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Cytomegalovirus (CMV) syndrome and infectious disease are defined as pathogen detection with appropriate clinical symptoms, but there are not pathognomonic signs of CMV disease. Although the prodrome of acute minor viral infections leukopenia (lymphopenia and neutropenia) is noted with onset of fever, followed by monocytosis, the role of monocytosis in CMV disease has not been described. Furthermore, under influence of corticosteroid therapy, CMV reactivation and monocytosis are described, but without a strict relationship with steroids dose. In the study, the monocyte level was investigated during the CMV infectious process. Regrettably, a non-selected group of 160 patients with high CMV viremia showed high dispersion of monocyte level and comparable with the median value for healthy subjects. Therefore, we investigated monocyte level in CMV-infected patients in relation to the logarithmic phase of the infectious process. Samples from patients with active CMV replication (exponential growth of CMV viremia) were tested. Significant monocytosis (above 1200/µL) during the logarithmic phase of CMV infection (with exponent between 3.23 and 5.77) was observed. Increased count and percentage of monocytes correlated with viral replication in several clinical situations except when there was a rapid recovery without relapse. Furthermore, glucocorticoids equivalent to 10 and 20 mg of dexamethasone during a 2-3-week period caused monocytosis-significant increase (to 1604 and 2214/µL, respectively). Conclusion: In light of the logarithmic increase of viral load, high monocytosis is a hallmark of CMV replication. In the COVID-19 era, presence of high virus level, especially part of virome (CMV) in the molecular technique, is not sufficient for the definition of either proven or probable CMV replication at any site. These preliminary observations merit additional studies to establish whether this clinical response is mediated by monocyte production or by decrease of differentiation to macrophages.
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COVID-19 , Infecções por Citomegalovirus , Neutropenia , Citomegalovirus/fisiologia , Glucocorticoides/uso terapêutico , Humanos , Monócitos , Viremia/complicações , Viremia/tratamento farmacológicoRESUMO
For the last 90 years (much later in Poland) the Tumor Board (TUB) provide a forum to discuss about individual cases of patients with malignancy. This global institution has not fully met the challenges, especially in recent years. Deviations in TUB and delay in therapeutic interventions is an increasing problem in the pandemic. Much less attention is paid to worse diagnostics, i.e. a comprehensive assessment of all diseases and general condition. This favors treatment only in lifethreatening situations (mild cases are delayed), and thus palliative treatment dominates over radical one. An additional problem is the significant deviation between TUB, which was noticed in large university centers, such as for the hospital in Bonn, published in 2018. AIM: The aim of the study was to perform a retrospective analysis of 942 patients' history included 100 patients, who were covered at various stages by the decisions of TUB. MATERIALS AND METHODS: Following the German study, the present paper shows significant deviations in TUB decision, where the co-morbidity (including AIDS, tuberculosis or COVID-19) cause the failure of the treatment of the underlying disease. The retrospective analysis especially included patients with two proliferative processes: endogenous (mutant clone / host clones) and exogenous/xenogenic (microbes). RESULTS: 100 patients with complete history were enrolled in the study, six of whom were selected with survival-relevant deviations in the TUB decisions. The main issues were poor or late diagnosis of a chronic disease, the lack of proper grading and differentiation of symptoms, and thus distinguishing the most life-threatening process. CONCLUSIONS: Infection with SARS-CoV-2, AIDS or even tuberculosis, or the second neoplasm cannot be analyzed in a superficial way and thus be an excuse for disqualification from cancer treatment. On the other hand, as in the German study, the most important causes of deviations were patient expectations, death, comorbidities or treatment side effects. It is a significant shortcoming that in a significant proportion of patients, prior to the initiation of treatment (oncological or antimicrobial, e.g. HAART), insufficient diagnostic procedures was performed to establish the leading pathophysiological process.
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Síndrome da Imunodeficiência Adquirida , COVID-19 , Tuberculose , Humanos , Estudos Retrospectivos , SARS-CoV-2RESUMO
The microbiome as a broad term defines the most dynamic ecological system in which, apart from the biocenosis, there is unique niche for its development, equally dynamic, because host-derived, contrary to physical environment in ecology. Although for years, antibodies, was recognized as a key element of the mucosal barrier, there is still no progress in comprehensive linking microbes and humoral elements. Which organism is a pathogen and which is a commensal - there are still no exact answers (and criteria). Also the discrepancy between experimental research, using more and more sophisticated techniques -showing the existence of nearly 900 bacterial species in our mouth was observed. On the contrary, bacterial infections caused by novel species have not been recognised in patients with humoral immunodeficiencies, apart from the capsular cocci and H. influenzae. Research on human virome, including CMV, is also focused on the cellular immunity, but in many situations in the clinic the humoral compartment are the exclusive, still effective, barrier against viral replication. AIM: The aim of study was to perform an integrated microbiome analysis (microbiota and host) for strict linking various microbiota constelation and end-stage clinical manifestation in humoral immunodeficiency. MATERIALS AND METHODS: This cross-study based on own clinical experience reveal crucial gap in the literature. RESULTS: It indicate the natural competition: why the sentinel microorganism in humoral deficiency - S. pneumoniae dominates in some patients, and in others - Viridans Group Streptococci. Crucial role of high specific IgM level in several CVID complication was described. Furthermore, respiratory microbiota translocation with cancer regression and influence of therapeutic regimen on clinical sequel (predominantly infectious or malignant) were presented. The studies indicates numerous methodological and microecological classification difficulties, which are the source of inadequate, often contradictory conclusions from experimental research. CONCLUSIONS: Microecology describe ecosystem that consists of all the organisms and the abiotic physical environment with which they interact: i.e. biocenosis and biotope but clinical immunology -microorganisms in biotic (cellular) niche in host. Unfortunately, these studies are focused on the anecdotal "healthy" biocenosis (healthy microbiome), without analyzing other elements of the niche, for example cancer. Overall, focusing on the gut microbiota clearly restrict our knowledge on the manifestation of humoral deficiencies in respiratory system. The work is a summary of the search for representative clinical models and microbiological methods (diagnostic chain) in clinical immunology practice.
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Microbioma Gastrointestinal , Microbiota , Humanos , Sistema Respiratório , Bactérias , Imunoglobulina MRESUMO
Veillonella spp is part of the normal flora of the mouth, bowels and vagina, but in most of the studies the immunomodulatory properties of intestinal microbiota was described. Despite of numerous studies on immunomodulatory activity of the microbiome's, most of them are focused on the intestinal microbiome. On the contrary, last finding of lung cancer patients shows higher level of Capnocytophaga and Veillonella, which may serve as potential biomarkers. Unfortunately, in local tumor microenvironment the competition for access to oxygen and nutrients within the microbiological context are not strictly described. In the case report such unique interaction with importance in clinical course of non small cell lung cancer (NSCLC) was described. A CASE REPORT: Patient with NSCLC was admitted to surgical procedure. Unluckily, patients before therapy suffered brain trauma (metastases and meningitis were excluded). The oncologic intervention delayed: patients has not receive neoadjuvant chemotherapy. Within near 2 months the infectious process dominated with high acute phase reaction. It predominated over the process of cancer with significant decrease of initial tumor size. After surgical procedure histological examination showed 60% of the tumor was necrotic. Microbiological analysis of tumor specimen reveal Veillonella spp., identified as Veillonella atypica with high abundance. Because the serious complication patients do not receive adjuvant chemotherapy: the surgical resection was complicated by severe systemic inflammatory response syndrome (SIRS) but with low level lactate. CONCLUSIONS: Our observation indicate significant role of commensal anaerobic bacteria in clinical history of cancer patient, opportunistic type of infectious process as well as therapeuthic prospect: proliferative potential and anaerobic glycolysis of commensal Veillonella reduce access of cancer cells to nutrition's. It shed light on crucial role of innate immune response, acute phase reaction and neutrophils in immunotherapy outcome. Contrary to previous studies with statistical coexistence of several bacteria and cancer our observation was evidence-based: tumor specimen was microbiologically analysed.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Boca , Microambiente Tumoral , VeillonellaRESUMO
Although the existing paradigm states that cytomegalovirus (CMV) reactivation is under the control of the cellular immune response, the role of humoral and innate counterparts are underestimated. The study analyzed the hostâ»virus interaction i.e., CMV-immune response evolution during infection in three different clinical situations: (1) immunodeficient CMV-positive human leukocyte antigen (HLA)-matched bone marrow recipients after immunoablative conditioning as well as immunocompetent, (2) adult, and (3) infant with primary immune response. In the first situation, a fast and significant decrease of specific immunity was observed but reconstitution of marrow-derived B and natural killer (NK) cells was observed prior to thymic origin of T cells. The lowest CMV-IgG (93.2 RU/mL) was found just before CMV viremia. It is noteworthy that the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was detected later, but in the first phase, phytohemagglutinin (PHA)-induced IFN-γ release was significantly lower than that of CMV-induced ("indeterminate" results). It corresponds with the increase of NK cells at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells using a pentamer technique. In immunocompetent adult (CMV-negative donor), the cellular and humoral immune response increased in a parallel manner, but symptoms of CMV mononucleosis persisted until the increase of specific IgG. During infancy, the decrease of the maternal CMV-IgG level to 89.08 RU/mL followed by clinical sequel, i.e., CMV replication, were described. My observations shed light on a unique host-CMV interaction and CMV-IgG role: they indicate that its significant decrease predicts CMV replication. Before primary cellular immune response development, the high level of residual CMV-IgG (about >100 R/mL) from mother or recipient prevents virus reactivation. The innate immune response and NK-dependent IFN-secretion should be further investigated.
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Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunocompetência , Hospedeiro Imunocomprometido , Imunoglobulina G/metabolismo , Anticorpos Antivirais/metabolismo , Linfócitos B/metabolismo , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Lactente , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
We studied the presence of triazole resistance of 121 Aspergillus fumigatus clinical isolates collected in two Polish cities, Warsaw and Wroclaw, to determine if resistance is emerging in our country. We identified five itraconazole resistant isolates (4.13%) carrying the TR34/L98H alteration in Cyp51A gene, four of which were cross-resistant to posaconazole and one to voriconazole. One isolate was intermediate susceptible to itraconazole and harbored no Cyp51A alterations. The study confirms the presence of azole resistant A. fumigatus strains in Poland at a level that is comparative to other European countries.
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Antifúngicos/farmacologia , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/isolamento & purificação , Farmacorresistência Fúngica , Triazóis/farmacologia , Cidades , Sistema Enzimático do Citocromo P-450/genética , Proteínas Fúngicas/genética , Genótipo , Humanos , Mutação de Sentido Incorreto , PolôniaRESUMO
BACKGROUND: Elizabethkingia miricola is a rare Gram-negative bacterium found in water and clinical specimens. Typical culturing methods often misidentify Elizabethkingia spp. as Flavobacterium or Chryseobacterium. Although diagnosis is based on culturing samples taken from sterile sites, such as blood, a proper identification of this bacterium requires an expertise that goes beyond the capabilities of a typical clinical laboratory. CASE PRESENTATION: A 35-year-old woman diagnosed with common variable immunodeficiency was admitted to our center. Previous treatment with antibiotics (amoxicillin plus clavulanate, first and third generation of cephalosporins, macrolides) and systemic corticosteroids (up to 120 mg/day of prednisolone) failed to arrest the spread of inflammation. Gingival recession was observed in her oral cavity, resulting in an apparent lengthening of her teeth. In addition to typical commensal bacteria, including streptococci and neisseriae, strains of Rothia mucilaginosa and Elizabethkingia miricola were identified upon a detailed microbiological examination using a MALDI-TOF MS Biotyper system. The presence of the latter strain correlated with severe periodontitis, lack of IgA in her saliva and serum, a very low IgG concentration (< 50 mg/dl), IgM-paraproteinemia, decreases in C3a and C5a and microvascular abnormality. High-dose immunoglobulin (to maintain IgG > 500 mg/dl) and targeted levofloxacin treatment resulted in immune system reconstitution, oral healing, and eradication of the Elizabethkingia infection. CONCLUSIONS: E. miricola rarely causes disease in healthy individuals. However, the overgrowth of commensal bacteria, lack of IgG/IgA, microvasculopathy and complement cascade activation in patients with humoral immunodeficiency may facilitate Elizabethkingia invasion. Overuse of antibiotics, particularly beta-lactams, may cause mucosal colonization by E. miricola, followed by its multiplication combined with periodontitis that prompts bacterial translocation. MALDI-TOF Biotyper analysis may become a method of choice for identification of Elizabethkingia infections.
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Infecções por Bactérias Gram-Negativas/diagnóstico , Periodontite/diagnóstico , Corticosteroides/uso terapêutico , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Complemento C3a/análise , Complemento C5a/análise , Feminino , Flavobacteriaceae/efeitos dos fármacos , Flavobacteriaceae/genética , Flavobacteriaceae/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/imunologia , Humanos , Imunidade Humoral , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Levofloxacino/uso terapêutico , Boca/microbiologia , Periodontite/tratamento farmacológico , Periodontite/imunologia , RNA Ribossômico 16S/isolamento & purificação , RNA Ribossômico 16S/metabolismo , Saliva/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID. METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.
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Imunodeficiência de Variável Comum/terapia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adolescente , Adulto , Causas de Morte , Criança , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/mortalidade , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Humoral memory and specific antibody levels depend on the kind of antigen and individual immunofactors. The presence of IgM antibodies or a fourfold rise in specific IgG levels are generally accepted as diagnostic factors in the serology of acute viral infections. This basic model is not adequate for the herpes virome, especially after hematopoietic stem cell transplantation (HSCT), due to continuous, usually multifocal antigenic stimulation, various donor serostatuses, immunosuppression, and individual immunoreconstitution. METHODS: A case-control study was conducted to identify active infection cases of human herpesvirus (HHV) (from 300 diagnosed immunocompromised patients) and to evaluate historically associated humoral factors to look at outcomes. We considered only the data of patients with meticulous differential diagnosis to exclude other causes, and thereby to observe pathways and temporal relationships, not the statistical ones usually collected in cohorts. Despite the small number, such data collection and analysis methods avoid a number of biases and indicate cause and effect. RESULTS: In this observational study, a retrospective analysis of data from 300 patients with clinical diagnosis of herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation showed a number of biases. Two well-differentiated cases (confirmed by a Tzanck test) with various diseases and conditioning evolutions of immune parameters showed an interesting pathway. Exponential decreases in specific IgGs after HSCT preceded virus replication were observed, with a cytopathic effect (shingles, VZV encephalitis and HSV-induced mucositis). The minima (lowest IgG levels) before herpesvirus reactivation were 234.23 mIU/mL and 94 RU/mL for VZV and HSV, respectively. This coincided with a low CD4 titer, but without other infectious processes. Other immune response parameters such as Treg, cytotoxic T cells, and complement and total IgG level were the same as they were before the transplant procedure. Interestingly, a second wave of immunoreconstitution with an anamnestic antibody response was not always observed. It coincided with prolonged herpes viral infection. A patient with lymphocyte depletion in conditioning showed an earlier second wave of immunoreconstitution (6th vs. 14th month). CONCLUSIONS: As is typical for infancy, the kinetics of the IgG level is unique after HSCT (the decline phase is first). Host microbiome factors (e.g., HHV1-3-serostatus) should be taken into account to predict risk of non-relapse mortality and survival after HSCT. The levels of specific antibodies help in predicting prognoses and improve disease management. A lack of differentiation and the confusing bias of the assessor (i.e., observer selection bias) are the main obstacles in statistical HHV1-3 research. Such time-lapse case studies may be the first to build evidence of a pathway and an association between immune parameters and HHV disease.
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Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 106 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.
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Cutaneous tuberculosis (CTB) is a very rare disease and accounts for only 1-2% of cases of extrapulmonary tuberculosis (EPTB). Due to the variety of its clinical manifestations, the uncharacteristic appearance of its lesions, resembling other dermatoses in the early stages, and the limited experience of clinicians due to the rarity of CTB, diagnosis is very difficult. Particularly noteworthy is the fact that most cases of EPTB, including skin tuberculosis (TB), can be a manifestation of systemic involvement. In this paper, we present a case of an immunocompromised patient who was diagnosed with CTB almost a year after the first dermatological lesions were located on the lower extremities. At the same time, due to respiratory symptoms, a diagnosis of pulmonary TB (PTB) was made, and radiological and microbiological confirmations were obtained.
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Background: Cutaneous tuberculosis (CTB) and its paucibacillary forms are rare and difficult to diagnose, especially in immunocompromised patients with significant comorbidity. The aim of the study was to introduce the modern concept of the microbiome and diagnostic chain into clinical practice (patient-centered care) with the presentation of an atypical form of cutaneous tuberculosis with necrotizing non-healing ulcers leading to polymicrobial infection. Methods: The study material included samples from sputum, broncho-alveolar lavage and skin ulcer, taken from a patient developing cutaneous tuberculosis. The microbiological investigation was performed, and identification of the isolates was carried out using genotyping and the matrix-assisted laser desorption ionization-time of flight mass spectrometry. Results: The immunocompromised patient with humoral abnormality (plasma cell dyscrasia) and severe paraproteinemia developed multiorgan tuberculosis. Although cutaneous manifestation preceded systemic and pulmonary symptoms (approximately half a year), the mycobacterial genotyping confirmed the same MTB strain existence in skin ulcers and the respiratory system. Therefore, the infectious chain: transmission, the portal of entry, and bacterial spreading in vivo, were unclear. Microbial diversity found in wound microbiota (among others Gordonia bronchialis, Corynebacterium tuberculostearicum, Staphylococcus haemolyticus, and Pseudomonas oryzihabitans) was associated with the spread of a skin lesion. The in vitro biofilm-forming capacity of strains isolated from the wound may represent the potential virulence of these strains. Thus, the role of polymicrobial biofilm may be crucial in ulcer formation and CTB manifestation. Conclusions: Severe wound healing as a unique biofilm-forming niche should be tested for Mycobacterium (on species and strain levels) and coexisting microorganisms using a wide range of microbiological techniques. In immunodeficient patients with non-typical CTB presentation, the chain of transmission and MTB spread is still an open issue for further research.
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Tuberculose , Humanos , BiofilmesRESUMO
Background: Treatment of respiratory tract diseases with inhaled glucocorticoids is a form of therapy that has been used for many years. It shows lower potency of side effects; nevertheless, microbiome change, sinopulmonary dysbiosis, secondary immunodeficiency, and immunomodulatory effects are underestimated. The latest guideline recommendations introduce the use of empirical antibiotic and/or multiplying inhaled glucocorticoids in therapeutic intervention of asthma and chronic pulmonary obstructive disease. Aims and objectives: The aim of the study was to describe a simple, universal, and cost-effective method of microbiome analysis for clinical trials. Such a general method for monitoring pharmacovigilance should be widely available and reliable. Methods: The study material included two kinds of swabs, taken from the same mouth ulcerations of patients with asthma treated with a temporary quadruple dose of fluticasone. The microbiological investigation was performed, and identification of the isolates was carried out using the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) Biotyper. Results: The analysis of dry swab demonstrated the presence of typical oral bacteria (Neisseria spp. and Streptococcus spp.), alongside with the potentially pathogenic Actinomyces spp. and three different Rothia species, identified simultaneously: R. aeria, R. dentocariosa, and R. mucilaginosa. Although quadrupled dose of corticoids was discontinued and ulcer healing was observed, the patients required topical therapy for maintained xerostomia. Progressive systemic autoimmunity (seronegative Sjögren's syndrome with major organ involvement) was observed later. Conclusion: Topical steroids (especially in quadruple dose) require attention to safety, immunomodulation, and microbiological outcome. They showed systemic side effects: microbiome alteration, humoral (IgG) immunodeficiency, and systemic autoimmunity. Isolation of three species of Rothia from a patient with mouth ulcers after steroid therapy suggests their participation in infectious and inflammatory processes. The proposed a methodology using MALDI-TOF-MS may be a prototype approach for microbial diagnostics in clinical trials of immunomodulatory drugs.
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Lymphoid interstitial pneumonia (LIP) is a rare lymphoproliferative disease. LIP in common variable immunodeficiency (CVID) was observed in a patient during immunomodulatory therapy after progression of the disease (i.e., glucocorticoids, immunoglobulin dose escalation, and finally rituximab). Due to humoral immunodeficiency and serious serum sickness rituximab was used initially at a low dose (150 mg/m2 weekly). It resulted in temporary remission with the decrease of serum paraproteinemia, ß2-microglobulin (ß2M) and SUV decrease as well as increase of FVC. Owing to the relapse after 6-month remission in the second cycle a standard dose of rituximab was used (375 mg/m2). Therapeutic regimen with 375 mg/m2 of Rtx in optimal schedule (i.e., every 3 weeks) resulted in no longer remission but higher incidence of opportunistic infections. Finally, after another cycle of immunotherapy FVC, paraproteinemia and ß2M level normalization were observed as well as the decrease of severe splenomegaly. In laboratory and immunological progress the increase of NK and NKT cells was observed after the initial dose but the standard one caused NK cell increase only. Unfortunately, the decrease of CD19+Bcells was comparable between both doses, as was the decline of FoxP3+ regulatory T cell. On the contrary, after the low dose absolute T cell (both CD4 and CD8) number decreased but after the standard one - it normalized. Rtx (especially in low dose) brought further increase of persistent T cell activation (CD38+ T cells made up 79%). Innate immune response and the decrease of Treg are a compensatory pathways for the decrease of B and T cells. Immunodeficiency requires a different investigative approach to a immunotherapy. Clinical Trial Registration: ClinicalTrials.gov, NCT02789397.
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[This corrects the article DOI: 10.1186/s13223-017-0213-x.].
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Hepatocyte transplantation is a promising treatment for several liver diseases and can also be used as a "bridge" to liver transplantation in cases of liver failure. It was known that human fetal liver multipotent progenitor cells are capable of differentiating into liver and mesenchymal cell lineages. Hepatoblast and ductal plate/bile duct cells development from common precursor mainly occurs during the second trimester. Functional differentiation of hepatocytes in adults resembles this phenomenon. Mesenchymal stem cells migrate from bone marrow to injured sites of liver under influence of hepatocyte growth factor and chemokine signal (CXCR3 and CXCR4 stimulation). Further, small, extraportal, hepatic parenchymal cells represent hepatic stem cells, canals of Hering, and/or ductal plate remnants. Human hepatic progenitor cells (HPCs) have been shown to coexpress the hematopoietic stem cell (HSC) markers - CD117, CD34 and also CD90. Taking together these observations confirm that cell-replacement may be useful tool in hepatic injury therapy. Low expression of MHC class II in liver and secretion MHC I by hepatocytes are source of immune tolerance and allow for HLA-nonidentical transplantation. Currently, one of the major limiting factors for clinical application is the insufficient access to suitable liver cell preparations.
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Hepatócitos/transplante , Falência Hepática/cirurgia , Antígenos CD34 , Humanos , Transplante de Fígado , Proteínas Proto-Oncogênicas c-kit , Antígenos Thy-1 , Resultado do TratamentoRESUMO
RATIONALE: Lymphoid interstitial pneumonia (LIP) is a rare disease with lymphocytic infiltration of the alveolar interstitial and air spaces, sometimes classified as a clonal lymphoproliferative disease (LPD) with high prevalence in patients with immunodysregulation. Although association of mucosa-associated lymphoid tissue (MALT) lymphoma development with infectious agents has been well described, it is not so in the case of LIP. Attempts to demonstrate an infective cause by direct microbe detection have failed, but association with atypical specific immune response to opportunistic infectious agent has not been studied. PATIENT CONCERNS AND DIAGNOSES: We performed clinical, biochemical, and immunologic analysis of patients LIP that arises primarily from the common variable immune deficiency (CVID) with normal immunoglobulin class M (IgM) level and mild infectious course as a result of immunodysregulation. At the age of 13 multiple nodules, areas of consolidation were observed and LIP was confirmed by histological examination. The progression of the disease with massive splenomegaly (17â27âcm), lymphadenopathy soft tissue infiltration coincides with high standardized uptake value (SUV was 3.1-5.2), regulatory T cells decrease (CD4+25FoxP3+ level -0.02%, i.e., 8 cells per 100âµL), oligoclonal gammapathy: very high IgM (3340âmg/dL) and ß2-microglobulin (18.8âmg/L) level observed 10 years later.Immune response polarization was observed in humoral and cellular compartment -Th and Tc-dependent: 10.8% of lymphocytes are CD8high+CMV pp65-pentamer positive cells (Epstein-Barr virus-specific not observed). Specific immune response polarization correlates with negative immunofixation, light chains κ/λâ=â2.84 and narrow, but non-monoclonal T cell receptor (TCR)/ B cell receptor (BCR) repertoire. LESSONS: Taking everything into account, this case report shows that LIP is a consequence of immune-dysregulation in CVID, that is, Treg deficiency, narrow lymphocyte repertoire, and abnormal ability to respond to cytomegalovirus (CMV) antigens. It may be visualized by positron emission tomography (PET) and monitored by CMV-specific immune response, ß2-microglobulin level, and IgM paraproteinaemia, but not by immunofixation and κ/λ ratio.
Assuntos
Imunodeficiência de Variável Comum/complicações , Doenças Pulmonares Intersticiais/etiologia , Transtornos Linfoproliferativos/complicações , Adolescente , Antígenos Virais/metabolismo , Imunodeficiência de Variável Comum/imunologia , Citomegalovirus/imunologia , Feminino , Humanos , Imunoglobulina M/metabolismo , Doenças Pulmonares Intersticiais/imunologia , Linfócitos/imunologia , Transtornos Linfoproliferativos/imunologia , Bandas Oligoclonais , Paraproteinemias/etiologia , Paraproteinemias/imunologiaRESUMO
BACKGROUND: Allergic, especially anaphylactic, reactions during immunoglobulin replacement therapy are rare, but their pathophysiology and classification remain ambiguous. Recent findings show positive results of skin tests with commercially available immunoglobulins, but target antigens and responsible compounds of the tested immunoglobulins have not been strictly identified. CASE DESCRIPTION AND FINDINGS: Four adult patients with recently diagnosed common variable immunodeficiency qualified for standard subcutaneous immunoglobulin replacement therapy regimen. They had no history of receiving immunoglobulins, blood or blood product transfusions. Edema, confluent wheals and erythema were observed at the site of subcutaneous immunoglobulin infusion: typical early and late phase reaction. A transient increase in various passively transferred IgG and IgE antibodies was responsible for misleading positive outcome of the serological testing for active humoral response such as type I allergy, anti-Rh, isohemagglutinins and rheumatoid factor (RF). Although the clinical presentation was very unusual and severe, the retrospective analysis showed no isohemagglutinins, RF and IgE in the patients' serum before but it was positive after the infusion (median IgE = 18 IU/ml, RF = 8 IU/ml). Type I allergic reaction (laryngeal edema, rhinoconjuctivitis) came out at +14 days of replacement therapy when the patient visited countryside. In the second patient anaphylactic reaction was observed 5 days after ScIg administration, and only when the patient consumed peanuts. Therefore, IgE concentration was measured retrospectively in a series of commercial preparations used in the initial subcutaneous immunoglobulin replacement therapy that caused the adverse event (AE) and it was determined between 138 and 232 IU/ml (kU/l), i.e. 690-2100 IU per g of protein. Specific IgE was within a wide range from 198 (mix of food) to 2809 kUA/l (mix of grass) but many of the tested allergen-specific IgE were class 2 or 3 (i.e. 0.71-17.5 kUA/l). CONCLUSIONS: The case resembles passive cutaneous anaphylaxis and Prausnitz-Küstner reaction but clinical significance of the classical phenomena has not yet been described. This observation indicates that anaphylactic reactions during immunoglobulin replacement therapy may result from IgE or pathological IgG content. Such IgE presence was sporadically reported (34.5-105 IU/ml, i.e. 862.5-1450 IU/g of protein) in intravenous immunoglobulins that are used and monitored by healthcare professionals. In clinical practice the definition of adverse events is inadequate since individual batches of immunoglobulins come with different specificity therefore, they should be classified as transfusion products (not bioequivalents). Such new approach implies establishing (1) new control methods and strategies to ensure introduction of the safety regulations for subcutaneous home self-administration of immunoglobulins as well as (2) guidelines for the prevention of anaphylaxis in patients receiving immunoglobulins (for example peanut).
RESUMO
Benzylpenicillin (penicillin G) is a model drug for studies of drug-protein biochemical interactions. Furthermore the literature indicates that benzylpenicillin and protein conjugation is a universal phenomenon: benzylpenicillin is known to readily conjugate to proteins-serum albumin, globulin and others peptides to modify space structure and electrophoretical properties. The aim of the study was to test if the benzylpenicillin is an allosteric effector. Serum benzylpenicillin concentration in geometric progression was used. Then acid phosphatase (AcP), alanine aminotransferase (AIAT) activity and international normalized ratio (INR) was tested. Although benzylpenicillin influences AcP and INR, only AcP activity is directly proportional to the benzylpenicillin concentration (Pc): change of AcP activity was the derivative of Pc in 76% (R2 = 0.7635). Furthermore, the benzylpenicillin appears to be uncompetitive inhibitor of acid phosphatase (inhibitory constant Ki = 95.67M; Vmax = 34.843 nKat). On the contrary no effect of AIAT activity was observed. Unexpectedly INR was modified in irregular manner: in some concentrations of benzylpenicillin INR was over 25% lower than in control probe (INR approximately 0.6 vs. 0.82). Unfortunately INR > 6.5 is accepted as an early indicator of poor prognosis in fulminant hepatic failure. This phenomenon may be useful in sepsis as a prevention of disseminated intravascular coagulation (DIC). These data indicate that high benzylpenicillin concentration may be the cause of artifacts. The facts allow of interpretation that the allosteric effect of benzylpenicillin on enzymes activity is a possible mechanism of unpredictable adverse drug reactions (i.e. intolerance).