Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited

Abstract

Summary:Various hypotheses have been proposed to explain why cytomegalovirus pneumonitis (CMV-P) is frequent and severe in bone marrow transplant patients while remaining rare and mild in HIV infected patients. One hypothesis suggests that CMV-P is an immunopathological condition that is common in bone marrow transplantation (BMT) under the effects of an abnormally regenerating immune system that reacts against CMV infected lung tissue. Such a hypothesis implicates CD4 T lymphocytes as one of the critical cell populations involved in immunopathology and also suggests that this process would be aborted by CD4 T cell deficiency in HIV infection. However, studies correlating the onset of CMV-P with lymphocyte reconstitution following BMT have revealed that CD4 cells are present at very low frequencies in the blood during the early period after transplantation when most cases of CMV-P occur. Furthermore, studies directly investigating bronchoalveolar lavage cell types during episodes of CMV-P in BMT patients have also failed to demonstrate significant CD4 involvement and, instead, have emphasized a predominance of natural killer (NK) cells and CD8 cells. These findings serve as the basis for questioning the validity of a CD4-driven immunopathological model of CMV-P in BMT. On the other hand, a variety of experimental and clinical observations support the protective role of CMV-specific CD3 + CD8 T lymphocytes against CMV in both immunocompetent individuals and BMT patients. In a murine BMT model, adoptive transfer of syngeneic BM cells was associated with massive increases in lung CD8 cells which resulted in the resolution rather than the exacerbation of existing CMV-P. In the light of these findings a more plausible hypothesis for CMV-P in BMT is that during the early period after transplantation adequate protective CD8 responses are absent and an uncontrolled CMV proliferation is allowed to develop. Once a critical viral load is reached a cytokine 'storm' may be triggered in the lung tissue that aggravates direct CMV-associated cytopathic

Murine Model of Interstitial Cytomegalovirus Pneumonia in Syngeneic Bone Marrow Transplantation: Persistence of Protective Pulmonary CD8-T-Cell Infiltrates after Clearance of Acute Infection

“…Since then, the literature on clinical CMV-IP has been filled with case reports that interpret single clinical observations in favor or disfavor of Grundy's immunopathogenesis hypothesis. Rebuttal came primarily from clinicians who outlined in detail that the immunopathological characteristics ascribed to mCMV pneumonia do not apply to most cases of hCMV pneumonia (4,29). Specifically, Morris (29) concluded that the murine model is not valid.…”

Role for Tumor Necrosis Factor Alpha in Murine Cytomegalovirus Transcriptional Reactivation in Latently Infected Lungs

“…Interstitial pneumonia is a frequent manifestation of CMV disease with a high fatality rate after lung and heart-lung transplantation and after allogeneic BMT (6,38,54), suggesting that recurrent virus may directly originate from the lungs due to reactivating transcriptional signals induced by cellular stress conditions and/or cytokines associated with transplantation procedures and host-versus-graft or graft-versus-host immunological responses.…”

Human cytomegalovirus infection and antiviral immunity in septic patients without canonical immunosuppression

“…Quantitative viral load is correlated with the development of end-organ-disease caused by cytopathic eVects following viral replication. However, HCMV associated disease may also occur due to indirect eVects of infection which are caused mostly by antiviral immunity of patients with low viral load (e.g., patients with septic shock) [2,49]. As outlined in this model, reactivation is stimulated independent from immunosuppression whereas the grade of viral dissemination (viral load) and the risk of end-organ-disease are inXuenced by the immune status of the host.…”

“…The indirect eVects of HCMV infection are very heterogeneous and even less characteristic from the clinical point of view [2,49]. The diagnosis of indirect eVects is diYcult to achieve because clear-cut criteria are missing.…”