**6. Clinical involvement**

It is very important to establish an early diagnosis based on clinical vigilance, contemporary diagnostic laboratory support (immunology and biopsy) for the pulmonary-renal syndrome in order to avoid the severe consequences of rapid and irreversible loss of renal function or from severe pulmonary hemorrhage. Both can be avoided by appropriate initial immunosup‐ pressive treatment [60]. In pulmonary-renal syndrome better understanding of interorgancrosstalk is of utmost importance, as current clinical care is many times limited to preventive and supportive measures [24].

The basic immunomodulatory mechanisms of IVIG in autoimmune and inflammatory diseases are twofold. One is its action on humoral immunity and the second involves mechanisms of cell-mediated immunity. Both mechanisms interdependently involve modulation of expression and function of Fc receptors, interference with complement activation and the cytokine network, provision of antiidiotypic antibodies, modulation of dendritic cells, T and B-cell activation and differentiation and their effector functions [75]. Analogous to normal circulating immunoglobulins intravenous immunoglobulins have also anti-inflammatory

Immunological Mechanisms and Clinical Aspects in Pulmonary-Renal Syndrome: A Review

http://dx.doi.org/10.5772/55181

85

According to BSR guidelines [76] IVIG may be considered as an alternative therapy in patients with refractory disease or in patients for whom conventional therapy is contraindicated, for example, in the presence of infection, in severely ill patients or in pregnancy (grade of recommendation B). In the management of refractory vasculitis it is important to identify causes of the vasculitis, such as, intercurrent infection or malignancy. In many European countries use of IVIG is limited for treatment of primary immune deficiencies where such treatment has been known to be life saving. Even though use of intravenous immunoglobulins in inflammatory diseases has been increased and a recent literature search revealed more than 150 off-label usages of IVIG, which included 6781 patients in clinical trials and 362 patients in

Until present immunological mechanisms of immunomodulatory effect of IVIG are not clearly known. In such context a question of adequate dosage appears in the relation of cost/benefits of unlabeled treatment. It is supposed that patients who respond to high-dose IVIG therapy would probably also respond to much lower doses, in many rheumatological indications vasculitides not excluded. In addition to economic reasons, low-dose regimen would likely help to reduce treatment related side effects. The lack of validated and generally accepted outcome measures as well as prospective clinical studies makes it difficult to compare the effect

Pulmonary-renal syndrome is a complex and heterogenous clinical picture involving rapid progressive glomerulonephritis and pulmonary capillaritis based on inflammation and necrosis of vessel wall. Morphological changes of pulmonary-renal syndrome are consequences of immunologically mediated processes and the unconctrolled derangement of

The diagnostic procedure should focus on recognizing the earliest phases of the initiation and progression of the inflammation through a reliable panel of immunological and organ specific functional markers. In the near future novel diagnostic tools should be introduced in the diagnosis and differential diagnosis of pulmonary-renal syndrome, including gene expression

Traditional clinical approach to treat pulmonary-renal syndrome was divided among rheumatologists, nephrologist and pneumologists but the improving knowledge of its

the immune system could cause multiorgan dysfunction and fatal outcome.

profiles, cytokine profiles, markers of oxidative stress and many others.

properties modulating systemic inflammation during various inflammatory states.

case reports [77].

**7. Conclusions**

of different interventions in different cases [78].

In main clinical entities (Goodpasture´s disease, ANCA associated vasculitis, SLE-associated vasculitis) induction and maintenance immunosupression is achieved by steroids and cyclophosphamide. Intensive plasma exchange to remove pathological antibodies, proinflammatory cytokines, complement compounds and factors of coagulation from circulation is beneficial for patients with pulmonary hemorrhage and severe kidney disease. Except of antibody removal, plasma exchange may have also other immunoregulatory effects and could potentiate the effects of immunosuppressive drugs [61]. Exchange procedures have beneficial effect on long-term renal recovery [62, 63]. Severe renal function impairment requires haemodialysis and progression to end stage renal failure renal replacement therapy is required [17]. In case of inevitable ICU admission supportive care is important as well.

During immunosuppressive regimes nosocomial infection used to be a common complication associated with high mortality [64]. Therefore minimizing the risk of infection has the highest of high priority. Patients with pulmonary-renal syndrome are often hypotensive because of a combination of dehydration, haemorrhage and systemic inflammatory response and may therefore require inotropic support [28]. Endotracheal intubation, tracheostomy, lung protective ventilation, transfusion and anticoagulation may be also necessary.

Antioxidant effect of N-acetylcystein published by Fernández-Fernández and Sesma [65] in one patient with WG and also our unpublished experience suggests clinical improvement of systemic inflammation. Administration of NAC is based on two significant studies: the IFIGENIA trial in 2005 [66] (Idiopathic Pulmonary Fibrosis International Group Exploring Nacetylcysteine I Annual study) and the study by Guilpain et al. [42]. Both studies have reported that NAC significantly reduced the activation of MPO and improved the survival of endothelial cells. In a recent experimental study by Lee et al. [67] continuous infusion of NAC attenuated inflammatory response and acute lung and kidney injury after hemorrhagic shock in rats. This result supports the clinical experience.

Some recent studies are focused on anti-TNF molecules, anti-B-cells blockers [68], anti-BlyS [69], anti-IL5 molecules [70], antithymocyte globulin [71], blockers of costimulatory molecules [72], tyrosine-kinase inhibitors [73] and proteasome inhibitors [74]. The results of these studies are sometimes controversial but there is a real hope that they will provide useful knowledge in the near future.

Many questions still remain unanswered also in the use of intravenous immunoglobulins (IVIG). Such treatment should be considered as an effective regimen in many "off label" indications particularly in cases where standard immunosuppressive regimes fail or could be harmful. Despite some evidence of efficacy, dosage and timing of IVIG therapy, as well as the question of its costs/benefit ratio still remain insufficiently documented and controlled trials with definitive conclusions for clinical indications are needed.

The basic immunomodulatory mechanisms of IVIG in autoimmune and inflammatory diseases are twofold. One is its action on humoral immunity and the second involves mechanisms of cell-mediated immunity. Both mechanisms interdependently involve modulation of expression and function of Fc receptors, interference with complement activation and the cytokine network, provision of antiidiotypic antibodies, modulation of dendritic cells, T and B-cell activation and differentiation and their effector functions [75]. Analogous to normal circulating immunoglobulins intravenous immunoglobulins have also anti-inflammatory properties modulating systemic inflammation during various inflammatory states.

According to BSR guidelines [76] IVIG may be considered as an alternative therapy in patients with refractory disease or in patients for whom conventional therapy is contraindicated, for example, in the presence of infection, in severely ill patients or in pregnancy (grade of recommendation B). In the management of refractory vasculitis it is important to identify causes of the vasculitis, such as, intercurrent infection or malignancy. In many European countries use of IVIG is limited for treatment of primary immune deficiencies where such treatment has been known to be life saving. Even though use of intravenous immunoglobulins in inflammatory diseases has been increased and a recent literature search revealed more than 150 off-label usages of IVIG, which included 6781 patients in clinical trials and 362 patients in case reports [77].

Until present immunological mechanisms of immunomodulatory effect of IVIG are not clearly known. In such context a question of adequate dosage appears in the relation of cost/benefits of unlabeled treatment. It is supposed that patients who respond to high-dose IVIG therapy would probably also respond to much lower doses, in many rheumatological indications vasculitides not excluded. In addition to economic reasons, low-dose regimen would likely help to reduce treatment related side effects. The lack of validated and generally accepted outcome measures as well as prospective clinical studies makes it difficult to compare the effect of different interventions in different cases [78].
