Prolonged subfebrile condition, pyretic fever and febrile attacks of unknown genesis: new approach to diagnosis and treatment. Part 1. Clinical picture

Background. The study was aimed to establish the true etiological cause of such pathological conditions as prolonged low-grade fever, fever of unknown genesis, and cases of rapid short-term febrile increase of temperature of unknown origin. Materials and methods. The design of the study was clinical-diagnostic and included the search for ways to diagnose and treat such pathological conditions as prolonged subfebrile fever, fever of unknown genesis, and cases of rapid short-term febrile increase of temperature of unknown origin. The studies were prospective-retrospective and were longitudinal with long-term periodic follow-up of a certain part of the same patients during 1–10 years after diagnosis of CBIS (chronic bacterial intoxication syndrome) and appropriate treatment. According to the effectiveness of the obtained results, the study was direct, because it undoubtedly led to the recovery of the patient with the improvement of his/her state and life. All patients (infants and adults aged till 80 years) who went to the hospital during 2009–2020 with complaints about violation of the temperature regime (subfebrile or febrile increase). Results. During 2009–2020, 3999 patients (adults — 2047/3999, 51.2 %, children — 1952/3999, 48.8 %) with a fever of unknown origin, namely 1578/2047 (77.1 %) adults and 1206/1952 (61.8 %) children with prolonged subfebrile fever, 70/2047 (3.4 %) and 25/1952 (1.3 %), respectively — with febrile fever and 399/2047 (19.5 %) and 721/1952 (36.9 %) — with febrile attacks (FA), were observed by the authors. In all 3999 (100 %) patients, there was detected a focus of chronic bacterial infection in the kidneys. Herewith in more than 2/3 cases (2780/3999 patients, 69.5 %), there was diagnosed the locally asymptomatic nephrodysbacteriosis without clinical, general laboratory (inclu­ding almost normal general analysis of urine) and instrumental signs of the inflammatory process in the kidneys. In 960/3999 (24.0 %) ca­ses, there was first established the latent form of delayed clinically asymptomatic chronic pyelonephritis. 259/3999 (6.5 %) patients were diagnosed with chronic pyelonephritis at the stage of clinical exacerbation. As a consequence of the formation of a focus of chronic bacterial infection in the kidneys, the patients developed monosymptomatic (only with temperature increase) or full-symptom CBIS, namely: 2024/2784 (72.7 %) children and adults with prolonged subfebrile fever there presented with typical clinical manifestations of CBIS in various combinations, but in 760/2784 (27.3 %) cases, the subfebrile temperature was monosymptoma­tic without other complaints and clinical symptoms. The diagnosis was confirmed by bacteriological examination of warm urine (three times, for three days running) and toxicological blood examination using the diagnostic system Toxicon. Urine cultures of various bacteria were isolated from urine in all 3999 (100 %) patients. Herewith in 2205/3999 (55.1 %) cases, there were isolated one culture of bacteria in each case, in 1608/3999 (40.2 %) patients — simultaneously two cultures of different bacteria, i.e. another 3216 strains, in 186/3999 (4,7 %) — three cultures (558 strains). That is, in general, there were isolated 5979 strains of different bacteria, which were considered as diagnostic confirmation of the presence of a focus of chronic bacterial infection in the kidneys in all 3999 patients with prolonged subfebrile fever, fever of unknown genesis, or febrile attacks. The main factors of the occurrence of temperature regime disorders on the background of CBIS were Enterococci (2471/3999 strains from 61.8 % of patients), Escherichia coli — 1495/3999 strains (from 37.4 % of patients) and Staphylococci (Staphylococcus aureus and Staphylococcus haemolyticus) and Streptococci (Streptococcus pyogenes): a total of 696/3999 strains (from 17.4 % of patients). In 818 (100 %) patients who were examined using the Toxi­con system, all, without exception, the indicators of cytolytic activity of toxic proteomes, which were tested, significantly exceeded the norm (p < 0.001). In the vast majority of patients (in 664/818 or 81.17 % of cases), there was detected severe toxemia, in 140/818 (17.11 %) — moderate and only in 14 (1.71 %) — mild. All 3999 patients with prolonged subfebrile fever, fever of unknown genesis, and FA were treated with bacterial autovaccines made from strains, isolated during the bacteriological examination. One cycle consisted of 2–3 courses of immunization with bacterial vaccines. One course included 10 or 12 subcutaneous injections in increasing dosage during 19–21 days. Between courses, there was maintained an interval of 3 to 4 weeks. The treatment cycle generally lasted from 70 to 110 days, depending on the number of courses. Intervals between treatment cycles were usually maintained for 3 months. The effectiveness of such treatment was 71.2 % after the first cycle, 92.8 % — after the second, and 99.2 % — after the third with full recovery of the ability to work, lost during the illness, and the emotional level of personal life. Conclusions. It has been established that the etiological cause of the occurrence of prolonged subfebrile fever, febrile fevers of unknown genesis, and febrile attacks is such a clinically and nosologically separate disease as chronic bacterial intoxication syndrome, which develops on the background of a chronic bacterial focus, usually locally asymptomatic infection in the kidneys, called nephrodysbacteriosis, and is usually associated with severe bacterial endotoxicosis that was confirmed by appropriate toxicological examination of the blood. The use of bacterial autovaccines was proved to be an effective method of treatment (up to 99.2 %) of patients with increased temperature of bacterial-toxic origin.

Prolonged subfebrile condition, pyretic fever and febrile attacks of unknown genesis: new approach to diagnosis and treatment. Part 2. Diagnostics and treatment

Background. The study was aimed to establish the true etiological cause of such pathological conditions as prolonged low-grade fever, fever of unknown genesis, and cases of rapid short-term febrile increase of temperature of unknown origin. Materials and methods. The design of the study was clinical-diagnostic and included the search for ways to diagnose and treat such pathological conditions as prolonged subfebrile fever, fever of unknown genesis, and cases of rapid short-term febrile increase of temperature of unknown origin. The studies were prospective-retrospective and were longitudinal with long-term periodic follow-up of a certain part of the same patients during 1–10 years after diagnosis of CBIS (chronic bacterial intoxication syndrome) and appropriate treatment. According to the effectiveness of the obtained results, the study was direct, because it undoubtedly led to the recovery of the patient with the improvement of his/her state and life. All patients (infants and adults aged till 80 years) who went to the hospital during 2009–2020 with complaints about violation of the temperature regime (subfebrile or febrile increase). Results. During 2009–2020, 3999 patients (adults — 2047/3999, 51.2 %, children — 1952/3999, 48.8 %) with a fever of unknown origin, namely 1578/2047 (77.1 %) adults and 1206/1952 (61.8 %) children with prolonged subfebrile fever, 70/2047 (3.4 %) and 25/1952 (1.3 %), respectively — with febrile fever and 399/2047 (19.5 %) and 721/1952 (36.9 %) — with febrile attacks (FA), were observed by the authors. In all 3999 (100 %) patients, there was detected a focus of chronic bacterial infection in the kidneys. Herewith in more than 2/3 cases (2780/3999 patients, 69.5 %), there was diagnosed the locally asymptomatic nephrodysbacteriosis without clinical, general laboratory (inclu­ding almost normal general analysis of urine) and instrumental signs of the inflammatory process in the kidneys. In 960/3999 (24.0 %) ca­ses, there was first established the latent form of delayed clinically asymptomatic chronic pyelonephritis. 259/3999 (6.5 %) patients were diagnosed with chronic pyelonephritis at the stage of clinical exacerbation. As a consequence of the formation of a focus of chronic bacterial infection in the kidneys, the patients developed monosymptomatic (only with temperature increase) or full-symptom CBIS, namely: 2024/2784 (72.7 %) children and adults with prolonged subfebrile fever there presented with typical clinical manifestations of CBIS in various combinations, but in 760/2784 (27.3 %) cases, the subfebrile temperature was monosymptoma­tic without other complaints and clinical symptoms. The diagnosis was confirmed by bacteriological examination of warm urine (three times, for three days running) and toxicological blood examination using the diagnostic system Toxicon. Urine cultures of various bacteria were isolated from urine in all 3999 (100 %) patients. Herewith in 2205/3999 (55.1 %) cases, there were isolated one culture of bacteria in each case, in 1608/3999 (40.2 %) patients — simultaneously two cultures of different bacteria, i.e. another 3216 strains, in 186/3999 (4,7 %) — three cultures (558 strains). That is, in general, there were isolated 5979 strains of different bacteria, which were considered as diagnostic confirmation of the presence of a focus of chronic bacterial infection in the kidneys in all 3999 patients with prolonged subfebrile fever, fever of unknown genesis, or febrile attacks. The main factors of the occurrence of temperature regime disorders on the background of CBIS were Enterococci (2471/3999 strains from 61.8 % of patients), Escherichia coli — 1495/3999 strains (from 37.4 % of patients) and Staphylococci (Staphylococcus aureus and Staphylococcus haemolyticus) and Streptococci (Streptococcus pyogenes): a total of 696/3999 strains (from 17.4 % of patients). In 818 (100 %) patients who were examined using the Toxi­con system, all, without exception, the indicators of cytolytic activity of toxic proteomes, which were tested, significantly exceeded the norm (p < 0.001). In the vast majority of patients (in 664/818 or 81.17 % of cases), there was detected severe toxemia, in 140/818 (17.11 %) — moderate and only in 14 (1.71 %) — mild. All 3999 patients with prolonged subfebrile fever, fever of unknown genesis, and FA were treated with bacterial autovaccines made from strains, isolated during the bacteriological examination. One cycle consisted of 2–3 courses of immunization with bacterial vaccines. One course included 10 or 12 subcutaneous injections in increasing dosage during 19–21 days. Between courses, there was maintained an interval of 3 to 4 weeks. The treatment cycle generally lasted from 70 to 110 days, depending on the number of courses. Intervals between treatment cycles were usually maintained for 3 months. The effectiveness of such treatment was 71.2 % after the first cycle, 92.8 % — after the second, and 99.2 % — after the third with full recovery of the ability to work, lost during the illness, and the emotional level of personal life. Conclusions. It has been established that the etiological cause of the occurrence of prolonged subfebrile fever, febrile fevers of unknown genesis, and febrile attacks is such a clinically and nosologically separate disease as chronic bacterial intoxication syndrome, which develops on the background of a chronic bacterial focus, usually locally asymptomatic infection in the kidneys, called nephrodysbacteriosis, and is usually associated with severe bacterial endotoxicosis that was confirmed by appropriate toxicological examination of the blood. The use of bacterial autovaccines was proved to be an effective method of treatment (up to 99.2 %) of patients with increased temperature of bacterial-toxic origin.

CHRONIC PYELONEPHRITIS AS A PRECIPITATING FACTOR OF HEPATORENAL SYNDROME IN PATIENTS WITH ALCOHOLIC LIVER CIRRHOSIS

Introduction. Most attempts to assess renal failure in alcoholic liver cirrhosis have so far focused on acute kidney injury and on the hepatorenal syndrome in particular. However, there are still limited data on the prevalence and clinical impact of chronic kidney disease in cirrhosis. Objectives. This study aimed to assess the influence of chronic pyelonephritis on the incidence of hepatorenal syndrome in patients with alcoholic liver cirrhosis. Material and methods. 165 patients with decompensated alcoholic liver cirrhosis and concomitant chronic pyelonephritis were enrolled in the study. They were divided into two groups according to the presence or absence of chronic pyelonephritis: group 1 had alcoholic liver cirrhosis only (n=82), group 2 had alcoholic liver cirrhosis + chronic pyelonephritis (n=83). Results. The general bacterial infections were more common in group 1 patients. The spectrum of the most frequent bacterial complications in the examined patients typical for alcoholic liver cirrhosis was as follows: the share of urinary tract infection made up 16.0% (95% confidence interval 14.4-27.9), pneumonia constituted 16.7% (95% confidence interval 10.5-22.7, bacteremia made up 4.0% (95% confidence interval 7.7-38.6), the share of skin infections (erysipelas) was 2.7% (95% confidence interval 0.7-6.6). Other infections including pulmonary tuberculosis, lung abscess, right leg abscess, osteomyelitis, bedsores, were less common (6.7%). Spontaneous bacterial peritonitis, taking into account all options, was found in 6 cases (10.5%, 95% confidence interval 4.0-21.5). As expected, the incidence of hepatorenal syndrome within 14 days of inpatient onset was almost twice higher in group 2 – 22 cases (27%), than in group2 – 13 cases (16%). The group 2 demonstrated a more severe course of alcoholic liver cirrhosis on the Child-Pugh scale compared with group I (class B - 29.9%; class C - 70.1% against class B - 46.4%; class C - 53, 6% ); the differences were statistically significant (χ2 = 4.30, p = 0.038). In patients of group 2, the lethal outcome in the hospital occurred in 6 (8.9%) cases. Conclusions: The results of the present study confirm the role of chronic pyelonephritis as one of the major precipitating factors of hepatorenal syndrome incidence in patients with alcoholic liver cirrhosis. This fact should be considered when making the treatment plan for these patients.

MICROBIOLOGICAL CHARACTERISTICS OF PATHOGENIC FLORA IN CHILDREN WITH ACUTE AND CHRONIC PYELONEPHRITIS

The study of dynamically changing antibiotic sensitivity of uropathogenic strains in children with pyelonephritis is of great scientific and practical interest, since the course and outcome of the disease and the success of cure depend on it. Objective of the study: to study the microbial landscape of urine and antimicrobial sensitivity of pathogens in children with acute (AP) and exacerbation of chronic pyelonephritis (CP) for timely correction of empirical antibacterial (AB) therapy. Materials and methods of research: a prospective open non-randomized controlled singlecenter study to study the microbial landscape of urine and antimicrobial sensitivity of pathogens in children with AP and CP was conducted at the Speransky Children's City Clinical Hospital No. 9. Inclusion criteria: compliance with the diagnostic criteria for the onset of AP and CP, age from 1 to 14 years, the possibility of assessing the microbiological spectrum of urine before starting AB therapy, determination in urine cultures of strains producing extended spectrum betalactamases (ESBL) and/or carbapenemases (CP-CRE). Results: 552 results of urine bacteriological tests were analyzed. Bacteriuria was detected in 68,3% (n=376) patients, of which 161 (42,8%) were diagnosed with AP, 215 (57,2%) with CP. The structure of pathogens was dominated by gram-negative flora (53,8–70,8%), among which enterobacteria prevailed (79,5%), the dominant microorganism was E. coli (48%). Gram-positive microflora was represented by Enterococcus faecalis (35%). Among enterobacteriaceae, there was a statistically significant increase (p<0,05) in the number of ESBL and/or CP producers, as well as their associations, from 8,8% in 2016 to 25% in 2019–2020 with a peak increase of up to 31% in 2018. A study of resistograms noted that E. coli retains high levels of sensitivity to amoxicillin/clavulanate, however, since 2019, a high frequency of ceftriaxone-resistant strains has been recorded, and in 2020, the detection rate of resistant strains has increased to cefotaxime of E. coli strains. The highest and most stable activity against E. coli ESBL was shown by meropenem and ertapenem. There is a tendency towards a decrease in the sensitivity of Kl. pneumoniae to amoxicillin/clavuanate, fosfomycin and amikacin. The emergence in 2020 of strains of Enterococcus faecalis resistant to amoxicillin/clavuanate and a tendency to a decrease in sensitivity to gentamicin while maintaining a high sensitivity to amikacin were recorded. Conclusion: the results obtained indicate the importance of monitoring the AB-sensitivity of uropathogenic strains in order to increase the effectiveness of empiric therapy and reduce the prescription of inactive antibacterial drugs in children with AP and CP.

Nonasthmatic Churg–Strauss syndrome superimposed on chronic pyelonephritis: a case report

Churg–Strauss syndrome (CSS) is a granulomatous small-vessel vasculitis. Asthma is seen in the majority of patients with CSS, but atypical nonasthmatic forms of CSS are also being recognized. We herein describe a 67-year-old woman with a history of chronic pyelonephritis and drug allergy reactions who was admitted to our hospital because of worsening renal function preceded by fever, purpura, sinusitis, and a positive urine culture that confirmed a urinary infection. She was initially treated with pipemidic acid for 7 days, followed by clarithromycin for sinusitis. Laboratory tests on admission showed an absolute eosinophil count of 1750 cells/µL and serum creatinine concentration of 4.72 mg/dL. Urine and blood cultures showed no growth. Kidney biopsy revealed crescent formations with diffuse interstitial fibrosis and foci of eosinophil infiltration. An atypical form of CSS was diagnosed based on tissue eosinophilia, peripheral eosinophilia, and sinusitis. Intravenous methylprednisolone and cyclophosphamide pulse therapy together with hemodialysis treatment improved the patient’s clinical condition but did not resolve the kidney damage. The onset of an atypical form of CSS in our patient manifested as symptoms and signs mimicking those of chronic pyelonephritis and drug allergy reactions. The patient’s chronic kidney disease finally progressed to dialysis dependence.

A Retrospective Review of Xanthogranulomatous Pyelonephritis - Our Experience at a Tertiary Care Center Located in Dharwad District, Karnataka

BACKGROUND Xanthogranulomatous pyelonephritis (XGP) is an uncommon form of chronic pyelonephritis that is characterized by extensive enlargement and destruction of the involved kidney which ultimately results in non-functioning kidney. It often mimics other inflammatory or neoplastic renal disorders. Unlike chronic pyelonephritis, it spreads to the perinephric space with formation of multiple abscesses and fistulas. It is now being recognized as an important cause of renal morbidity and mortality worldwide. METHODS This is a case series undertaken in a tertiary care center. Clinical data was collected from last 6 years. Clinical features, radiological findings, treatment, and its outcome were analysed and presented. RESULTS A total of 23 cases diagnosed clinically were included in our study. The disease is more prevalent in females than in males with ratio of 1.8 : 1, with mean age of 47.04 years. Most of the patients presented with flank pain and fever. 2 patients had unusual presentations that are nephrocutaneous fistula and necrotising fasciitis of flank region. In our study, disease was associated with urolithiasis in 43.47 % and diabetes mellitus (DM) in 60.8 %. E. coli was the most commonly grown organism in urine culture. Most of the patients underwent initial percutaneous nephrostomy (PCN) or double-J (DJ) stenting followed by definitive treatment that is nephrectomy (21 patients, 2 patients lost to follow up). Extraperitoneal flank approach was most commonly chosen compared to subcostal transperitoneal approach. Excess blood loss was the most common complication encountered during surgery; 8 patients required post-operative blood transfusion. 5 patients required intensive care unit (ICU) care with inotropic support postoperatively. 6 patients had post-operative superficial surgical site infection. CONCLUSIONS XGP is a rare form of chronic pyelonephritis resulting in enlarged non-functioning kidney. UTI (urinary tract infection) and urolithiasis are the most important factors involved in pathogenesis. Prompt diagnosis and treatment is essential. Initial antibiotic treatment with drainage procedure (PCN or DJ stenting) followed by nephrectomy is treatment of choice. Early diagnosis and treatment may limit the disease process and associated morbidity, thus leading to good outcome. KEYWORDS Xanthogranulomatous Pyelonephritis, UTI (Urinary Tract Infection), Urolithiasis, Nephrectomy

Experience of rehabilitation in children with chronic pyelonephritis living in industrial city

The consistently high frequency of pathology of urinary system in children dictates the need to find new methods for the treatment and prevention of pyelonephritis.Goal. To study clinical and laboratory indicators of health status in children with chronic pyelonephritis living in the industrial city of Tomsk and evaluate the effectiveness of various rehabilitation treatment regimens.Material and Methods. The kidney and urology examinations were performed in 58 children with a diagnosis of chronic pyelonephritis aged 7 to 12 years. Two treatment schemes including administration of mineral water and physiotherapy were used.Results and Discussion. The following symptoms were detected before treatment: oxaluria in 22.41% of children, microhematuria in 17.24% of children, significant increase in serum and morning urine nitrate/nitrite levels, and microalbuminuria suggesting the instability of cell membranes and inflammatory process in renal tissue.Conclusion. The administration of low-mineralized magnesium-sodium chloride-sulfate water in combination with physical therapy, manual massage, sapropel applications, interference therapy, and enteric oxygen therapy lead to normalization of clinical and laboratory health status indicators in the main group of patients.

Immunotropic effects of nitrogenous metabolites in patients with chronic pyelonephritis

Background. We have previously shown that nitrogenous metabolites have immunomodulatory effects in healthy rats and humans as well as in patients with encephalopatia. The purpose of this study is their immunotropic activity in patients with chronic pyelonephritis. Materials and Methods. The object of observation were 24 men (aged 23-76 years) with chronic pyelonephritis in remission. The plasma levels and urinary excretion of uric acid, urea and creatinine and parameters of immunity twice (on admission and after 10 days of balneotherapy at the Truskavets’ Spa) was performed. Results. Judging by the multiple correlation coefficient uricemia exhibits maximal immunotropic activity (R=0,772), followed by creatininemia (R=0,643), urea plasma (R=0,584) and creatinineuria (R=0,506) instead, urea and uric acid excretion correlate with immune parameters insignificantly (R=0,327 and 0,262 respectively). Nitrogenous metabolites together upregulate most parameters of phagocytosis by neutrophils Staph. aureus and E. coli, the level in the blood of CD8 T-lymphocytes, CIC, IgM, componentes of leukocytogram as well as entropy of leukocytogram and immunocytogram. Instead, they downregulate the relative level of lymphocytes in general and of CD4 T-lymphocytes in particular. Conclusion. Nitrogenous metabolites exhibit immunotropic activity in both healthy humans and in patients with chronic pyelonephritis in remission. Both common and distinctive features of immunomodulation were revealed.