Anatomic Pathology / MICROVASCULAR INJURY AND EVOLUTION OF IDIOPATHIC PULMONARY FIBROSIS

Interstitial lung disease compatible with idiopathic pulmonary fibrosis (IPF) developed in 19 previously healthy patients. Although interstitial and/or honeycomb parenchymal fibrosis was present in all, there were patchy areas of paucicellular septal capillary injury along with corroborative direct immunofluorescent evidence of a humorally mediated microvascular injury syndrome. Significantly elevated factor VIII levels were seen in 17 of 18 patients tested. Antiphospholipids were present in all 18 patients tested, comprising antibodies of phosphatidylethanolamine, beta-2 glycoprotein, phosphatidylcholine, and/or phosphatidylserine. Anti-Ro and/or anti-ribonucleoprotein (RNP) antibodies were seen in 4 patients. Serologic evidence of infection with cytomegalovirus (CMV) was found in 9 patients and parvovirus B19 (B19) in 9 patients; 1 patient was not tested. Molecular studies revealed B19 DNA in 6 of 6 B19-seropositive patients. In situ hybridization studies revealed CMV RNA in pulmonary cells in patients with serologic evidence of active CMV infection despite the absence of cytopathic changes typical of CMV infection. Antiphospholipid antibodies, antiendothelial cell antibodies, and/or endotheliotropic viral infections related to B19 and CMV may be of pathogenetic importance to the evolution of IPF. This report underscores the potential importance of microvascular injury in the evolution of IPF. Idiopathic pulmonary fibrosis (IPF) encompasses a distinctive subgroup of interstitial pneumonias associated with substantial pulmonary fibrosis for which the cause is obscure.1,2 The current classification scheme recognizes 4 distinct subtypes of IPF: usual interstitial pneumonitis (UIP), desquamative interstitial pneumonitis, acute interstitial pneumonitis, and nonspecific interstitial pneumonitis (NSIP). Most cases fall into the UIP and NSIP categories.1,2 The morphologic criteria for each of these entities are well defined.1 Nevertheless, the pathogenesis leading to the parenchymal changes remains elusive, and the mechanisms evoking a state of parenchymal change categorized as UIP, desquamative interstitial pneumonitis, acute interstitial pneumonitis, or NSIP are claimed to be largely unidentifiable.1 We describe the clinical, laboratory, and lung biopsy findings of 19 patients in whom pulmonary fibrosis developed in the absence of significant extrapulmonary disease; they were all categorized as having IPF. Open lung biopsy material available for all patients revealed morphologic changes compatible with UIP or NSIP according to the currently accepted criteria; however, in each case, there was septal capillary injury along with direct immunofluorescent (DIF) findings compatible with an immune-based microvascular injury syndrome. We explored the pathogenetic basis for the microvascular changes and herein describe the potential role of microvascular injury in the evolution of IPF. Materials and Methods