In protected soil environments, near water sources, that are disturbed either naturally or by human activity, P. brasiliensis has been epidemiologically observed (although not isolated). A known animal carrier is the armadillo. In the natural environment, the fungi are found as filamentous structures, and they develop infectious spores known as conidia.Human to human transmission has never been proven. Mechanism
Primary infection, although poorly understood due to lack of data, is thought to occur through inhalation of the conidia through the respiratory tract, after inhaling fungal conidia produced by the mycelial form of P. brasiliensis. This occurs predominantly in childhood and young adulthood, after exposure to agricultural activity. Infection may occur through direct skin inoculation, although this is rare.After inhalation into the alveoli, there is rapid multiplication of the organism in the lung tissue, sometimes spreading via the venous and lymphatic systems. Approximately 2% of people develop clinical features after the initial asymptomatic infection.The type of immune response determines the clinical manifestation of the infection, with children and HIV co-infected individuals most commonly developing the acute/subacute disseminated disease. Most of those infected develop a Type 1 T-cell (Th1) mediated immune response, resulting in fibrosing alveolitis and compact granuloma formation that control fungal replication, and latent or asymptomatic infection. It then is thought to remain dormant in residual lung lesions and mediastinal lymph nodes. A deficient Th1 cell response results in the severe forms of the disease.
Givosiran, sold under the brand name Givlaari, is a medication used for the treatment of adults with acute hepatic porphyria. Givosiran is a small interfering RNA (siRNA) directed towards delta-aminolevulinate synthase 1 (ALAS1), an important enzyme in the production of heme. The most common side effects include nausea and injection site reactions.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses
Givosiran is indicated for the treatment of adults with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood). History
In November 2019, givosiran was approved in the United States for the treatment of adults with acute hepatic porphyria (AHP).Efficacy was evaluated in ENVISION (NCT03338816), a randomized, double‑blind, placebo‑controlled, multinational trial enrolling 94 participants with acute hepatic porphyria. Participants were randomized (1:1) to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during a six‑month double‑blind period. The performance of givosiran was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Participants who received givosiran experienced 70% fewer porphyria attacks compared to patients receiving a placebo.The U.S. Food and Drug Administration (FDA) granted the application for givosiran breakthrough therapy designation, priority review designation, and orphan drug designation. The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals. References
External links
"Givosiran". Drug Information Portal. U.S. National Library of Medicine (NLM).