ABSTRACT
Members of the Cryptococcus gattii species complex are notorious causes of cryptococcosis as they often cause severe, life-threatening infections. Here we describe a case of a severe disseminated C. deuterogattii infection in a previously healthy patient who was initially treated with amphotericin B, 5-fluorocytosine and fluconazole, which led to a good neurological response, but the infection in the lungs remained unaltered and was not completely resolved until switching the antifungal therapy to isavuconazole. The infection was likely acquired during a one-month stay at the Azores Islands, Portugal. Environmental sampling did not yield any cryptococcal isolate; therefore, the source of this apparent autochthonous case could not be determined. Molecular typing showed that the cultured C. deuterogattii isolates were closely related to the Vancouver Island outbreak-genotype.
Subject(s)
Cryptococcosis , Cryptococcus gattii , Antifungal Agents/therapeutic use , Cryptococcosis/diagnosis , Cryptococcosis/drug therapy , Cryptococcus gattii/genetics , Genotype , Humans , Nitriles/therapeutic use , Pyridines , Salvage Therapy , TriazolesABSTRACT
BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.
Subject(s)
Alleles , Gene Frequency , Immunologic Deficiency Syndromes/genetics , Mosaicism , Family , Female , High-Throughput Nucleotide Sequencing , Humans , Immunologic Deficiency Syndromes/immunology , MaleABSTRACT
Después de varias décadas de investigación en biología celular y molecular, se ha logrado un gran avance en el conocimiento de la patogenia del asma. Hoy se conoce, en gran parte, la secuencia de las reacciones biológicas que ponen en marcha los rasgos fenotípicos del asma: la obstrucción al flujo aéreo, la inflamación y la hiperrespuesta bronquial. Este conocimiento ha permitido señalar a la inmunoglobulina (Ig) E como una de las dianas a neutralizar, ya que es un componente inicial en los complejos procesos inflamatorios del asma. El omalizumab, un anticuerpo monoclonal humanizado, consigue bloquear la IgE libre y mejorar enfermedades alérgicas como la rinitis y el asma. En esta revisión, se analizan los fundamentos del tratamiento con anticuerpos monoclonales y se actualiza la acción del omalizumab desde el punto de vista farmacológico y clínico (AU)
After several decades of research in cell and molecular biology, a great step forward has been made in our knowledge of the pathogenesis of asthma. Today, the sequence of biological reactions that lead to the phenotypic features of asthma are largely known: airflow obstruction, inflammation and bronchial hyperreactivity. This knowledge has allowed us to identify IgE as one of the targets to be neutralized as it is an initial component in the complex inflammatory processes of asthma. Omalizumab, a humanized monoclonal antibody, blocks free IgE and has a beneficial effect on allergic diseases such as rhinitis and asthma. The present review analyzes the basic principles of therapy with monoclonal antibodies and provides an update of the action of omalizumab from the pharmacological and clinical points of view (AU)
