Long Covid (eng)

POST-COVID SYNDROME ("LONG-COVID"): 

A POSSIBLE ALTERNATIVE VARIANT OF DIAGNOSIS. 

ETIOLOGICAL ORIGIN AND TREATMENT

Markov I.S.¹, Markov A.I.^1,2 

Vitacell clinic¹, Markov clinic¹,

National Medical University of the name Bogomolets O.O.² (Kyiv, Ukraine),

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

Abstract (Summary)

The aim of the study was to determine the etiological origin of post-Covid syndrome, taking into account the close clinical similarities between Long-COVID and ME/CFS, and to treat it effectively.

Materials and methods. The design of the study was clinical-diagnostic and included searching a way of etiological identification and treatment of patients with Long-COVID. The studies were prospective-retrospective and longitudinal with periodic follow-up of a certain part of patients for up to 1 year after diagnosis and appropriate treatment. Due to the effectiveness of the obtained results the studies had direct character, because it undoubtedly led to the recovery of the patient with the improvement of the general condition and quality of life. Conditions: the studies were two-center and conducted in an outpatient conditions on the basis of 2 specialized in the field of chronic infectious diseases clinics with a full range of laboratory studies. Participants in the study were adult patients who did not recover fully after the acute phase of coronavirus infection, caused by SARS-CoV-2, and who had evident Long-COVID symptoms, with which they visited clinics to be consulted.  

Results. During 18 months (from September 2020 to February 24, 2022) under our supervision were 29 adult patients aged 18 to 70 years, who after an acute stage of the disease caused by SARS-CoV-2, confirmed clinically-epidemiologically and laboratory, were affected with Long-COVID. The duration of Long-COVID in 15/29 (51.7%) cases ranged from 3 to 6 months, in 14/29 (48.3%) - from 6 to 12 months and more. 11/29 people (37.9%) were hospitalized in the acute period, including 3/29 (10.3%) in the intensive therapy unit. In 22/29 cases (75.6%) treatment was carried out with the prescription of 1-3 antibiotics in the acute period. It was detected that the pathological condition of all patients with Long COVID had clinical signs of classic ME/CFS and this condition was verified as a previously unknown Chronic Bacterial Intoxication Syndrome^© (CBIS) that developed on the background of a locally asymptomatic focus of chronic bacterial infection in kidneys, called as Nephrodysbacteriosis^©. It’s presented the clinical picture of CBIS, which included 53 symptoms. The diagnosis was confirmed by bacteriological examination of warm urine, from which there were isolated 47 strains of 3 types of bacteria: enterococci (Enterococcus faecalis - 14/47 strains or 29.8% and Enterococcus faecium - 5/47 strains or 10.6%), staphylococci (Staphylococcus haemolyticus - 11/47 strains or 23.4% and Staphylococcus aureus - 6/47 or 12.8%) and Escherichia coli - 11/47 (23.4%). The clinical and bacteriological diagnosis of CBIS also had therapeutic confirmation. For all patients with Long-COVID/CBIS it was prescribed treatment with bacterial autovaccines prepared from strains of bacteria isolated mainly from patients’ urine. The results of treatment could be considered as established in 23/29 (79.3%) patients. Complete clinical recovery occurred in 15/23 (65.2%) cases after the first cycle of treatment, which lasted from 70 to 110 days, and else in 5/23 (21.7%) cases - after the second cycle, in 3/23 (13.0%) cases the treatment is still ongoing.

Conclusions. It has been established that one of the possible variants of the development of post-Covid syndrome (Long-COVID), which is accompanied by the clinical picture of classical ME/CFS, is the previously unknown Chronic Bacterial Intoxication Syndrome^© (CBIS). This pathological condition occurs on the background of locally asymptomatic focus of chronic bacterial infection in the kidneys, which is called Nephrodysbacteriosis^©. The main etiological factors of CBIS were enterococci, pathogenic staphylococci and Escherichia coli. The use of bacterial autovaccines proved to be an effective method of treatment of patients with Long-COVID/CBIS: complete clinical recovery after the first cycle of treatment occurred in 15/23 (65.2%) cases and else in 5/23 (21.7%) after the second cycle. 

Known: there is such a pathological condition as post-Covid syndrome or Long-COVID with an uncertain etiological origin, there is no adequate and effective treatment of Long-COVID. 

New: for the first time in clinical practice, it’s determined and laboratory confirmed by the results of bacteriological studies that under the mask of Long-COVID, which runs with the clinical picture of classic ME/CFS, may be hidden a previously unknown Chronic Bacterial Intoxication Syndrome^© (CBIS). This pathological condition occurs on the background of locally asymptomatic focus of chronic bacterial infection in the kidneys, which is called Nephrodysbacteriosis^©. For the first time for the treatment of Long-COVID/CBIS there were used bacterial autovaccines with high clinical efficacy that indirectly confirms the bacterial-toxic origin of this pathological condition.  

Key words: Long-COVID, ME/CFS, Nephrodysbacteriosis^©, Chronic Bacterial Intoxication Syndrome^© (CBIS), bacterial autovaccines.

Published for the first time. 

Today's pandemic of coronavirus infection COVID-19, caused by the SARS-CoV-2 virus and lasting for 2 years, seems to be the most endless and perhaps the most ruthless. Among the approximately 300 million people who fell ill at the beginning of 2022, nearly 5.5 million died. The end is not in sight. However, the deads were not the last victims of this pandemic, which came as an insidious invader to take away, go away but leave behind destruction and unresolved problems. Because even those patients who have recovered externally, usually do not feel themselves healthy. They really stay sick. Therefore, even when the acute phase of the pandemic itself ends, humanity can still suffer for a long time and overcome its consequences, called postcovid syndrome or Long-COVID. People who have suffered an acute coronavirus infection, but after a formal recovery can not return to a normal healthy lifestyle, gather among themselves on social networks. Among them, the general opinion is that humanity, as it turned out, remains completely unprepared for the transnational global crisis, the name of which is Long-COVID, which continues to widespread rapidly.

After an acute illness of viral origin (influenza, SARS, previously known respiratory coronaviruses, viral hepatitis, etc.), so-called post-infectious or post-viral asthenia is a known and relatively widespread phenomenon and can usually persist for several weeks, rarely months. But after recovering from COVID-19, that was not an easy task for many patients, the rehabilitation period is often lasting much more than for the usual post-viral asthenia. Acute COVID-19 is accompanied by symptoms lasting up to four weeks. In post-Covid syndrome, when patients are no longer contagious, symptoms lasting more than 4 weeks have a wavy course and can change over time, disappearing and returning, affecting many body systems. This pathological condition cannot currently be explained by an alternative diagnosis. Because it is still missing.

This pathological condition for a long time becomes an independent almost insurmountable problem, without having any clear explanation for its occurrence. Post-COVID-19 syndrome, also known as Long-COVID or post-acute sequelae of COVID-19, or PASC, or chronic COVID syndrome, or long-haul COVID, has been included in the International Classification of Diseases (ICD-10), heading code U09.9 "Condition after COVID-19 unspecified", which also includes a post-covid condition. The term "Long-COVID" is usually understood as a condition in which the manifestations of the acute period of the disease not only do not disappear, but may be supplemented by new symptoms and last more than four weeks.

In the second half of 2021 alone, there were dozens of publications in the journal Lancet on the long-running-COVID and related issues. In the report devoted to Long-COVID and the conceptual basis for accelerating the clinical effectiveness of researches on this issue [1], the number of which continues to increase significantly, there is a reference to the frequency of occurrence of this unusual condition. At least 22% of people who have experienced the acute phase of coronavirus infection, even 5 weeks after its onset, still have symptoms of the disease. According to the authors, doctors have not still a clear explanation for the origin of the symptoms inherent for Long-COVID, and, accordingly, there is no adequate treatment. But in addition, people with long-term COVID simply try to be heard, to prove that they are, that they are ill and that after a formal recovery and discharge from the hospital they do not feel themselves healthy. Therefore, the recognition of the so-called long-term COVID by the scientific and medical community as a new, previously unknown disease will be a great emotional relief and hope for many struggling with COVID-19 [2]. Hundreds of millions of dollars have already been allocated to long-term research programs on COVID-19 with the still-unspecified name Long-COVID to collect and study the symptoms of the condition after disease COVID-19. The disease that, according to all available estimates, should not be chronic. The ultimate and main goal of such research is to create an adequate method of treatment of this new etiologically still undetermined pathological condition.

There are several non contradictory each other hypotheses about the causes of post-Covid syndrome. Among them there are several main ones. The most common explanation given by most researchers is that Long-COVID, firstly, is the result of direct damage to organs and tissues during both the prolonged course of the disease and direct intensive therapy measures used in the treatment of a severe disease. And, secondly, that Long-COVID develops due to exacerbations of chronic diseases such as diabetes, venous insufficiency, hypertension, asthma and others.

There has been established neurotropicity of the virus, which, entering the nervous system through olfactory receptors in the upper nasal cavity, can directly damage to brain structures, namely the limbic system, hypothalamus [3], brain, respiratory center and others. Damage to the multifunctional vagus nerve (nervus vagus) causes a large number of different symptoms, as well as determines their wavy course. This disorder is associated with the imbalance of two systems - parasympathetic and sympathetic [4], with a certain dominance of the latter. As a result, there are problems with heart rate, tachycardia, sleep problems, similar panic attacks and anxiety disorders [5].

The virus multiplies well in the vascular endothelium that can lead to coagulation problems. Microthrombi in the bloodstream disrupt organs which are abundantly vascularized: endocrine glands (thyroid, adrenal glands, pituitary gland, gonads) and kidneys. There are many cases when the virus directly caused inflammation of the heart muscle (myocarditis) and cerebral ischemia [6]. Blood clots and products of their lysis remain in the body and can provoke the development of additional foci of inflammation. The effect of the virus on blood vessels is not limited to inflammation of the vascular endothelium and vasculitis [7]. Virus or viral antigens have been detected in monocytes isolated from peripheral blood of patients [8] and more than once in macrophages [9, 10]. But still there are no evidences that the virus can multiply in these cells. Although the ability of the virus to multiply in some types (CD4 +) of lymphocytes has been reported [11]. There is a discussion about the possibility of persistence of the SARS-CoV-2 virus in the body of immunosuppressed patients and even in people with a normal immune system who have no symptoms of disease at all. Detection of the virus in the small intestine and nervous system has been reported [12].

There are also reports that the virus can provoke autoimmune reactions. A certain percentage of patients with coronavirus infection are women who have more reactive immunity and may suffer from both acute and possibly chronic autoimmune diseases. The wave nature of post-Covid manifestations in women is also associated with the menstrual cycle [13]. 

Perhaps antiphospholipid syndrome brings in an additional contribution to the pathogenesis of complications of the disease. This is due to the fact that the virus, multiplying in many tissues and organs, uses for its shell phospholipids of the host, which, in combination with capsid proteins of the surface of the virus, become a target for antibodies. Taking into account that similar structures may exist in the body itself, these autoantibodies will also attack healthy tissues [14]. It is possible that antibodies may help the virus to enter immune cells on the principle of antibody-dependent enhancement of infection (ADE), although this is only a hypothetical assumption reported by some researchers [15]. There is a thought that changes in circulating serotonin levels due to hemostasis disorders may cause painful migraines and deep depression [16]. Post-Covid syndrome has also been linked to the development of mast cell activation syndrome (MCAS), when mast cells secrete excessive amount of mediators that leads to chronic inflammation [17].

Summarizing the results of numerous observations, which analyze the long-term clinical manifestations of Long-COVID, as well as our personal clinical observations, it could be identified the following problems that either do not disappear after an acute period of the disease, or even occur after its completion and/or after finishing of treatment in hospital and usually have a wavy flow. Let's try to group some known symptoms of post-Covid syndrome by clinical and/or pathophysiological features.

Almost the main manifestation of Long-COVID is increased fatigue, weakness, which is sometimes even called "paralyzing" [18]. Patients constantly experience increased exhaustion, inconsistency of physical activity with the degree of exhaustion, which does not disappear even after prolonged rest. Typical is the reduction of tolerance to physical and habitual sports activities: gym classes, which were the physiological and social norm, become an unattainable dream. There are problems with sleep: insurmountable drowsiness in the morning, when there are no strengths to get out of bed before noon, and insomnia at night; a full night's sleep that does not bring a feeling of freshness and vitality in the morning. 

Shortness of breath, apnea, heaviness behind the chest are often mentioned, less often - cough. In some cases, just shortness of breath is considered to be one of the most common symptoms of long-term COVID [19], which persists mainly after severe pneumonia caused by the virus. Thus, follow-up of 83 patients who survived after severe coronavirus pneumonia [20] detected that even in 12 months after formal clinical recovery from COVID-19, pulmonary gas exchange dysfunction remained. DLCO levels (pulmonary diffusion capacity on carbon monoxide) remained low (<80% of normal) in 27 (33%) patients, herewith in 20 (24%) patients remained roentgenographic changes such as frosted glass turbidity. Although none of them was not diagnosed with fibrosis or progressive interstitial damage. 

The next typical manifestation of Long-COVID, which could be called a pain syndrome, is the sensation of pain of different location: headache, chest pain, myalgic muscle pain, sometimes even very strong by type of fibromyalgia syndrome, neurological and joint pain [21]. Reactive arthralgias and arthritis, especially when they occur concomitantly with an increase of certain “proteins of acute phase", such as antistreptolysin-O (ASLO), C-reactive protein (CRP) and/or rheumatoid factor (RF), which are markers of inflammation and damage, are largely reminiscent the pathological condition of rheumatoid origin, to which, however, they have no clinical or pathophysiological relationship.

A separate group of manifestations of post-Covid syndrome includes vegetative-vascular disorders associated with damage to a multifunctional nerve such as the vagus nerve. Disruption of the interaction of parasympathetic and sympathetic nervous systems [4] leads to dysregulation of vital functions of the body - blood circulation, respiration, digestion, excretion, metabolism, thermoregulation - to maintain homeostasis and ensure physical and mental activity. In such cases, patients suffer from headache, dizziness, sudden jumps in pressure and pulse, arrhythmias, tachycardia, including orthostatic tachycardia [22]. There may be numerous gastrointestinal disorders, diarrhea that are wavy and independent on diet or medication [23], temperature disorders in the form of prolonged low-grade fever or jumps in temperature, or, conversely, hypothermia with subnormal temperature.

Cognitive impairment is also typical: memory impairment and loss of memory, “brain fog”, complications and slowing of logical and associative thinking, difficulties with words choice during conversation, disorientation in space, anxiety, depression and panic attacks, mood swings and inconsistencies in reaction to external stimuli. Almost all neurological and psychiatric disorders were more common in patients after more severe forms of COVID-19 than in patients with mild COVID-19. However, these psycho-neurological symptoms are more due to the effects of general consequences, including the psychosocial aspects of the infection, than due to the direct effects of the virus on the brain [24]. Possible damage to the olfactory nerve is associated with loss of sense of smell, distortion of smell or taste, phantosmia - when a person begins to experience odors and tastes that do not exist. The more rare but well-known symptoms of Long-COVID include a variety of skin rashes: erythema (even ring-shaped erythema as in Lyme disease), small and large urticaria and other dermatitis, as well as increased hair loss up to alopecia and sometimes - appearance of externally unusual "covid tongue" and "covid nails". Often during the long-term course of Long-COVID it may occur anemia, the clinical manifestations of which patients may not even notice, and it may develop kidney damage.

Summarizing the information about the clinical manifestations of Long-COVID, we want to draw attention to the following report. Interesting evidences were obtained from an online-questionnaire of 3,762 people with clinically and laboratory confirmed diagnose COVID-19 and of 2,742 only with clinically established this diagnose from 56 countries with a disease duration of more than 28 days based on an analysis of 203 symptoms related to 10 systems of patients' body [25]. The authors concluded that for the majority of respondents (> 91%) the recovery time exceeded 35 weeks, herewith the most common symptoms after 6 months were fatigue, post-exercise malaise and cognitive impairment. In 85.9% of respondents there were observed recurrences, primarily due to physical exercises, physical or mental activity and stress. Moreover, 86.7% of unrecovered respondents felt tired even during the survey, 1,700 respondents (45.2%) needed a reduced work schedule compared to the period before the illness, and another 839 (22.3%) did not work at all at the time of the survey due to illness. Cognitive dysfunction or memory problems were common in all age groups (~ 88%). According to the authors, the survey of patients with long-term COVID indicates their long-term multisystem damage and significant disability.

Reading and studying the results of this large transnational study it can occur a double impression. On the one hand, you understand that in the study the authors say about Long-COVID, its symptoms and consequences, the origin of which remains unclear and unknown. On the other hand, it seems that this is a well-known pathological condition with typical clinical manifestations of another long-known diagnosis - myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the origin of which also remained unclear for a very long time. According to the International Definition from 1994, for ME/CFS it’s necessary at least 6 months of unexplained fatigue, which does not disappear and is not relieved after rest and significantly limits the level of daily activity. In addition to fatigue, four or more of the following 8 symptoms should be present:    

- substantial impairment in short-term memory or concentration;

- sore throat;

- tender lymph nodes;

- muscle pain;

- multi-joint pain without swelling or redness;

- reccurent headaches of a new type, pattern or severity;

- unrefreshing sleep;

- post-exertional malaise lasting more than 24 hours.

It is no coincidence that of these 8 known symptoms of ME/CFS, the authors were able to identify at least 6 in most patients with Long-COVID, to which patients themselves drew attention. Other researchers also point to the close relationship between Long-COVID and ME/CFS. Thus, a well-known authoritative scientist and doctor in the field of infectious diseases and chronic fatigue syndrome, professor of medicine at Harvard Medical School Anthony L.Komaroff, in August 2020 in the Guardian said that “the symptoms of post-Covid long haulers can be indistinguishable from those typical of ME/CFS”. Moreover, in many people with ME/CFS, the disease does begin after an infection-like illness or a well-documented infection. It has been suggested that the pathogenesis of post-Covid syndrome in some patients may be similar to ME/CFS syndrome [26].

In the presence of clinical manifestations of post-Covid syndrome, which still remains etiologically undefined, there is performed symptomatic treatment. There are no official protocols for the treatment of post-Covid syndrome.

One year ago, in February 2021, we published the results of our 12-year study (2009-2020) of 4,500 patients with established diagnosis or clinically similar condition to chronic fatigue syndrome [27]. On the basis of bacteriological [28] and toxicological [29] studies it was proved that under the mask of etiologically undetermined ME/CFS actually hides a previously unknown Chronic Bacterial Intoxication Syndrome^© (CBIS), which developed on the background of usually clinically locally asymptomatic focus of chronic bacterial infection in the kidneys, called Nephrodisbacteriosis^©. It is just toxins of bacteria, mainly intestinal group and staphylococci, that persist chronically in the kidneys, cause the dominant majority of clinical symptoms that are associated with the development and progression of ME/CFS and which are in fact a manifestation of CBIS. In the year that has passed since then, our confidence in the true existence of such a diagnosis has only increased. During this short period of time, hundreds of new patients came to our clinic, who were for a long period of their lives more than once treated with symptoms of ME/CFS, but in vain: their condition did not improve at all or only for a short period of time. This disease, which we have observed in our patients, does not lead to death, but takes away a previously healthy happy life, turning it into endless torture. Many patients feel themselves as if they are in a death row, waiting for the sentence to be carried out. After appropriate etiopathogenetic treatment, used for the first time for patients with CBIS with clinical signs of ME/CFS, there usually was complete clinical recovery and they returned to their normal previous life.

There is still no balanced and proven by results of clinically effective treatment alternative diagnosis instead of temporary and indeterminate Long-COVID. In order to determine the etiological origin of the post-Covid syndrome and try to treat it effectively, taking into consideration the close clinical similarities between Long-COVID and ME/CFS, we decided to examine and treat patients with post-Covid syndrome according to the same scheme under which during many years we examine patients with clinical picture of ME/CFS, and in fact - with CBIS. And what we have seen in the result…

Materials and methods.

During 18 months (from September 2020 to February 24, 2022) under our supervision were 34 adult patients aged 18 to 70 years, who visited the clinic with complaints of incomplete recovery after COVID-19, diagnosis of which was confirmed clinically and laboratory. In 5/34 (14.7%) cases, the patients' illness was possibly associated with an exacerbation of chronic diseases such as diabetes (in 3 patients), hypertension and bronchial asthma (one each). It was difficult to say what did cause largely their poor health, so they were not included in the observation group. In all 29/34 (85.3%) patients included in the observation group, the diagnosis was clinically and epidemiologically confirmed. SARS-CoV-2 coronavirus was detected in nasopharyngeal smears by PCR in 22/29 (75.9%) cases during the acute period. Positive seroconversion of IgM and / or IgG antibodies to S protein (or S1 and N protein) was observed in all 29 patients, depending on the used diagnostic test system. There were 13/29 men (44.8%) and 16/29 women (55.2%). There were 9/29 (31.0%) patients aged 18 to 30 years, 12/29 (41.4%) between 31 and 50 years of age, and 8/29 (27.6%) between 51 and 70 years of age. From the anamnesis it was established that 11/29 people (37.9%) were hospitalized in the acute period of the disease, including 3/29 (10.3%) in the intensive therapy unit. The other 18/29 (62.1%) patients, in whom COVID-19 was mild or moderate, were treated at home. In 22/29 cases (75.6%) treatment was carried out with the prescription of 1-3 antibiotics in the acute period, in 5/29 (17.2%) - with a predominantly short course of corticosteroids. The duration of post-Covid syndrome at the time of visiting the clinic in 15/29 (51.7%) cases ranged from 3 to 6 months, in 14/29 (48.3%) - from 6 to 12 months or more, during which patients more than once asked for medical assistance and underwent little or no effective symptomatic treatment. Despite the different duration of post-Covid disease and almost constant treatment, the etiological origin of these pathological conditions, which run under undefined diagnosis Long-COVID with clinical signs of ME/CFS, remained unclear until visiting the clinic.

All patients were examined by bacteriological cultural method using appropriate nutrient media. Bacteriological confirmation of the diagnosis of Nephrodysbacteriosis and CBIS was performed by culturing morning warm urine three times (three days in a row), which was usually performed at home using the appropriate test devices Diaslide^® DS-101 and DS-105 (Novamed, Israel) with nutrient media CLED agar, McConkey agar and UriSelect chromogenic agar. In the case of growing microorganisms, they were re-cultured on Petri dishes with nutrient media such as meat peptone agar (MPA) with the addition of 5% blood, Endo medium, Saburo agar, Mueller-Hinton agar (to identify bacteria of the genus Pseudomonas) and some others with the following standard procedure for identifying of isolated cultures. Urine for bacteriological examination was obtained naturally without the use of invasive method of catheterization of the bladder. In all cases, there were also performed bacteriological examination of nasal and throat swabs, and in cases of clinical necessity, bacteriological examination of swabs from skin, conjunctiva, gums, urethra, cervical canal, vagina, prostate secretion, ejaculate, wound and fistula secretions.

There were also performed general clinical examinations, which included general analyzes of blood, urine, feces, etc., determined coagulogram and D-dimer level, in cases of clinical necessity -  biochemical examination (Beckman Coulter AU480 biochemical analyzer, USA) of liver and kidney samples, protein fractions and rheumatic tests, glucose and glycated hemoglobin, metabolism of lipids, vitamins, trace elements, etc. For differential diagnostics, almost all patients underwent ELISA and PCR studies (real-time) for herpes viruses (HSV 1/2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8), due to clinical and epidemiological indicators – for Borrelia, HIV and other viral and bacterial infections. Almost all patients underwent examination for immunological status with determination of: cellular link by flow cytometry with immunophenotyping of peripheral blood cells (CytoFLEX flow cytofluorimeter, Beckman Coulter, USA); IgA, IgM, IgG immunoglobulins; complement systems C3 and C4; phagocytosis and circulating immune complexes. Pursuant to clinical indicators there were additionally determined markers of autoimmune diseases, autoimmune hepatitis, allergies (general and specific IgE), tumor markers, hormones (primarily thyroid); microscopic examination of urogenital smears, prostate juice, sputum, nasal secretions. Pursuant to clinical indicators, patients underwent instrumental examination: ultrasound, X-ray, MRI and/or CT, ECG, EEG, etc.

Patients with Long-COVID, in whom there were found Nephrodysbacteriosis and CBIS, were treated with bacterial autovaccines according to Local Protocols^©, approved by Vitacell Clinic and Markov Clinic and registered by the State Intellectual Property Service of Ukraine [30]. The preparation of thermally inactivated bacterial vaccines from autostrains of bacteria, isolated by cultural method, was performed in the bacteriological department of the Markov Clinic laboratory according to the improved standard method described in the Patent "Inactivated Staphylococcal Liquid Vaccine, Method of its Preparation and Method of Treatment and Prophylaxis" [31]. To control sterility, vaccine samples were cultured on nutrient bouillon and incubated in a thermostat at 37°C for 24-48 hours. Bacterial autovaccines did not contain antibiotics and preservatives. The shelf life of autovaccines at a temperature of +6+8°C was 6 months.  

Results and discussion.

Clinical manifestations and complaints in 29 patients with Long-COVID were quite diverse. It should be noted that we observed only 53 symptoms and clinical manifestations during post-Covid syndrome that is significantly lower than the previously observed 203 symptoms, which were distributed and associated with 10 systems of patients’ organism [25] with clinically and laboratory confirmed diagnosis COVID-19 with a disease duration of more than 28 days. This might be due to the significantly higher number of patients surveyed by the authors in an online survey of 6,504 people from 56 countries.

Taking into account our previous experience of studying the clinical symptoms of CBIS, which developed on the background of Nephrodysbacteriosis [27] and hides under the mask of ME/CFS, all manifestations of post-Covid syndrome or Long-COVID, that we observed, were grouped and conditionally distributed according to the probable toxic damage to certain organs and systems, namely: generally toxic, as well as mainly neurotropic, vegetative-vasotropic, psychotropic, dermatotropic and arthromyotropic. The following table 1 shows the clinical manifestations of Long-COVID, which we observed in 29 sick adults.  

Table 1. 

Clinical manifestations of Chronic Bacterial Intoxication Syndrome (CBIS) in 29 patients with Long-COVID

Comparing the clinical symptoms observed in the supervised patients with the main 8 symptoms of CFS (which, according to the Definition 1994, must be at least 4 to diagnose CFS), it should be noted the following. Among 29 adult patients with Long-COVID with a clinical picture of CFS-CBIS (ME/CFS-CBIS) at least 4 main symptoms in different combinations were found in all 100% of cases, 5 - in 27/29 (93.1%), 6 - in 23/29 (79.3%), 7 - in 19 (65.5%) and all 8 - in 10 (34.5%). This could most likely indicate that under normal conditions prior to the onset of the pandemic caused by SARS-CoV-2 virus, all of these patients should be diagnosed with a previously known diagnosis of CFS of unknown etiology. It should be noted that in 12/29 (41.4%) cases, the symptoms of CFS-CBIS appeared for the first time after acute coronavirus infection as an independent disease. In the vast majority of patients (17/29 or 58.6%) their clinical condition was not normal and corresponded to the diagnosis of CFS during the previous period lasting from 2-3 to 15 years, and Long-COVID developed and progressed as a continuation of already existing disease.  

Clinical manifestations of toxins of general toxic action during the development of Long-COVID were accompanied by the appearance and/or progression of the most typical symptoms of the disease, which were previously associated with CFS. Gradually, after the completion of the acute phase of coronavirus infection, 28/29 (96.6%) patients began to experience a persistent feeling of unexplained increasing fatigue, which did not correspond to the intensity of previous physical or mental load and did not disappear after rest. Normal physical work, which a person performed at work or at home on the eve of SARS-CoV-2 infection without even noticing, figuratively speaking, singing, became difficult and unbearable for 25/29 (86.2%) patients. This was especially noticeable for patients of professionally active age, who before the onset of CBIS were characterized by high efficiency, by professional and life perseverance, creative productivity and were successful in education, their professional activities and in life in general.

After the onset of the disease, patients of creative work lost all interest in their favorite or most urgent activities, which they could do before, figuratively speaking, 24 hours a day. Tolerance to physical, sports and mental loads significantly decreased in more than half of the patients (15/29 or 51.7%). Almost two thirds of patients (19/29 or 65.5%) experienced a decrease in life inspiration from a slight level to almost complete exhaustion: inability to raise eyelids and open eyes, get out of bed, raise a spoon to mouth, comb hair, dress on one’s own, etc. More than a third of patients (11/29 or 37.9%) during this period noted uncharacteristic amimia, when the face was constantly immobile and did not reflect any emotions or feelings.

8/29 (27,6%) patients complained with overpowering daytime sleepiness, sleep disturbances, difficulty in falling asleep, not a good night's sleep, waking up early with the inability to fall asleep again, sometimes on the contrary - a long full night's sleep, which did not bring a sense of rest, recovery and freshness. In 4/29 (13.8%) cases, the sick thought that their condition could now be called as "living in bed" - the weakness was such that they could not even get out of bed. This is how the patients themselves determined their condition during the illness, direct speech: "I have no strength and desire to get up", "I lie in bed all day", "from morning till noon - and the strength is running out", "the body seems not mine – muscles do not obey", "hand does not hold a spoon - I am fed", "I do not have the desire and strength even to talk", "powerless and helpless - I do not want to live like this."

Gradually, a wasting constant headache could join to the dominant fatigue and decrease in vital energy. Almost half of the patients (14/29 or 48.3%) experienced this constant pain, which returned again and again, which sometimes did not calm down even after painkillers, almost did not disappear during the day or night. In two cases, women described the headache as "hellish" and "painful." This headache has forced some patients to seek the cause of this uncertain condition, visiting more than once neurologists and other doctors, to repeat MRI and CT-scans of the brain, fearing reports from the Internet about the possible similar course of brain tumors. Sometimes the headache was paroxysmal in nature, could appear after some external provoking factors (e.g. hot shower, stay in the cold or in the stuffy room, plant or animal odors, etc.) and reminded in 5/29 (17.2 %) women exacerbation of a typical migraine, which they usually experienced before and agreed to continue to tolerate for life. That is why it was surprising for both patients and their doctors, when such constant attacks of pain, which had not responded to any attempts of modern treatment and control, completely disappeared after treatment of a focus of chronic bacterial infection in the kidneys that confirmed the toxic nature of its primary origin.

One of the typical manifestations of CBIS, which often dominated the clinical picture of the disease, was a violation of temperature homeostasis of the organism, as we have previously reported [32, 33]. 12 (41.4%) patients with Long-COVID had prolonged daily subfebrile, usually with periods of temporary normalization of temperature (more often in the morning and before night sleep). In 5 (17.2%) patients, it developed febrile attacks^©, when, as some say, "on an equal footing" without any clinical warnings and reports, the temperature critically quickly reached usually 39-40°C. The fever in these cases lasted from 1-2 to 5-7 days, and was clinically almost monosymptomatic without clinical signs of a focus of bacterial inflammation. In 3/29 (10.3%) cases after the end of the acute period, patients had subnormal temperature, more often in the morning, which did not bother them at all.

In more than half of patients (16/29 or 55.2%) under the eyes appeared or intensified intoxication shadows - dark circles with different radii from small to almost, as patients said, half of the face, different color intensity, often - with additional swelling and edema under the eyes. In this state of severe intoxication, 7/29 (24.1%) patients began rapidly to lose body weight, and body weight could decrease in a short time for 3-6 months from 4-5 kg ​​to 15-20 kg. It is clear that when such rapid loss of body weight combined with subfebrile temperature or, moreover, with febrile fever and general exhaustion, it did not inspire patients and they had various phobias, especially locally undetermined cancer and fear of death. The absence of any more or less clear diagnosis that would explain to a person the origin and causes of terrible physical and mental condition, and the ineffectiveness of the prescribed treatment only strengthened these fears.

Clinical manifestations of neurotropic toxins included paresthesias of the extremities (fingers and toes, palms, feet) and torso, which were noted by 8/29 (27.6%) patients; loss of balance and coordination of movements (6/29 or 20.7%); complications of driving, experienced by 3 of 19 patients (15.8%) who drived a car; muscle weakness (7/29 or 24.1%); local convulsions and/or muscle twitching (4/29 or 13.8%). Vegetative-vasotropic manifestations of action of bacterial toxins included vegetative-vascular dystonia (14/29 or 48.3%), dizziness (10/29 or 34.5%), tachycardia (6/29 or 20.7%), increased heart rate (4/29 or 13.8%), blood pressure drops (5/29 or 17.2%), increased sweating (14/29 or 48.3%), which was sometimes so profuse that, according to the man 45 years old, "my pajamas was full of sweat."

Among clinical manifestations of action of psychotropic toxins, it dominated asthenic syndrome, which was verified in almost all patients (28/29 or 96.6%); and cognitive impairment due to memory impairment and logical thinking (13/29 or 44.8%); decreased mental ability (7/29 or 24.1%), decreased concentration, attention (8/29 or 27.6%), difficulty in choosing words and in even simple calculations (5/29 or 17.2%), difficulty decision making (3/29 or 10.3%). Almost a third of patients noticed a decrease, in some cases significant, in life motivations and interest to the surroundings (9/29 or 31.0%), social and domestic apathy (11/29 or 37.9%), manifestations of anhedonia (3/29 or 10.3%). Diagnostic uncertainty of the situation after the acute phase of the disease, which did not end with full recovery, and the absence of any effective treatment of this completely incomprehensible, not only for the patient but also for doctors, clinical condition which even worsened, led to the further development of phobias in 12/29 (41.4%) patients, in 7/29 (24.1%) - panic attacks and/or depression. At the same time, if in 3/29 (10.3%) cases the patients felt an insurmountable fear of death, so in 2/29 (6.9%) - on the contrary, there were suicidal thoughts. One young 24-year-old woman in this serious condition had depersonalization/derealization syndrome for almost a month. In 4/29 (13.8%) cases, after consulting a psychiatrist, patients began taking antidepressants, which, however, did little to improve their malaise, and in one case - even used drugs.

In almost a third of cases, dermatotropic toxic lesions were accompanied by itching of the skin and mucous membranes (10/29 or 34.5%); increased hair loss (12/29 or 41.4%), which in one case was even accompanied by temporary focal alopecia; and fragility and nail lesions (3/29 or 10.3%). In almost a third of cases, in 9/29 (31.0%) patients with Long-Covid under supervision, there were skin lesions by type of bacterial toxicoderma, which are a typical feature of CBIS on the background of Nephrodysbacteriosis [27]. Bacterial toxicoderma run with clinical signs just of toxicoderma (papular or vesicular) as well as of urticaria and erythema. In one case, a 33-year-old woman had indurative erythema with bullous elements, which lasted for almost 3 weeks. In cases of predominance of arthromyotropic toxins, patients experienced joint pain (13/29 or 44.8%) and spine pain (4/29 or 13.8%), less often there were reactive arthritis (2/29 or 6.9%). In 5/29 (17.2%) cases, patients complained of muscle pain, in one case - muscle stiffness, even with limited mobility.  

Additionally, there were observed such locally-inflammatory and toxic lesions of the mucous membranes of the nasopharynx and eyes as: pharyngitis - in 11/29 (37.9%) cases, glossitis - in 3/29 (10.3%), stomatitis - in 2 (6.9%); conjunctivitis: purulent - in 2 (6.9%) and toxic with burning and a feeling of "sand" in the eyes - in 5 (17.2%). An increase in cervical and submandibular lymph nodes remained for a long time in 7/29 (24.1%) patients.  

During laboratory tests there were not found any significant, fundamental and constant changes in the results of the obtained analyzes. In 13/29 (44.8%) cases there was detected an increase in level of lymphocytes (from 39% to 52%) in the blood formula, in 8/29 (27.6%) - a temporary and moderate decrease in hemoglobin and/or erythrocytes, in 7/29 (24.1%) - increase in the level of C-reactive protein (CRP) and in 3/29 (10.3%) – in the level of antistreptolysin O (ASLO). When examining the immunogram, changes in cellular and humoral links of immunity in 22/29 (75.9%) cases were completely absent, and in 7/29 (24.1%) they were unprincipled, insignificant and temporary. D-dimer levels and coagulogram values ​​remained within the age norm. It has not been found any case of serological features of autoimmune-systemic diseases and clinically significant activation of chronic EBV, CMV infections and other herpes viruses. In cases of additional radiological and/or CT-examination of the lungs, there were not detected pathological changes inherent for acute SARS-CoV-2 infection.   

Bacteriological examination of warm urine of 29 patients with Long-COVID revealed urine cultures of different strains of bacteria in all patients. In 14/29 (48.3%) cases, there were isolated per 1 culture of bacteria. i.e.14 strains. Strains of the same species of the same bacterium which were isolated during bacteriological examination from warm urine within two or three consecutive days in one patient (i.e. twice or three times), however, were counted as one strain. Else in 12/29 (41.4%) patients there were isolated simultaneously per 2 cultures of different bacteria, i.e. else 24 strains. Per 3 cultures from one portion of urine there were isolated much less often - only in 3/29 (10.3%) cases (else 9 strains). Thus, totally there were isolated 47 strains of different bacteria that was considered as diagnostic confirmation for the presence in all supervised patients of a focus of chronic bacterial infection in the kidneys. The absence of external contamination of urine was evidenced by the fact that in different portions of the morning warm urine, collected on different days, there was found just the same strain of bacteria whose sensitivity to antibiotics and bacteriophages, for which they were tested (in total - at least 34-35 names), in each case coincided by 100 percent.  

In the vast majority of cases (24/29 or 82.8%), there was diagnosed locally asymptomatic Nephrodysbacteriosis without clinical, general laboratory (including almost normal general urine analysis) and instrumental signs of inflammatory process in the kidneys. Else in 5/29 (17.2%) cases, there was determined slow latent formation of clinically asymptomatic chronic pyelonephritis with newly detected proteinuria, leukocyturia and cylindruria, about which patients themselves did not even guess, including in 2 cases with a clinically manifest debut during acute episode of SARS-CoV-2.  

Among the isolated urine cultures of bacteria, enterococci significantly dominated, the level of isolation of which from the urine, compared to other bacteria, significantly prevailed and totaled 40.4% or 19 from 47 generally isolated strains. The undisputed leader among the isolated urine cultures of enterococci was Enterococcus faecalis: 14/19 strains (73.7%) or almost a third (14/47 - 29.8%) of all isolated strains of bacteria; Enterococcus faecium was isolated much less often - only 5 strains (26.3% and 10.6%, respectively). The next large group of bacteria, isolated from urine, was staphylococci: totally 17/47 (36.2%) strains. Staphylococcus haemolyticus prevailed - 11/17 (64.7%) and almost a quarter of all isolated strains - 11/47 (23.4%); less often there was isolated Staphylococcus aureus: 6/17 (35.3%) and 6/47 (12.8%), respectively. 11/47 (23.4%) cultures Escherichia coli were also isolated. In many cases, these bacteria in different combinations were isolated simultaneously.

Thus, these three bacteria - enterococci, pathogenic staphylococci and Escherichia coli - were the main dominant etiological factors which caused Long-COVID, diagnosed in 29 patients who came to our clinic. These patients had a clinical picture of classic ME/CFS, and actually suffered from CBIS due to the presence of mostly locally asymptomatic focus of chronic bacterial infection in the kidneys. Although with the expansion of the search and the number of patients with post-Covid syndrome whose clinical picture formally is within the diagnosis of ME/CFS, the list of isolated urinary cultures of bacteria will certainly expand, provided that these patients will be appropriately bacteriologically examined.

Bacteriological examination of separate smears from the nose and pharynx in 28/29 (96.6%) patients revealed 39 strains of pathogenic staphylococci. At this location, Staphylococcus aureus predominated with 25/39 (64.1%) strains and else there were isolated 14/39 (35.9%) strains of Staphylococcus haemolyticus. At the same time, 15/29 (51.7%) strains of Streptococcus pyogenes were isolated mainly as a mixed-infection and more often from the pharynx. Due to these two pathogens, patients had such local inflammatory processes as pharyngitis, stomatitis, glossitis, purulent conjunctivitis and enlargement of the cervical and submandibular lymph nodes. In one case, a 33-year-old man in 1 month after the completion of the acute phase of SARS-CoV-2 had the debut of furunculosis due to Staphylococcus aureus. Another 45-year-old man had in 5 months a septic condition with left-sided gonarthrosis with contracture and phlegmon of the left leg, with isolation from the pus of St. aureus and Escherichia coli.

Treatment.

All patients with Long-COVID, due to incomplete recovery and unsatisfactory general condition before visiting our clinic, have more than once visited other medical institutions, where they underwent many different powerful examinations and usually received multiple courses of various treatment. They were prescribed antibiotics, antivirals, antiprotozoals, anthelmintics. They also were treated from deficiency of vitamin and microelements, lactase deficiency, allergies, depression and other mental disorders; performed immunomodulation and immunocorrection, despite the fact that immunity indicators were almost normal; administered interferons, immunoglobulins, donor plasma. At the same time, in 19/29 (65.5%) cases it was possible to state the presence of polypragmasia syndrome with the prescription of 5-10 preparations simultaneously, and in some cases even more. But all was in vain - the condition of the patients did not improve. Gradually, they lost faith in the doctors and in the treatment they were prescribed. The combination of psychiatric disorders of intoxication nature on the background of CBIS with a diagnostically uncertain situation and post-treatment despair, caused by the absence of any noticeable positive response to treatment, performed more than once, became an explosive mixture. Such frustration on the brink of a kind of medical nihilism was sometimes very difficult to overcome, explaining to the patient the real cause of such a painful condition and/or prescribing treatment with bacterial autovaccines.

As noted in previous reports [27, 33], it has been found a clear link between Nephrodysbacteriosis/CBIS and prior antibiotic use. So, among 29 patients under supervision, 22/29 (75.6%) patients received antibiotics during the acute period, although radiologically and/or on CT pneumonia was confirmed only in 17/29 (58.6%) cases. Herewith, the vast majority of patients (21/29 or 72.4%) in the near and/or in the distant anamnesis had repeated episodes of treatment with antibiotics for various reasons.

23/29 (79.3%) patients underwent in the clinic treatment with bacterial autovaccines, the consequences of which could be considered as established. In another 6/29 (20.7%) cases, under various circumstances, such treatment either did not take place or did not have time to begin, or due to beginning the Russia’s war in Ukraine the results remained unknown. Treatment schemes were 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 dosages during 19-21 days. An interval of 3 to 4 weeks was maintained between courses. One cycle of treatment lasted in general from 70 to 110 days, depending on the number of courses. Intervals between treatment cycles were usually maintained during 3 months. Taking into account autostrains of bacteria, isolated from the urine, as well as from the nose, throat, sputum, nasal mucus and from other local foci, there was in general the following sequence of prescription of autovaccines: first monovalent vaccine from one dominant specie of bacteria, then - divalent and then - polyvalent with the addition of autostrains of bacteria, accumulated during preliminary and monitoring examinations and previously preserved. The number of immunization cycles depended on the results of previous treatment, namely on the presence/absence of clinical, microscopic and bacteriological manifestations of CBIS, due to which the treatment was prescribed.   

The results of treatment were evaluated according to three main criteria: clinical, microscopic and bacteriological. That is, clinical complaints and symptoms, results of general urine and blood analyses (sometimes some other indicators such as ASLO, CRP, ALT, IgE, etc.) and of bacteriological examination of warm urine were compared before and after treatment.

The overall success of treatment meant: a) the disappearance of more than 50% of the main dominant symptoms and complaints that were present before treatment; b) restoration of working capacity and return to normal life, which existed before the disease; c) normalization of general urine and blood analyses, possibly other indicators (in cases of their violation before treatment) and d) absence of isolation of bacteria from urine in control and monitoring bacteriological examinations. Moreover, each patient was able independently to assess the effectiveness of treatment compared to his/her previous condition, that was additionally taken into account when determining the overall success, answering a simple question: how do you personally assess the success of the performed treatment on a scale from 0% to 100% ?

The clinical efficacy of treatment with bacterial autovaccine in 23 patients with Long-COVID syndrome, which, according to our data, was diagnosed as CBIS on the background of Nephrodysbacteriosis, was quite encouraging. So, already after the first cycle of vaccination, which consisted of 2-3 courses, the clinical condition returned to normal in 15/23 (65.2%) cases. In another 5/23 (21.7%) cases, patients considered themselves to have recovered by 90-100% after the second cycle of vaccination with 2-3 additional courses. In 3/23 (13.0%) cases, treatment is still ongoing but the condition of patients clinically and subjectively improved by 30-40%. There were no complications or side effects of allergic or anaphylactic nature due to treatment with bacterial autovaccines, which by the way reduce the sensibilization level of the patient’s organism with inflammatory pathogens and usually contribute to a significant reduction in IgE levels, elevated before treatment [33]. There was neither comeback nor relapses of Long-COVID symptoms during follow-up observation of most patients within 6-12 months.

Here are some examples of successful treatment of patients with CBIS, which ran under the mask of a diagnosis of Long-COVID, with bacterial autovaccines.  

Example 1. 

Patient B., USA, went remotely to the clinic 8.01.22 online with complaints that, despite ongoing treatment, can not recover for more than 20 months after suffering a severe form of coronavirus infection in April 2020 with several courses of antibiotics. At the place of residence, the patient was diagnosed as Long-COVID, which ran as CFS/ME. After several virtual consultations and having filled out the available Questionnaire for Preliminary Clinical Diagnostic of ME/CFS-CBIS, he delivered to Kyiv dipslides with morning urine for 3 consecutive days, from which there were isolated by cultural method 3 strains of Enterococcus faecalis and 2 strains of Staphylococcus haemolyticus. The following diagnosis was made: "Nephrodysbacteriosis (at the time of consultation - predominantly enterococcal-staphylococcal). Chronic bacterial intoxication syndrome (CBIS) with clinical manifestation after severe coronavirus infection in April 2020 with several courses of antibiotic treatment; CBIS runs under the mask of Long-Covid-ME/CFS with increased fatigue, weakness, sweating, hair loss, loss of vital energy ("Living in bed" or "Couch bound") with exhaustion after normal loading for more than 24 hours, decreased tolerance to physical and sports activities, sleep disorders (sleep does not provide a feeling of freshness), headache, dizziness, tachycardia, increased heart rate, changes in blood pressure, "hot flashes" and feeling of heat in the body, peripheral vascular spasms with paresthesias and cold extremities, local cramps and muscle twitching, muscle weakness, intermittent loss of balance and loss of coordination with complications when driving a car, periodic itching of the skin and mucous membranes, fragility of nails, heartburn and a feeling of "sand" in the eyes, prolonged reflex cough, pain in the joints, spine, muscles, heart; cognitive impairments (impaired memory, concentration, attention, logical and associative thinking, decreased mental abilities, difficulty in choosing words) with a feeling of "brain fog"; reduced life motivations and interest to surroundings; social and domestic apathy, phobias, depression with panic attacks and suicidal thoughts, intoxication "shadows" and pastosity under the eyes. Condition after multiple and long-term courses of treatment with antibiotics in the distant anamnesis, including at the age of 12 years due to peritonitis after perforated appendicitis and at the age of 16 years after "traumatic jaw fracture". There was prescribed sequential immunization, firstly with monovalent staphylococcal vaccine No.7, then in 3 weeks - with divalent E.coli-enterococcal vaccine No.10 and then in 1 month - re-vaccination with staphylococcal vaccine No.5 and else in a month - immunization with polyvalent urovaccine from auto- and museum-strains No.10. Treatment began on February 17, 2022 and has to last 5 months.

Here is how the patient felt the own condition (incl.evident ”brain fog”) before February 17, 2022 when the treatment began and preparations received before the treatment:

long covid/me/cfs. Severe. Couch bound. Very neurologically limited. Also emotionally and physically limited. Current medicaionts. Ivermectin 3mlg. Lithium 500mlg. Metoprolol 25mlg. Low dose naltrexone. 4.5 mlg supplements. Tmg, b12, b3, resveratrol, magnesium, zinc, b1, choline, d3.

Judging by reports of the patient, already after the first some injections/shots of monovalent staphylococcal autovaccine, the “brain fog” began to disappear.

Here it should be noted that in some cases of treatment with bacterial autovaccine it’s possible some deterioration of the general condition in the first days of treatment that is quite typical due to the massive immune-related death of a large number of bacteria in the kidneys with a corresponding significant temporary increase in intoxication of organism.

Example 2.

Patient Natalia, 24 years, Kyiv, Ukraine, visited the clinic on October 21, 2021 with complaints of very high fatigue and insurmountable weakness (it was difficult for her to sit down on a chair, she looked at the couch standing next to her as if she wanted to lie down on it), irritability bordering on aggression (she said “shut down mouth” her mother who led her to the clinic), severe headache, dizziness, shakiness of gait; peripheral neuropathies with the tingling sensation in the back of the head, upper back, upper and lower extremities; intoxication "shadows" under the eyes, which have never been before. Also she noticed symptoms of an exacerbation of chronic rhinosinusitis with excretion of green mucus from the nose and along the back wall of the pharynx, pharyngitis with pain when swallowing, facial pyoderma and enlargement of the cervical lymph nodes more on the right. According to the nearest anamnesis, 1 month ago she had a coronavirus infection of moderate course, confirmed by a positive PCR-test, was treated at home, took antibiotics. After the acute stage of the disease, recovery did not occur, developed Long-COVID. For 2 weeks, she underwent treatment due to “Epstein-Barr virus infection” which ran with "enlarged lymph nodes", using normal human immunoglobulin intravenously and high-dose interferon by 24 million per day without any positive clinical result. The patient was recommended to be examined at the clinic, but she, being desperate in doctors, disappeared and returned for a second time only 3 months later.

After examination at the clinic on January 27, 2022, she was diagnosed: "Nephrodysbacteriosis (E.coli-enterococcal - 3 strains E.coli and 2 strains Ent.faecium were isolated from urine). CBIS, running under the mask of Long-COVID, with the above mentioned symptoms and additionally with increased sweating and hair loss. Chronic staphylococcal infection of the nasopharynx (streptococcal-Escherichia coli mixed – it was isolated per one strain of Str.pyogenes and E.coli) with the above mentioned clinical manifestations, including cervical lymphadenopathy. Chronic herpes mixed-infection: EBV and CMV, latent stage (does not require treatment)”. Immunization with bacterial autovaccines is prescribed: firstly, monovalent staphylococcal No.7, in 3 weeks - divalent E.coli-enterococcal and else in 1 month - divalent streptococcal-staphylococcal. On the 2nd-3d day of treatment, the patient's general condition significantly deteriorated that caused an attack of her undisguised panic and aggression. We considered this condition, also as in the previous example No.1 with patient B., as a "mild" form of the well-known bacteriemic shock, connected with massive death of bacteria persisting in the kidneys, due to the immune response to the first 1-2 injections/shots of bacterial autovaccine. After intensifying detoxification therapy, the general condition quickly improved, immunization was not interrupted. The patient appeared in the clinic on February 14, 2022, to make the 7th injection of staphylococcal vaccine, in a good mood, balanced, smiling, with good makeup, happy with herself and the world around her and said that in 2 days she will fly away with her boyfriend on vacation to the "beautiful islands". We did not understand whether she will need the next vaccination courses, whether everything is over as in a nightmare and the girl will continue to recover thanks to the own immune system and a caring boyfriend.

Example 3.

Patient Oleksandr, 70 years old, Kyiv, Ukraine, visited the clinic on June 4, 2021. His wife and daughter almost dragged him to the clinic, because he himself, exhausted, could not even move without external assistance. From the anamnesis it was found out that on March 20, 2021 he felt sick with SARS-CoV-2 and from April 3, 2021 to April 22, 2021 he was hospitalized with a diagnosis of Covid-19 (PCR SarsCov2 +), moderate form; out-hospital bilateral polysegmental pneumonia. For 3 weeks he received antibiotics and corticosteroids. After discharge from the hospital, his condition not only did not improve, but on the contrary continued to deteriorate. It developed CBIS with the debut of chronic latent formed pyelonephritis and with two febrile attacks^© (since 15.05.2021 for 5 days with a maximum temperature 38.6°C and 28.05.2021 for 4 days with a maximum temperature of up to 39,1°C), hormone-dependent: the temperature returned after the abolition of corticosteroids and normalized after their re-prescription, as in Marshall's (PFAPA) syndrome. General blood analysis June 3, 2021: reduced hemoglobin (HGB) - 125 g/l and erythrocytes (RBC) - 3.92 x10¹²/l; platelets (PLT) - 276x10⁹/l, elevated leukociti (WBC0) - 13,0х10⁹/l, formula of blood with left shift: B. - 0%, E. - 1%, P. - 26%, C. - 49%, L. - 12%, M. - 12 %, toxic granularity of neutrophils (TGN) - 30%, ESR - 54 mm/h. General urine analysis on 3.06.2021: protein - 0.033%, leukociti - 8-10 in sight area, erythrocytes - 5-7 in sight area, cylinders hyaline and grain. - 1-2 in sight area. Coagulogram June 3, 2021: IF - 78 sec., Prothrombin index (PTI) - 17%, MNO - 5.77, thrombin time - 100 sec, fibrinogen - 99 mg/dl. After correction of previously prescribed anticoagulant therapy on June 7, 2021: PTI - 68.1%, MNO - 1.46, CRP - 20.6 mg/l, elevated ASLO - 233.6 IU/ml, PCR on SARS-CoV-2 RNA gene E, gene N and similar SARS-CoV 3.06.2021 - negative. IgG antibodies (S-protein) to SARS-CoV-2 3.06.2021 - 250, 24 BAU/ml (positive> 15 BAU/ml).  

After examination at the clinic on 14.06.2021 it was diagnosed: “Nephrodysbacteriosis (at the time of consultation dominant staphylococcal - 3 strains of Staphylococcus haemolyticus were isolated from warm urine) with latent formation of chronic sluggish pyelonephritis (according to the general urine analysis on 12.04.21 and ultrasound of the kidneys on 14.05.2021) with exacerbation after treatment of coronavirus infection with antibiotics. Chronic bacterial intoxication syndrome (CBIS) which ran under diagnosis Long-COVID, with two febrile "attacks" (15.05.2021 and 28.05.2021, hormone-dependent), with sharply increased fatigue, insurmountable weakness, intermittent pain in the knee joints (especially under load). Reconvalescent of coronavirus infection (acute period - from 20.03.21 to 22.04.2021). Condition after 3 courses of antibiotics treatment (for 3 weeks from 03.04.21 to 22.04.2021 - 3 preparations and additionally from 20.05.21 to 28.05.2021 – else 1 preparation). Chronic staphylococcal infection of the nasopharynx with the isolation of 2 strains of Staphylococcus aureus (candidal mixed) with minor clinical symptoms: cough in the morning during recent times; symptoms of laryngotracheitis with hoarseness/husky in the voice in the anamnesis. The optimal level of vitamin D (29.18 ng/ml). Decrease in relative and absolute content of B-lymphocytes (CD3-, CD19 +) and monocytes/macrophages (CD14) on the background of increased content of T-suppressors (CD3+, CD4-, CD8+). Absence of serological signs of autoimmune-systemic diseases. Post-antibiotic intestinal dysbacteriosis (constipation)". There was prescribed immunization with staphylococcal vaccine No.7, followed by re-vaccination in 3 weeks with injections No.5 (which was carried out from 14.06.2021 to 23.07.2021). During control examination at the clinic on September 14, 2021, in 3 months after the start of treatment, the patient was difficult to recognize. He went quickly on his own upstairs to the consulting room, was in a good mood and smiled. He said that he has no complaints at the moment, several weeks ago he went to work, he resumed regular visits to the gym, drives his favorite car. It was established the complete disappearance of clinical symptoms of CBIS/Long-COVID. Due to Nephrodysbacteriosis that still remained (re-dominant staphylococcal with a change of the strain of pathogen), despite the complete normalization of the general urine analysis, there was prescribed additional immunization with staphylococcal vaccine No.5 (No.No.13-17) and in 2-3 months - else No.5 (No.No.18-22) with control bacteriological culturing in 2-3 months after the full completion of treatment (according to clinical indications). 

It may seem a little strange that for such a complex issue as the origin and treatment of post-Covid syndrome or Long-COVID there is such a simple explanation. We consider this report as pilot and preliminary. It deserves additional in-depth and broader study, which today in the conditions of the patriotic war against the Russia’s invasion on the territory of Ukraine is technically impossible. The first positive results of effective treatment with bacterial autovaccines, even two dozen patients with this till the moment being uncertain diagnosis, which can actually lead to disability, look very promising and encouraging. Moreover, the impression is that the earlier the treatment with bacterial autovaccines starts from beginning of Long-COVID, the better and faster there are its impressive results. Millions of patients with Long-COVID are currently tensely waiting for the true etiology of Long-COVID and its effective treatment. Therefore, it impossible to ignore such even a small our experience and findings.  

Conclusions.

1. One of the etiologically verified variants of Long-COVID is a previously unknown pathological condition called as Chronic Bacterial Intoxication Syndrome^© (CBIS), which develops on the background of a focus of chronic mostly locally asymptomatic (82.8%) bacterial infection in the kidneys - Nephrodysbacteriosis^©.

2. Nephrodysbacteriosis in the vast majority of cases (72.4%) emerged in patients whose distant or/and nearest anamnesis was oversaturated with use of antibiotics and who received antibiotics during the treatment of acute phase of disease SARS-CoV-2 (75.6%) regardless of the place of treatment - in the hospital or at home.

3. Clinical manifestations of CBIS that ran under diagnosis Long-COVID, in all supervised 29 patients with post-Covid syndrome had typical clinical signs of ME/CFS and remained at the moment of visiting clinic in 15/29 (51.7%) cases for 3 to 6 months and in 14/29 (48.3%) cases - from 6 to 12 months and more.

4. Bacteriological examination of warm urine detected that the main etiological factors in occurrence of  Nephrodysbacteriosis and CBIS, which runs under the unverified diagnosis of Long-COVID, were enterococci, namely Enterococcus faecalis (isolated 14/47 or 29.8% of all generally isolated strains of bacteria) and Enterococcus faecium - 5/47 strains (10.6%), staphylococci (Staphylococcus haemolyticus - 11/47 strains or 23.4% and Staphylococcus aureus - 6/47 or 12.8%) and Escherichia coli - 11/47 (23.4%) cultures. In many cases, these bacteria in different combinations were isolated simultaneously.

5. An effective method of treatment of patients with Long-COVID/CBIS was the use of bacterial autovaccines prepared from strains of bacteria, isolated mainly from the urine of patients, with complete clinical recovery: in 15/23 (65.2%) cases after the first cycle of treatment, which lasted from 70 to 110 days (depending on the number of vaccination courses within one cycle - 2 or 3) and else in 5/23 (21.7%) cases - after the second cycle of treatment.

REFERENCES / LITERATURE

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