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This indicates that they possess certain proinflammatory effects that may be the cause of some of its adverse effects&#44; such as pneumonitis&#44; which is the inflammation of lung tissue&#46;<span class="elsevierStyleSup">2</span> Table 1 shows the main studies on pneumonitis in patients treated with mTOR inhibitors&#46;<span class="elsevierStyleSup">6-10</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">INCIDENCE</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A lot of cases of pneumonitis due to mTOR inhibitors have been reported since they were first marketed&#44; most associated with sirolimus treatment&#44; although cases have also been described that involve everolimus and temsirolimus&#46;<span class="elsevierStyleSup">3&#44;11</span> The incidence of this adverse effect was estimated at 4-11&#37;&#46;<span class="elsevierStyleSup">6&#44;8&#44;9</span> However&#44; the recent introduction of this group of drugs&#44; specifically everolimus and temsirolimus as antineoplastic treatment&#44; provides more case studies and suggests that the incidence is probably higher&#46; Given that cancer patients periodically undergo computed axial tomography &#40;CAT&#41;&#44; we have been able to observe pulmonary abnormalities suggestive of pneumonitis in asymptomatic patients&#46; The overall incidence of pneumonitis for mTOR inhibitors in this type of patient&#44; symptomatic or not&#44; seems to be over 20&#37;&#46;<span class="elsevierStyleSup">11&#44;12</span> Mortality associated with pneumonitis due to sirolimus and everolimus is estimated at around 5&#37;&#46;<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">The overwhelming majority of cases described occurred in kidney transplant patients&#44; since it is in this type of transplantation that mTOR inhibitors were first administered&#46; Nevertheless&#44; cases of pneumonitis have also been reported in liver and heart transplant patients who presented similar characteristics&#46;<span class="elsevierStyleSup">6&#44;13&#44;14</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CLINICAL PRESENTATION</span></p><p class="elsevierStylePara">Pneumonitis caused by mTOR inhibitors has heterogeneous clinical manifestations and may begin with fever&#44; fatigue&#44; coughing and dyspnoea&#44; nonspecific signs and symptoms&#44; which does not facilitate diagnosis&#46; It may appear at the beginning or after several years of treatment&#46; In many cases&#44; the chest X-ray did not show abnormalities&#44; which were only observed in CAT scans&#46; The most common findings in CAT scans were ground glass opacities&#44; although additional peripheral infiltrates and patterns of bronchiolitis obliterans with organising pneumonia have also been observed&#46; In some cases&#44; signs of pulmonary fibrosis were also observed&#46; Diagnosis is difficult and tends to be made by excluding other causes&#44; such as infections&#44; autoimmune diseases or toxicity due to other products&#46;<span class="elsevierStyleSup">8&#44;9&#44;15&#44;16</span> Clinical improvement upon discontinuation of the drug can confirm the diagnosis&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The pathophysiology of pneumonitis associated with mTOR inhibitors is not very well understood&#46; Direct toxicity by drugs&#44; immunological toxicity or a combination of both mechanisms has been proposed&#46; In lung biopsies of affected patients&#44; lymphocytic alveolitis has been observed&#44; which favours the immune mediated toxicity hypothesis&#46; However&#44; the rapid response to drug discontinuation favours the direct toxicity hypothesis&#46;<span class="elsevierStyleSup">2&#44;15-17</span></p><p class="elsevierStylePara">Interestingly&#44; it has been observed that patients who began post-transplant immunosuppression directly with mTOR inhibitors have a lower incidence of pneumonitis than those who started treatment with calcineurin inhibitors and subsequently changed to sirolimus or everolimus&#46; The reason for this lower incidence is not known&#44; but some authors suggest that it may be due to differences in renal function&#44; since an increased incidence of pneumonitis in patients with abnormal renal function has been observed&#46;<span class="elsevierStyleSup">9&#44;18</span> Sometimes the reason for switching from calcineurin inhibitors to mTOR inhibitors is nephrotoxicity due to the former&#46; Therefore&#44; when switching to treatment with mTOR inhibitors&#44; patients typically present worse renal function&#46; This hypothesis is not very plausible since sirolimus and everolimus are metabolised by CYP3A4 and their renal excretion is negligible&#46;<span class="elsevierStyleSup">4&#44;5</span> However&#44; other mechanisms by which renal function modifies tolerance to mTOR inhibitors cannot be discarded and it has been questioned whether a metabolite of renal elimination may be the cause of symptoms&#46;</p><p class="elsevierStylePara">The potential relationship between the occurrence of pneumonitis and plasma drug concentrations has also been researched&#46; In the sirolimus efficacy studies published to date&#44; different target treatment concentrations have been used&#46; While some authors have used predose concentrations of 5-10ng&#47;ml&#44; others opt for 10-15ng&#47;ml or greater&#44; depending on whether or not the treatments were combined with calcineurin inhibitors&#44; as well as the post-transplant period&#46;<span class="elsevierStyleSup">19</span> In the study by Weiner et al&#46;&#44; although in most cases of pneumonitis&#44; sirolimus concentrations were higher than both treatment margins &#40;mean 16&#46;7ng&#47;ml&#41;&#44; cases were also observed with concentrations below 10ng&#47;ml&#46; As such&#44; plasma concentrations within therapeutic margins do not allow pneumonitis caused by mTOR inhibitors to be ruled out&#46;<span class="elsevierStyleSup">9-15</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TREATMENT</span></p><p class="elsevierStylePara">The first measure to be taken in a potential case of pneumonitis due to mTOR inhibitors is the suspension of the drug involved in the process&#46; This eliminates symptoms completely in many cases&#46;<span class="elsevierStyleSup">8&#44;9&#44;20&#44;21</span> The administration of high doses of corticosteroids is also advised&#44; although no recommended dose has been established&#46; It is necessary to bear in mind that most of these patients are already treated with low levels of corticosteroids to avoid graft rejection&#46; However&#44; in some case series&#44; patients have evolved favourably without having received corticosteroids&#46;<span class="elsevierStyleSup">9</span> Therefore&#44; some authors suggest administering corticosteroids only in the most serious cases&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">Likewise&#44; cases have been described in which the reduction of the mTOR inhibitor dose has been sufficient to eliminate pneumonitis&#46;<span class="elsevierStyleSup">3</span> As an alternative to sirolimus discontinuation&#44; switching to everolimus has also been proposed and has yielded good results in several cases&#46; Everolimus is a more hydrophilic drug than sirolimus&#44; making it easier to eliminate from the body and less likely to cause hypersensitive reactions&#46;<span class="elsevierStyleSup">10&#44;22</span> It seems that it presents a lower incidence of pneumonitis with respect to sirolimus<span class="elsevierStyleSup">3</span>&#44; although some studies have not found any differences&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In solid organ transplant patients who are treated with mTOR inhibitors and have respiratory symptoms&#44; after ruling out infection and other causes&#44; we should suspect iatrogenic pneumonitis&#44; in order that the appropriate treatment may begin as soon as possible&#58; discontinuation or a change of immunosuppressive treatment and addition of corticosteroid treatment if necessary&#46;</p><p class="elsevierStylePara">Given that pneumonitis due to mTOR inhibitors is more common in patients with renal failure and that cases have been described in which dose reduction eliminates clinical manifestations&#44; we may be led to believe that this toxicity is dependent on concentrations of the drug in the body&#46; However&#44; patients with plasma concentrations within the treatment margin have presented this complication&#46; Details of the pathophysiology of this disease are still unknown&#44; but for drugs with a high volume of distribution&#44; one possibility would be specific accumulation of the mTOR inhibitor or its metabolites in the lung parenchyma&#46; This could explain the presence of serum concentrations within the therapeutic interval in patients with pneumonitis&#46;</p><p class="elsevierStylePara">It seems that the mTOR inhibitors&#44; although they have the same mechanism of action&#44; seem to differ in terms of their adverse effects&#44; with there being greater tolerance to everolimus&#46; However&#44; there is still a lack of data to confirm this&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11439&#95;16025&#95;46549&#95;en&#95;t111439&#46;jpg" class="elsevierStyleCrossRefs"><img src="11439_16025_46549_en_t111439.jpg" alt="Main studies on pneumonitis in patients treated with mTOR inhibitors"></img></a></p><p class="elsevierStylePara">Table 1&#46; Main studies on pneumonitis in patients treated with mTOR inhibitors</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n&#58;</span> Los inhibidores de mTOR &#40;del ingl&#233;s <span class="elsevierStyleItalic">mammalian target of rapamycin</span>&#41;&#44; sirolimus y everolimus&#44; utilizados como tratamiento inmunosupresor en el trasplante de &#243;rganos s&#243;lidos&#44; pueden producir efectos adversos graves&#44; como la neumonitis intersticial&#46; <span class="elsevierStyleBold">Incidencia y presentaci&#243;n cl&#237;nica&#58;</span> La incidencia de neumonitis intersticial se ha estimado entre el 4 &#37; y el 11 &#37;&#44; aunque podr&#237;a ser mayor&#46; La mayor&#237;a de los casos publicados se ha producido en pacientes trasplantados renales en tratamiento con sirolimus&#46; La presentaci&#243;n cl&#237;nica es heterog&#233;nea&#44; lo que dificulta el diagn&#243;stico&#46; Se acostumbra a observar alteraciones en la tomograf&#237;a axial computarizada tor&#225;cica&#44; como opacidades en vidrio deslustrado&#46; La fisiopatolog&#237;a es poco conocida&#46; Sin embargo&#44; se ha observado una mayor incidencia en pacientes con funci&#243;n renal alterada y en pacientes que hab&#237;an recibido inhibidores de calcineurina previamente&#46; La relaci&#243;n entre aparici&#243;n de neumonitis y concentraciones plasm&#225;ticas de inhibidores de mTOR no est&#225; bien definida&#46; <span class="elsevierStyleBold">Tratamiento&#58;</span> La suspensi&#243;n del f&#225;rmaco y la administraci&#243;n de dosis altas de corticoides parecen ser efectivos&#46; Otras alternativas terap&#233;uticas&#44; aunque m&#225;s discutidas&#44; son la reducci&#243;n de la dosis del inhibidor de mTOR y el cambio de sirolimus a everolimus&#46; <span class="elsevierStyleBold">Conclusi&#243;n&#58;</span> Se debe sospechar de neumonitis iatrog&#233;nica en pacientes trasplantados en tratamiento con inhibidores de mTOR y con s&#237;ntomas respiratorios&#46; Faltan datos concluyentes en cuanto a estrategias de tratamiento&#46; Parece que everolimus podr&#237;a ser mejor tolerado que sirolimus&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">Introduction&#58;</span></span><span class="elsevierStyleItalic"> mTOR &#40;<span class="elsevierStyleItalic">mammalian target of rapamycin</span>&#41; inhibitors sirolimus and everolimus&#44; used as immunosuppressants in solid organ transplantation&#44; may cause severe adverse effects&#44; such as interstitial pneumonitis&#46; <span class="elsevierStyleBold">Incidence and clinical presentation&#58;</span> The estimated incidence of interstitial pneumonitis is 4-11&#37; although it may be higher&#46; Most reported cases have occurred in renal transplant recipients treated with sirolimus&#46; Clinical presentation is heterogeneous&#44; which makes diagnosis difficult&#46; Abnormalities&#44; such as ground glass opacities&#44; are often found in computerised axial tomography scans of the chest&#46; Physiopathology is not well-known&#46; However&#44; patients with abnormal renal function and those with previous calcineurin inhibitor treatment display a higher incidence&#46; The relationship between pneumonitis and mTOR inhibitor plasma concentrations is not well defined&#46;&#160;<span class="elsevierStyleBold">Treatment&#58;</span> Drug discontinuation and administration of high doses of corticosteroids seems to be an effective treatment&#46; mTOR inhibitor dose reduction and replacing sirolimus with everolimus are other alternatives&#44; but they are still under discussion&#46;&#160;<span class="elsevierStyleBold">Conclusion&#58;</span> Iatrogenic pneumonitis must be suspected when a transplant recipient being treated with mTOR inhibitors presents respiratory symptoms&#46; There is lack of conclusive data on treatment strategies&#46; It appears that everolimus may be tolerated better than sirolimus&#46;</span></p>"
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Interstitial pneumonitis as an adverse reaction to mTOR inhibitors
Neumonitis intersticial como reacción adversa a inhibidores de mTOR
Gloria Molas Ferrera, Gloria Molas-Ferrerb, Dolors Soy Munera, Dolors Soy-Munerb, Helena Anglada Martíneza, Helena Anglada-Martínezb, Gisela Riu Viladomsa, Gisela Riu-Viladomsb, Anna Estefanell Tejeroa, Anna Estefanell-Tejerob, Josep Ribas Salaa, Josep Ribas-Salab
a Servicio de Farmacia Hospitalaria, Hospital Clínic de Barcelona, Barcelona, Barcelona, Spain,
b Servicio de Farmacia Hospitalaria, Hospital Clínic de Barcelona,
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">mTOR &#40;<span class="elsevierStyleItalic">mammalian target of rapamycin</span>&#41; inhibitors&#44; sirolimus &#40;rapamycin&#41; and everolimus&#44; act by inhibiting T and B lymphocyte proliferation&#46; They were proposed as a safer alternative to immunosuppressant treatment of solid organ transplantations&#44; compared with calcineurin inhibitors already widely used&#44; such as tacrolimus and cyclosporine&#46; However&#44; in clinical practice&#44; it has been demonstrated that mTOR inhibitors are not exempt from toxicity&#46;<span class="elsevierStyleSup">1</span> At the time of their introduction to the market&#44; the absence of nephrotoxicity was highlighted as its main advantage over calcineurin inhibitors but subsequent studies on patients with a kidney transplant called into question this assertion&#46;<span class="elsevierStyleSup">2&#44;3</span></p><p class="elsevierStylePara">The pharmacokinetics of sirolimus and everolimus are very similar in terms of metabolism and excretion&#46; Both are metabolised by CYP3A4 to inactive metabolites&#44; which are fundamentally eliminated through faeces&#44; with excretion through the kidney being minimal&#46; The pharmacokinetic parameters&#44; which are altered in the event of liver failure&#44; are not affected by renal failure&#46; Both drugs are also substrates of P-glycoprotein&#44; which is involved in the clearance processes&#46; The elimination half-life is about 30 hours for everolimus and around double for sirolimus&#46; These drugs are extensively distributed around the body&#44; as their high volume of distribution suggests&#46;<span class="elsevierStyleSup">4&#44;5</span> A new mTOR inhibitor&#44; temsirolimus&#44; has been recently introduced to the market&#44; which is indicated in the treatment of advanced renal cell carcinoma&#46;</p><p class="elsevierStylePara">It has been shown that mTOR inhibitors stimulate the production of some proinflammatory cytokines in monocytes and macrophages and promote the proliferation of memory T cells&#46; This indicates that they possess certain proinflammatory effects that may be the cause of some of its adverse effects&#44; such as pneumonitis&#44; which is the inflammation of lung tissue&#46;<span class="elsevierStyleSup">2</span> Table 1 shows the main studies on pneumonitis in patients treated with mTOR inhibitors&#46;<span class="elsevierStyleSup">6-10</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">INCIDENCE</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A lot of cases of pneumonitis due to mTOR inhibitors have been reported since they were first marketed&#44; most associated with sirolimus treatment&#44; although cases have also been described that involve everolimus and temsirolimus&#46;<span class="elsevierStyleSup">3&#44;11</span> The incidence of this adverse effect was estimated at 4-11&#37;&#46;<span class="elsevierStyleSup">6&#44;8&#44;9</span> However&#44; the recent introduction of this group of drugs&#44; specifically everolimus and temsirolimus as antineoplastic treatment&#44; provides more case studies and suggests that the incidence is probably higher&#46; Given that cancer patients periodically undergo computed axial tomography &#40;CAT&#41;&#44; we have been able to observe pulmonary abnormalities suggestive of pneumonitis in asymptomatic patients&#46; The overall incidence of pneumonitis for mTOR inhibitors in this type of patient&#44; symptomatic or not&#44; seems to be over 20&#37;&#46;<span class="elsevierStyleSup">11&#44;12</span> Mortality associated with pneumonitis due to sirolimus and everolimus is estimated at around 5&#37;&#46;<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">The overwhelming majority of cases described occurred in kidney transplant patients&#44; since it is in this type of transplantation that mTOR inhibitors were first administered&#46; Nevertheless&#44; cases of pneumonitis have also been reported in liver and heart transplant patients who presented similar characteristics&#46;<span class="elsevierStyleSup">6&#44;13&#44;14</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CLINICAL PRESENTATION</span></p><p class="elsevierStylePara">Pneumonitis caused by mTOR inhibitors has heterogeneous clinical manifestations and may begin with fever&#44; fatigue&#44; coughing and dyspnoea&#44; nonspecific signs and symptoms&#44; which does not facilitate diagnosis&#46; It may appear at the beginning or after several years of treatment&#46; In many cases&#44; the chest X-ray did not show abnormalities&#44; which were only observed in CAT scans&#46; The most common findings in CAT scans were ground glass opacities&#44; although additional peripheral infiltrates and patterns of bronchiolitis obliterans with organising pneumonia have also been observed&#46; In some cases&#44; signs of pulmonary fibrosis were also observed&#46; Diagnosis is difficult and tends to be made by excluding other causes&#44; such as infections&#44; autoimmune diseases or toxicity due to other products&#46;<span class="elsevierStyleSup">8&#44;9&#44;15&#44;16</span> Clinical improvement upon discontinuation of the drug can confirm the diagnosis&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The pathophysiology of pneumonitis associated with mTOR inhibitors is not very well understood&#46; Direct toxicity by drugs&#44; immunological toxicity or a combination of both mechanisms has been proposed&#46; In lung biopsies of affected patients&#44; lymphocytic alveolitis has been observed&#44; which favours the immune mediated toxicity hypothesis&#46; However&#44; the rapid response to drug discontinuation favours the direct toxicity hypothesis&#46;<span class="elsevierStyleSup">2&#44;15-17</span></p><p class="elsevierStylePara">Interestingly&#44; it has been observed that patients who began post-transplant immunosuppression directly with mTOR inhibitors have a lower incidence of pneumonitis than those who started treatment with calcineurin inhibitors and subsequently changed to sirolimus or everolimus&#46; The reason for this lower incidence is not known&#44; but some authors suggest that it may be due to differences in renal function&#44; since an increased incidence of pneumonitis in patients with abnormal renal function has been observed&#46;<span class="elsevierStyleSup">9&#44;18</span> Sometimes the reason for switching from calcineurin inhibitors to mTOR inhibitors is nephrotoxicity due to the former&#46; Therefore&#44; when switching to treatment with mTOR inhibitors&#44; patients typically present worse renal function&#46; This hypothesis is not very plausible since sirolimus and everolimus are metabolised by CYP3A4 and their renal excretion is negligible&#46;<span class="elsevierStyleSup">4&#44;5</span> However&#44; other mechanisms by which renal function modifies tolerance to mTOR inhibitors cannot be discarded and it has been questioned whether a metabolite of renal elimination may be the cause of symptoms&#46;</p><p class="elsevierStylePara">The potential relationship between the occurrence of pneumonitis and plasma drug concentrations has also been researched&#46; In the sirolimus efficacy studies published to date&#44; different target treatment concentrations have been used&#46; While some authors have used predose concentrations of 5-10ng&#47;ml&#44; others opt for 10-15ng&#47;ml or greater&#44; depending on whether or not the treatments were combined with calcineurin inhibitors&#44; as well as the post-transplant period&#46;<span class="elsevierStyleSup">19</span> In the study by Weiner et al&#46;&#44; although in most cases of pneumonitis&#44; sirolimus concentrations were higher than both treatment margins &#40;mean 16&#46;7ng&#47;ml&#41;&#44; cases were also observed with concentrations below 10ng&#47;ml&#46; As such&#44; plasma concentrations within therapeutic margins do not allow pneumonitis caused by mTOR inhibitors to be ruled out&#46;<span class="elsevierStyleSup">9-15</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TREATMENT</span></p><p class="elsevierStylePara">The first measure to be taken in a potential case of pneumonitis due to mTOR inhibitors is the suspension of the drug involved in the process&#46; This eliminates symptoms completely in many cases&#46;<span class="elsevierStyleSup">8&#44;9&#44;20&#44;21</span> The administration of high doses of corticosteroids is also advised&#44; although no recommended dose has been established&#46; It is necessary to bear in mind that most of these patients are already treated with low levels of corticosteroids to avoid graft rejection&#46; However&#44; in some case series&#44; patients have evolved favourably without having received corticosteroids&#46;<span class="elsevierStyleSup">9</span> Therefore&#44; some authors suggest administering corticosteroids only in the most serious cases&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">Likewise&#44; cases have been described in which the reduction of the mTOR inhibitor dose has been sufficient to eliminate pneumonitis&#46;<span class="elsevierStyleSup">3</span> As an alternative to sirolimus discontinuation&#44; switching to everolimus has also been proposed and has yielded good results in several cases&#46; Everolimus is a more hydrophilic drug than sirolimus&#44; making it easier to eliminate from the body and less likely to cause hypersensitive reactions&#46;<span class="elsevierStyleSup">10&#44;22</span> It seems that it presents a lower incidence of pneumonitis with respect to sirolimus<span class="elsevierStyleSup">3</span>&#44; although some studies have not found any differences&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In solid organ transplant patients who are treated with mTOR inhibitors and have respiratory symptoms&#44; after ruling out infection and other causes&#44; we should suspect iatrogenic pneumonitis&#44; in order that the appropriate treatment may begin as soon as possible&#58; discontinuation or a change of immunosuppressive treatment and addition of corticosteroid treatment if necessary&#46;</p><p class="elsevierStylePara">Given that pneumonitis due to mTOR inhibitors is more common in patients with renal failure and that cases have been described in which dose reduction eliminates clinical manifestations&#44; we may be led to believe that this toxicity is dependent on concentrations of the drug in the body&#46; However&#44; patients with plasma concentrations within the treatment margin have presented this complication&#46; Details of the pathophysiology of this disease are still unknown&#44; but for drugs with a high volume of distribution&#44; one possibility would be specific accumulation of the mTOR inhibitor or its metabolites in the lung parenchyma&#46; This could explain the presence of serum concentrations within the therapeutic interval in patients with pneumonitis&#46;</p><p class="elsevierStylePara">It seems that the mTOR inhibitors&#44; although they have the same mechanism of action&#44; seem to differ in terms of their adverse effects&#44; with there being greater tolerance to everolimus&#46; However&#44; there is still a lack of data to confirm this&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11439&#95;16025&#95;46549&#95;en&#95;t111439&#46;jpg" class="elsevierStyleCrossRefs"><img src="11439_16025_46549_en_t111439.jpg" alt="Main studies on pneumonitis in patients treated with mTOR inhibitors"></img></a></p><p class="elsevierStylePara">Table 1&#46; Main studies on pneumonitis in patients treated with mTOR inhibitors</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n&#58;</span> Los inhibidores de mTOR &#40;del ingl&#233;s <span class="elsevierStyleItalic">mammalian target of rapamycin</span>&#41;&#44; sirolimus y everolimus&#44; utilizados como tratamiento inmunosupresor en el trasplante de &#243;rganos s&#243;lidos&#44; pueden producir efectos adversos graves&#44; como la neumonitis intersticial&#46; <span class="elsevierStyleBold">Incidencia y presentaci&#243;n cl&#237;nica&#58;</span> La incidencia de neumonitis intersticial se ha estimado entre el 4 &#37; y el 11 &#37;&#44; aunque podr&#237;a ser mayor&#46; La mayor&#237;a de los casos publicados se ha producido en pacientes trasplantados renales en tratamiento con sirolimus&#46; La presentaci&#243;n cl&#237;nica es heterog&#233;nea&#44; lo que dificulta el diagn&#243;stico&#46; Se acostumbra a observar alteraciones en la tomograf&#237;a axial computarizada tor&#225;cica&#44; como opacidades en vidrio deslustrado&#46; La fisiopatolog&#237;a es poco conocida&#46; Sin embargo&#44; se ha observado una mayor incidencia en pacientes con funci&#243;n renal alterada y en pacientes que hab&#237;an recibido inhibidores de calcineurina previamente&#46; La relaci&#243;n entre aparici&#243;n de neumonitis y concentraciones plasm&#225;ticas de inhibidores de mTOR no est&#225; bien definida&#46; <span class="elsevierStyleBold">Tratamiento&#58;</span> La suspensi&#243;n del f&#225;rmaco y la administraci&#243;n de dosis altas de corticoides parecen ser efectivos&#46; Otras alternativas terap&#233;uticas&#44; aunque m&#225;s discutidas&#44; son la reducci&#243;n de la dosis del inhibidor de mTOR y el cambio de sirolimus a everolimus&#46; <span class="elsevierStyleBold">Conclusi&#243;n&#58;</span> Se debe sospechar de neumonitis iatrog&#233;nica en pacientes trasplantados en tratamiento con inhibidores de mTOR y con s&#237;ntomas respiratorios&#46; Faltan datos concluyentes en cuanto a estrategias de tratamiento&#46; Parece que everolimus podr&#237;a ser mejor tolerado que sirolimus&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">Introduction&#58;</span></span><span class="elsevierStyleItalic"> mTOR &#40;<span class="elsevierStyleItalic">mammalian target of rapamycin</span>&#41; inhibitors sirolimus and everolimus&#44; used as immunosuppressants in solid organ transplantation&#44; may cause severe adverse effects&#44; such as interstitial pneumonitis&#46; <span class="elsevierStyleBold">Incidence and clinical presentation&#58;</span> The estimated incidence of interstitial pneumonitis is 4-11&#37; although it may be higher&#46; Most reported cases have occurred in renal transplant recipients treated with sirolimus&#46; Clinical presentation is heterogeneous&#44; which makes diagnosis difficult&#46; Abnormalities&#44; such as ground glass opacities&#44; are often found in computerised axial tomography scans of the chest&#46; Physiopathology is not well-known&#46; However&#44; patients with abnormal renal function and those with previous calcineurin inhibitor treatment display a higher incidence&#46; The relationship between pneumonitis and mTOR inhibitor plasma concentrations is not well defined&#46;&#160;<span class="elsevierStyleBold">Treatment&#58;</span> Drug discontinuation and administration of high doses of corticosteroids seems to be an effective treatment&#46; mTOR inhibitor dose reduction and replacing sirolimus with everolimus are other alternatives&#44; but they are still under discussion&#46;&#160;<span class="elsevierStyleBold">Conclusion&#58;</span> Iatrogenic pneumonitis must be suspected when a transplant recipient being treated with mTOR inhibitors presents respiratory symptoms&#46; There is lack of conclusive data on treatment strategies&#46; It appears that everolimus may be tolerated better than sirolimus&#46;</span></p>"
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Nefrología (English Edition)