Knowledge of the diverse clinical, pathologic, and radiographic presentations of IR-pneumonitis may inform patient management and lead to improved patient outcomes. with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically unique from other types of lung toxicity Philanthotoxin 74 dihydrochloride and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this Rabbit polyclonal to GAPDH.Glyceraldehyde 3 phosphate dehydrogenase (GAPDH) is well known as one of the key enzymes involved in glycolysis. GAPDH is constitutively abundant expressed in almost cell types at high levels, therefore antibodies against GAPDH are useful as loading controls for Western Blotting. Some pathology factors, such as hypoxia and diabetes, increased or decreased GAPDH expression in certain cell types setting are also highlighted. pneumonia (PJP) in HIV-negative patients requiring continuous, high-dose steroid therapy remains a clinical challenge, as the dose of steroids that delimits high dose and the period of steroids that defines continuous have not been clearly established [51C56]. Adding to this conundrum is the fact that this predilection for PJP may vary among this patient populace, rendering some patients, such as those with hematologic malignancies and those who have undergone stem cell and solid organ transplantation, more susceptible to PJP at relatively lower doses of steroids [54]. We, therefore, recommend PJP prophylaxis in our malignancy patient population throughout the duration of systemic corticosteriod therapy. The addition of TNF- Philanthotoxin 74 dihydrochloride blocking brokers may increase the susceptibility to severe infections, including tuberculosis [57, 58]. Accordingly, baseline screening for tuberculosis should be performed on all patients before initiating TNF- inhibiting brokers. The need for gastrointestinal prophylaxis may also be appropriate in some patients undergoing prolonged steroid therapy. Clinical improvement is generally observed within the first 48C72 h of treatment, beyond which pneumonitis is considered steroid refractory. In patients with high grade and/or steroid refractory disease, additional immunosuppressive therapy with azathioprine, mycophenolate mofetil, Philanthotoxin 74 dihydrochloride cyclophosphamide, and/or tocilizumab may be considered. However, the clinical impact of augmented immunosuppressive therapies and optimal dose, period, and timing of these agents have not been analyzed [9, 59]. Evidence favoring the use of intravenous immunoglobulin (IVIG) in the management of steroid refractory high-grade pneumonitis has also emerged in recent literature [60]. These studies require validation in larger prospective trials. The use of immunosuppressive therapies in the management of ICI-related toxicities has prompted concerns regarding the potential for systemic corticosteroids to interfere with the therapeutic efficacy of immune checkpoint blockade. None of these issues has been substantiated in any clinical Philanthotoxin 74 dihydrochloride data. In two individual studies, overall malignancy treatment outcomes among patients receiving prolonged immunosuppression for anti-CTLA-4 induced IrAEs were not statistically different compared to patients not requiring immunosuppressive therapies [61, 62]. Twenty-five to thirty-three percent of patients may experience recurrent pneumonitis with drug re-challenge after initial resolution of signs and symptoms. Resumption of the same ICI agent after resolution of the initial IrAE unprovoked pneumonitis, occurring despite drug discontinuation has also been reported. Rapid steroid tapers (less than 5 weeks) may increase the risk of recurrent events, which tend to be earlier in onset than the first event and more severe [17, 63C65]. Life-threatening toxicities, particularly those involving the lungs, heart, or central nervous system, are considered complete contraindications to drug re-challenge. Fatal ICI-related pneumonitis is usually, fortunately, rare (0.3%) and varies significantly between treatment regimens. In a recent large multicenter retrospective review of ICI-associated fatalities, neurologic and cardiac events associated with CTLA-4 harmful effects accounted for nearly half of all deaths. By contrast, the majority of patients who succumbed to pneumonitis had been treated with PD-1/PD-L1 blockers or PD-1/CTLA-4 combinations [66]. IrAE: sarcoid-like reactions Sarcoid-like reactions are uncommon IrAEs, which have been observed among 5C7% of patients following both CTLA-4 and PD-1 blockers. sarcoid-like reactions as well as exacerbation of pre-existing disease have been reported in association with both classes of ICI therapies [15, 47, 67, 68]. Enlarged mediastinal lymph nodes may occur in isolation or Philanthotoxin 74 dihydrochloride in association with bilateral upper- or middle-lobe predominant consolidations or ground glass opacities (Fig. ?(Fig.4).4). Concomitant sarcoid-like reactions involving the skin and kidneys have also been reported. Biopsies of enlarged lymph nodes or the lung parenchyma are required to exclude competing diagnoses such as cancer progression. Elevated CD4:CD8 ratios and overexpression of TH17 on BAL fluid with biopsy.