or 14.6%) or absent at all (35/96 or 36.5%) that could explain the rapid dynamic change of the clinical state of a child from pronounced intoxication syndrome with febrile fever up to almost normal well-being.

9. All 721 children with FA and a full complex of classic manifestations of Marshall's syndrome were treated with bacterial autovaccines, the use of which had no complications or side effects of allergic or anaphylactic nature. The effectiveness of treatment was quite high: the next febrile attacks of sudden fever (febrile attacks) in all children, which were under supervision, discontinued mainly within 1-3 months (74.1%) and 5-8 months (21.4%). During the follow-up observation for most patients for 1-5 years, in some cases up to 10 years, there was neither return nor relapses of FA.

Conflict of interest. The authors state that there is no conflict of interest and own financial interest during the preparation of this article.

LITERATURE

1. Marshall G.S., Edwards K.M., Butler J., Lauton A.R. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J. Pediatr. 1987, 110 (1): p. 43−46.

2. Marshall G.S., Edwards K.M., Lauton A.R. PFAPA syndrome {letter}. Pediatr. Infect. Dis. J. 1989; 8: 658−659.

3. Edwards, K. M., Hofer, M. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome. Textbook of Autoinlammation. 2019; 541-561.

4. Padeh, Shai; (eight others).Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: Clinical characteristics and outcome // Journal of Pediatrics. - 1999. - Vol. 135, no. 1. - P. 98—101. - doi:10.1016/S0022-3476(99)70335-5.

5. Padeh, S; Stoffman, N; Berkun, Y. Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults.// The Israel Medical Association journal: IMAJ: journal. - 2008. - May (vol. 10, no. 5). - P. 358-360. - PMID 18605359.

6. Burton M.J., Pollard A.J., Ramsden J.D., Chong L.Y., Venekamp R.P. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)//Cochrane Database Syst Rev: journal. - 2014. - No. 9. - P. CD008669. - doi:10.1002/14651858.CD008669.pub2. - PMID 25209127.

7. Vanoni, F., Theodoropoulou, K., Hofer, M. PFAPA syndrome: a review on treatment and outcome. Pediatric Rheumatology. 2016; 14 (1); 38.

8. Hapchenkova D.S., Dubina S.A. (2020). PFAPA-syndrome: literature review and own clinical observation. Modern pediatrics. Ukraine. 6 (110): 57-61. doi 10.15574/SP.2020.110.57.

9. Kuznetsova S.A., Zryachkin N.I., Tsareva Yu.A., Elizarova T.V., Zakharova G.R. PFAPA- syndrome: a modern paradigm and a description of a clinical case. Almanac of Clinical Medicine. 2018; 46(2):184-193. https://doi.org/10.18786/2072-0505-2018-46-2-184-193.

10. Babachenko I.V., Tyan N.S., Ivanova M.A., Sharipova E.V., Belikova T.L. Marshall’s syndrome in the practice of an infectologist and a pediatrician (clinical case). Volume 12, No.4, 2020. Journal of Infectology. DOI: 10.22625/2072-6732-2020-12-4-114-119.

11. Barron K., Athreya B., Kastner D. Periodic fever syndromes and other inherited autoinflammattory diseases. Textbook of pediatric rheumatology / Ed. by J.T. Cassidy et al. — 6th ed. — Elsevier Saunders, 2011: 642–660.

12. Jaravello W., Pomagnoli M., Gaini R.M. Effectiveness of adenotonsillectomy of PFAPA syndrome randomized study // J. Pediatr. 2009; 155: 230–233.

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LITERATURE

1. Marshall G.S., Edwards K.M., Butler J., Lauton A.R. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J. Pediatr. 1987, 110 (1): p. 43−46.

2. Marshall G.S., Edwards K.M., Lauton A.R. PFAPA syndrome {letter]. Pediatr. Infect. Dis. J. 1989; 8: 658−659.

3. Edwards, K. M., Hofer, M. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome. Textbook of Autoinlammation. 2019; 541-561.

4. Padeh, Shai; (eight others).Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: Clinical characteristics and outcome // Journal of Pediatrics. - 1999. - Vol. 135, no. 1. - P. 98—101. - doi:10.1016/S0022-3476(99)70335-5.

5. Padeh, S; Stoffman, N; Berkun, Y. Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults.// The Israel Medical Association journal: IMAJ: journal. - 2008. - May (vol. 10, no. 5). - P. 358-360. - PMID 18605359.

6. Burton M.J., Pollard A.J., Ramsden J.D., Chong L.Y., Venekamp R.P. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) // Cochrane Database Syst Rev: journal. - 2014. - No. 9. - P. CD008669. - doi:10.1002/14651858.CD008669.pub2. - PMID 25209127.

7. Vanoni, F., Theodoropoulou, K., Hofer, M. PFAPA syndrome: a review on treatment and outcome. Pediatric Rheumatology. 2016; 14 (1); 38

8. Хапченкова Д.С, Дубина С.А. (2020). РFАРА–синдром: литературный обзор и собственное клиническое наблюдение. Современная педиатрия. Украина. 6(110): 57-61. doi 10.15574/SP.2020.110.57.

9. Кузнецова С.А., Зрячкин Н.И., Царева Ю.А., Елизарова Т.В., Захарова Г.Р. PFAPA-синдром: современная парадигма и описание клинического случая. Альманах клинической медицины. 2018;46(2):184-193. https://doi.org/10.18786/2072-0505-2018-46-2-184-193.

10. Бабаченко И.В., Тян Н.С., Иванова М.А., Е.В. Шарипова Е.В., Беликова Т.Л. Синдром Маршалла в практике инфекциониста и педиатра (клинический случай). Том 12, №4, 2020. Журнал инфектологии. DOI: 10.22625/2072-6732-2020-12-4-114-119.

11. Barron K., Athreya B., Kastner D. Periodic fever syndromes and other inherited autoinflammattory diseases. Textbook of pediatric rheumatology / Ed. by J.T. Cassidy et al. — 6th ed. — Elsevier Saunders, 2011: 642–660.

12. Jaravello W., Pomagnoli M., Gaini R.M. Effectiveness of adenotonsillectomy of PFAPA syndrome randomized study // J. Pediatr. 2009; 155: 230–233.

13. Марков И.С. Клинические дневники доктора Маркова. – Киев: Издательство «АртЭк», 2011. - 360 с.

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