Normal pulmonary defense begins with the mucociliary escalator and the alveolar macrophage. When a patient inhales Histoplasma microconidia, particles small enough to reach the alveoli, resident alveolar macrophages phagocytose the spores as they would any foreign particle. Here the pathophysiology diverges from ordinary bacterial clearance. Inside the macrophage, the warmth of the human body triggers conversion of the spore to the yeast phase, and the yeast is uniquely adapted to survive intracellularly. It modulates the phagosome to blunt acidification and resist killing, so the very cell meant to destroy it becomes its sanctuary and its vehicle. Infected macrophages then travel through lymphatics to hilar and mediastinal lymph nodes and, before immunity matures, seed the bloodstream and the reticuloendothelial organs, meaning the liver, spleen, and bone marrow, in nearly every host. What happens next depends entirely on cellular immunity. Over roughly two weeks, the host mounts a T helper 1 response. Activated macrophages, marshaled by interferon gamma and tumor necrosis factor alpha, finally kill the yeast and wall off residual organisms inside granulomas. In the immunocompetent patient this containment is so...