Pathogenesis of pulmonary aspergillosis. Granulocytopenia versus cyclosporine and methylprednisolone-induced immunosuppression.

Abstract

Patients with chemotherapy-induced granulocytopenia for neoplastic diseases and those receiving cyclosporin A plus corticosteroids for prevention and treatment of organ transplant rejection are two immunologically distinct patient populations with high risks for development of invasive pulmonary aspergillosis. In order to compare the pathogenesis of aspergillosis in these two high-risk populations and to further characterize the role of cyclosporin A in development of pulmonary aspergillosis, we studied the patterns of infection and inflammation in two clinically applicable rabbit models of invasive pulmonary aspergillosis. There were striking differences in the patterns of infection and inflammation of invasive pulmonary aspergillosis according to the type of underlying immune defect. Among rabbits challenged with the same intratracheal inoculum, there was a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% survival in rabbits immunosuppressed with cyclosporin A plus methylprednisolone (CsA+MP). Lesions of pulmonary aspergillosis in granulocytopenic rabbits consisted predominantly of coagulative necrosis, intraalveolar hemorrhage, and scant mononuclear inflammatory infiltrate. By comparison, pulmonary foci in rabbits immunosuppressed by CsA+MP consisted mainly of neutrophilic and monocytic infiltrates, inflammatory necrosis, and scant intraalveolar hemorrhage. There was extensive infiltration by hyphae with angioinvasion in granulocytopenic rabbits, whereas conidia in various stages of germination predominated in CsA+MP treated animals in which there was a paucity of hyphae or angioinvasion. Extrapulmonary disease predominated in granulocytopenic rabbits. Methylprednisolone was the major immunosuppressive drug in rabbits treated with CsA+MP. Cyclosporin A alone did not increase the progression of pulmonary aspergillosis and did so only when used chronically with methylprednisolone.

Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

“…In the former, the immune response is characterised by an important influx of neutrophils into the lung parenchyma and interleukin-10 production [59]; histological analyses demonstrate large foci of pneumonia, exudative bronchiolitis with bronchial and alveolar destructions, and haemorrhagic necrosis with neutrophil infiltration. In contrast, only a few Aspergillus are observed and are mostly in their nongerminated form when present [59,69]. Thus, in comparison with neutropenic animals, steroid-treated animals seem to die from an excessive host response rather than from a fungal invasion.…”

Extrapulmonary Aspergillus infection in patients with CARD9 deficiency

“…Similar necrosis without neutrophil infiltration was seen in the infected mesenteric lymph node of patient 1 (Supplemental Figure 4). Because aspergillosis in nonneutropenic mice and humans is accompanied by robust neutrophilic tissue accumulation (28,30,31), the lack of tissue neutrophil infiltration in CARD9 deficiency despite normal peripheral neutrophil numbers represents a suboptimal innate immune response and is consistent with a defect in neutrophil recruitment from the blood into the Aspergillus-infected tissue.…”

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…For example, a study showed a 100% mortality rate in granulocytopenic rabbits given ara-C but a 100% survival rate in those given CsA and methylprednisolone. 90 In another, A. fumigatus model, survival rates were significantly higher and survival durations were significantly longer in mice receiving low-dose (1 mg/ kg/day) intravenous tacrolimus but not CsA. Also, researchers observed numerous Aspergillus hyphae in the brains and kidneys of CsA-treated mice but no hyphae in the brains of tacrolimustreated animals; it is unclear if these observations are directly related to an in vitro drug effect and/or from effects on the host…”