Pulmonary Cryptococcosis in Apparently Immunocompetent Hosts: Host Susceptibility, Occult Immunodeficiency and Clinical Implications.

Pulmonary cryptococcosis (PC) in apparently immunocompetent hosts-now the majority of non-HIV cases in Asia-cannot be explained by the traditional opportunistic infection paradigm. Three epidemiological observations point toward occult immune susceptibility: familial clustering documented in multiple case reports and small family studies despite shared environmental exposure, normal routine immunological screening, and species-specific infection patterns between Cryptococcus neoformans and Cryptococcus gattii. We propose a three-layer framework: upstream genetic variants in pattern recognition, Fcγ receptor, complement-lectin, and macrophage-regulatory loci (Layer 1) act in concert with intermediate immune phenotypes (Layer 2)-the genetically influenced IL-17/Th17 axis and IgG2 subclass deficiencies, and acquired anti-GM-CSF neutralising autoantibodies-that are proposed to converge on alveolar macrophage dysfunction and defective pulmonary fungal clearance (Layer 3). The three Layer 2 phenotypes differ substantially in evidence strength: anti-GM-CSF autoantibodies have reached clinical validation; IgG2 deficiency remains a mechanistic hypothesis; and IL-17/Th17 deficiency is supported by a single unreplicated study and should be treated as preliminary. This framework is hypothesis-generating, derived from candidate-gene studies, limited immunophenotyping data, and animal models; it has not been validated by genome-wide association studies or prospective functional research, and its clinical value requires confirmation by higher-quality evidence.