Pneumocystis jirovecii pneumonia prophylaxis in immunocompromised patients with systemic autoimmune diseases

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"documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2019;152:495-501" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "PDF" => 2 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Usefulness of imaging techniques in the management of giant cell arteritis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "495" "paginaFinal" => "501" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de las técnicas de imagen en la valoración de la arteritis de células gigantes" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2774 "Ancho" => 2500 "Tamanyo" => 437271 ] ] "descripcion" => array:1 [ "en" => "Doppler ultrasound showing a hypoechoic ring (halo) in a cross-sectional view of the parietal branch of the temporal artery – panel A) – and the left primitive carotid artery – panel B) – in a patient with a recent diagnosis of giant cell arteritis. Axial section of a PET/CT performed in a patient with recently diagnosed giant cell arteritis that shows linear circumferential uptake of the radiotracer in the ascending aorta wall – arrow in panel C) – descending – arrowhead in panel C) – and aortic arch – panel D). Transversal image of a CT angiography of a patient with recently diagnosed giant cell arteritis showing circumferential parietal thickening of the descending thoracic aorta in the arterial phase – arrow in panel E) – with contrast uptake in the venous phase – arrow in panel F)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sergio Prieto-González, Michelle Villarreal-Compagny, María C. Cid" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Sergio" "apellidos" => "Prieto-González" ] 1 => array:2 [ "nombre" => "Michelle" "apellidos" => "Villarreal-Compagny" ] 2 => array:2 [ "nombre" => "María C." "apellidos" => "Cid" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775318307334" "doi" => "10.1016/j.medcli.2018.10.030" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775318307334?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020619301937?idApp=UINPBA00004N" "url" => "/23870206/0000015200000012/v1_201906160657/S2387020619301937/v1_201906160657/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Pneumocystis jirovecii pneumonia prophylaxis in immunocompromised patients with systemic autoimmune diseases" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "502" "paginaFinal" => "507" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Beatriz P. Braga, Sergio Prieto-González, José Hernández-Rodríguez" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Beatriz P." "apellidos" => "Braga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Sergio" "apellidos" => "Prieto-González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "José" "apellidos" => "Hernández-Rodríguez" "email" => array:1 [ 0 => "jhernan@clinic.ub.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Internal Medicine, Hospital do Divino Espírito Santo de Ponta Delgada, São Miguel, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Profilaxis de la neumonía por Pneumocystis jirovecii en pacientes inmunodeprimidos con enfermedades autoinmunes sistémicas" ] ] "textoCompleto" => "IntroductionPneumocystis jirovecii (P. jirovecii) is a ubiquitous fungus transmitted by the airborne route. Immunocompetent adults may have asymptomatic lung colonization, participating in the circulation of P. jirovecii as an infective reservoir.<a class="elsevierStyleCrossRefs" href="#bib0275">1–3</a>P. jirovecii causes Pneumocystis pneumonia (PcP), a severe opportunistic and potentially life-threatening infection in immunocompromised individuals that rarely occurs in patients without immunodeficiency. PcP usually presents with fever, cough and dyspnea.<a class="elsevierStyleCrossRefs" href="#bib0275">1–5</a> Typical chest X-ray features of PcP comprise diffuse and bilateral interstitial infiltrates, and high-resolution computed tomography scan may demonstrate extensive ground glass opacities and cystic lesions.<a class="elsevierStyleCrossRefs" href="#bib0275">1,4</a> Serum lactate dehydrogenase and beta-d-glucan (a cell wall component of most pathogenic fungi) concentrations are elevated in PcP and usually associated with disease severity.<a class="elsevierStyleCrossRefs" href="#bib0300">6,7</a> The definitive diagnosis of P. jirovecii infection or colonization requires identification of the organism by tinctorial staining, fluorescent antibody staining or polymerase chain reaction-based assays of respiratory specimens (induced sputum or bronchoalveolar lavage).<a class="elsevierStyleCrossRefs" href="#bib0275">1–3</a>Trimethoprim–sulfamethoxazole (TMP–SMX) is the treatment of choice for PcP and also for PcP prophylaxis. Therapy for an acute P. jirovecii infection should be initiated based upon the patient's risk, clinical severity and suggestive complementary tests, even if the diagnosis is only presumptive.<a class="elsevierStyleCrossRefs" href="#bib0275">1–5</a>Apart from HIV-infected patients, other individuals at substantial risk for PcP include hematopoietic cell and solid organ transplant recipients, those with cancer (particularly hematologic), autoimmune diseases, primary immunodeficiencies and severe malnutrition, who are indeed on glucocorticoid (GC) therapy, immunosuppressive or chemotherapeutic agents.<a class="elsevierStyleCrossRefs" href="#bib0275">1,6,8–10</a> Therefore, patients with systemic autoimmune diseases suffer from a primary dysfunction of the immune system and also from an induced or secondary immunodeficiency because of the use of GC and other immunosuppressive agents.<a class="elsevierStyleCrossRef" href="#bib0325">11</a> Suppression of cell-mediated immunity with low CD4+ counts and alterations in lung surfactant have been suggested as some of the mechanisms by which GC and other drugs predispose to the development of PcP.<a class="elsevierStyleCrossRefs" href="#bib0275">1,6</a>Patients with autoimmune diseases comprise 25%–28% of non-HIV cases who develop PcP.<a class="elsevierStyleCrossRefs" href="#bib0330">12,13</a>P. jirovecii asymptomatic lung colonization can be found in 16%–29% of them.<a class="elsevierStyleCrossRefs" href="#bib0340">14–16</a> However, P. jirovecii colonization does not imply a direct development of an overt infection in patients with autoimmune diseases,<a class="elsevierStyleCrossRefs" href="#bib0340">14,15</a> as demonstrated in a cohort of patients with different autoimmune conditions prospectively followed during one year.<a class="elsevierStyleCrossRef" href="#bib0345">15</a> Anyway, the incidence of PcP in non-HIV immunosuppressed patients is increasing as more people are receiving GC and other immunosuppressive medications.<a class="elsevierStyleCrossRefs" href="#bib0275">1,6,17</a>In patients with autoimmune diseases, PcP typically occurs abruptly with fulminant respiratory failure, usually requiring intensive care unit admission and intubation.<a class="elsevierStyleCrossRefs" href="#bib0275">1,6</a> Remarkably, PcP in non-HIV patients exhibits higher mortality rates (27%–62%) than in those with HIV infection (4%–15%).<a class="elsevierStyleCrossRefs" href="#bib0290">4,6,9,12,13,18–20</a> Concurrent respiratory infections (mainly by different bacteria, aspergillus and cytomegalovirus) have been found in 34%–50% of patients with autoimmune diseases and may complicate patients’recovery.<a class="elsevierStyleCrossRefs" href="#bib0285">3,4,11</a>Although there are guidelines for prophylaxis of P. jirovecii infection in HIV-infected patients, hematological and solid organs cancer or transplant,<a class="elsevierStyleCrossRefs" href="#bib0375">21–23</a> there are no specific consensus guidelines for patients with autoimmune diseases receiving immunosuppressive drugs.<a class="elsevierStyleCrossRefs" href="#bib0370">20,24,25</a> In real life, a survey of 727 US rheumatologists with experience in autoimmune diseases revealed that two-thirds of them prescribed PcP prophylaxis for patients with granulomatosis with polyangiitis (GPA or Wegener), more than one-third for systemic lupus erythematosus (SLE), polyarteritis nodosa (PAN) and other systemic vasculitides, 17% for inflammatory myopathies and 6% for rheumatoid arthritis (RA).<a class="elsevierStyleCrossRef" href="#bib0355">17</a> Prophylaxis was prescribed to only 12.5% of patients on GC monotherapy, regardless of the dose. However, 75% of professionals would recommend PcP prophylaxis to patients treated with cyclophosphamide, and 50%, to patients treated with a combination of prednisone and other immunosuppressive agents.<a class="elsevierStyleCrossRef" href="#bib0355">17</a> Similarly, 50% of SLE patients treated with cyclophosphamide received PcP prophylaxis in a large series.<a class="elsevierStyleCrossRef" href="#bib0400">26</a>This review tries to shed light on the reported occurrence of PcP in the different autoimmune diseases and the current evidence for PcP prophylactic treatment of patients with autoimmune diseases receiving any type of immunosuppressive agents (GC, cytotoxic or biologic agents).Pneumocystis pneumonia in systemic autoimmune diseasesA recent observational study of 1092 patients with different autoimmune diseases found an incidence rate of PcP of 2.37 (95%CI: 1.59–3.41)/100 person-years.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> Overall, reported mortality rates are usually high, ranging from 30% for RA to 62% for GPA.<a class="elsevierStyleCrossRefs" href="#bib0360">18,19</a>Pneumocystis pneumonia in systemic vasculitisThe incidence and mortality of PcP vary among the different forms of systemic vasculitis. In small-vessel vasculitides, PcP has been more frequently reported in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, particularly in those with GPA, mostly during remission induction regimens,<a class="elsevierStyleCrossRefs" href="#bib0405">27,28</a> but also several months even years after the treatment onset.<a class="elsevierStyleCrossRef" href="#bib0415">29</a> While sporadic cases of PcP have been reported in microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg–Strauss),<a class="elsevierStyleCrossRefs" href="#bib0330">12,25,27,29</a> in patients with GPA non-receiving prophylactic drugs, the occurrence of PcP is of 12%–20%.<a class="elsevierStyleCrossRefs" href="#bib0365">19,27</a> Indeed, PcP can also occur in GPA patients preventively treated for PcP.<a class="elsevierStyleCrossRefs" href="#bib0405">27,30</a> Mortality due to PcP in GPA patients is specially high, ranging in most studies from 25% to 62%.<a class="elsevierStyleCrossRefs" href="#bib0360">18–20,27,28</a> Although with discrepancies among investigators,<a class="elsevierStyleCrossRef" href="#bib0325">11</a> the use of cyclophosphamide has been considered a relevant risk factor for developing PcP in ANCA-associated vasculitis, particularly in GPA.<a class="elsevierStyleCrossRefs" href="#bib0285">3,11,28,29</a> Other risk factors identified include a low lymphocyte count before and during therapy and GC use >1 month at doses >15mg/day.<a class="elsevierStyleCrossRef" href="#bib0405">27</a>P. jirovecii infection has been sporadically reported in other small-vessel vasculitis, such as cryoglobulinemic vasculitis and IgA vasculitis (Henoch–Schonlein).<a class="elsevierStyleCrossRefs" href="#bib0370">20,25,31</a>In PAN, a medium-vessel vasculitis, few studies have reported a concomitant PcP,<a class="elsevierStyleCrossRefs" href="#bib0330">12,18,25,32</a> although when present mortality is as high as 48%.<a class="elsevierStyleCrossRef" href="#bib0360">18</a> Among large-vessel vasculitis, no cases of PcP have been found in patients with Takayasu's arteritis<a class="elsevierStyleCrossRefs" href="#bib0325">11,27</a> and it appears to be rare in patients with GCA.<a class="elsevierStyleCrossRefs" href="#bib0295">5,12,33</a> Kermani et al. analyzed 7543 patients with GCA and only 7 (0.1%) of them developed PcP, with a median time from GCA to PcP diagnosis of 4 months.<a class="elsevierStyleCrossRef" href="#bib0295">5</a> All patients were on high doses of prednisone (a median of 50mg/day) at the time of PcP and none of them were on specific prophylaxis. The mortality rate was of 29%.<a class="elsevierStyleCrossRef" href="#bib0295">5</a> By contrast, a study of 62 consecutive diagnosed GCA patients revealed that four (6.5%) of them developed PcP and all four patients were concomitantly receiving GC and methotrexate, without receiving prophylactic drugs.<a class="elsevierStyleCrossRef" href="#bib0440">34</a> Mortality similarly occurred in 25% of patients.<a class="elsevierStyleCrossRef" href="#bib0440">34</a> However, no cases of PcP have been reported in clinical trials about GCA, even in the absence of any PcP prophylactic approach.<a class="elsevierStyleCrossRef" href="#bib0405">27</a> Therefore, despite of the use of initial high doses of GC and their long-term administration in GCA, current data available do not support any strong recommendation for the routine use of PcP prophylaxis in GCA patients.<a class="elsevierStyleCrossRef" href="#bib0445">35</a> Nevertheless, preventive therapy could be reserved for patients treated with GC and methotrexate.<a class="elsevierStyleCrossRef" href="#bib0440">34</a>Pneumocystis pneumonia in systemic lupus erythematosusA 2007 systematic review including 2120 SLE patients found a 5% incidence of PcP.<a class="elsevierStyleCrossRef" href="#bib0365">19</a> However, in 2008, a 10-year period study of 76,156 patients with SLE treated with cyclophosphamide, in which prophylaxis was given to 50% of them, showed a lower frequency of PcP (0.16%).<a class="elsevierStyleCrossRef" href="#bib0400">26</a> Other study in 2013 analyzed the occurrence of PcP in 2013 hospitalized patients with SLE (without PcP prophylaxis) and similarly found a low prevalence of 0.3%.<a class="elsevierStyleCrossRef" href="#bib0450">36</a> Although PcP occurrence in SLE appears to be low, mortality rates are remarkably high, ranging from 32% to 46%.<a class="elsevierStyleCrossRefs" href="#bib0360">18,19,26</a> The authors of the larger studies concluded that routine prophylaxis against PcP was not supported, but suggested that it could be considered in cases with severe leukopenia/lymphopenia or in those with severe disease activity, usually requiring higher GC doses.<a class="elsevierStyleCrossRefs" href="#bib0400">26,36</a>Pneumocystis pneumonia in rheumatoid arthritisA systematic review of 4977 patients with RA found that 1% of them developed PcP.<a class="elsevierStyleCrossRef" href="#bib0365">19</a> This proportion seems to be lower in larger studies, such as in a British prospective observational cohort of 19,282 RA patients that found 24 (0.12%) cases of PcP (all of them received either rituximab or anti-tumor necrosis factor [TNF] therapy),<a class="elsevierStyleCrossRef" href="#bib0455">37</a> or in a nationwide Japanese multicenter study including 18,668 RA patients and 60 (0.32%) cases of PcP.<a class="elsevierStyleCrossRef" href="#bib0460">38</a> None of them were taking prophylactic drugs for PcP.<a class="elsevierStyleCrossRefs" href="#bib0455">37,38</a> A 6-year review of the FDA Adverse Event Reporting System on infliximab-treated patients found 84 cases (49 with RA) of PcP following infliximab therapy. Despite the concomitant administration with traditional immunosuppressive medications, the authors concluded that infliximab is associated with PcP.<a class="elsevierStyleCrossRef" href="#bib0465">39</a>P. jirovecii infection has been also described in RA patients treated with etanercept.<a class="elsevierStyleCrossRef" href="#bib0470">40</a>These studies identified several factors increasing the risk for developing PcP, such as and age ≥65 years, the presence of lung disease and the use of GC, methotrexate and TNF inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0460">38,40–42</a> Mortality rate in patients with RA and PcP was about 30% in most studies, including those receiving biologic agents.<a class="elsevierStyleCrossRefs" href="#bib0360">18–20,39</a>Pneumocystis pneumonia in inflammatory myopathies, systemic sclerosis, sarcoidosis and other systemic autoimmune diseasesPcP has rarely been reported in inflammatory myopathies. A recent study of 204 patients with dermatomyositis, polymyositis and sporadic inclusion body myositis with a long-term follow-up found only one (0.5%) case who had developed PcP.<a class="elsevierStyleCrossRef" href="#bib0485">43</a> In other studies, PcP occurrence ranged from 0% to 11% of patients with inflammatory myopathies, particularly affecting those patients with interstitial lung disease.<a class="elsevierStyleCrossRefs" href="#bib0330">12,19,43,44</a> In a series of four patients with dermatomyositis and PcP, three (75%) of them died.<a class="elsevierStyleCrossRef" href="#bib0495">45</a>No studies about prevalence of PcP in systemic sclerosis have been found. A series of 223 patients with autoimmune diseases and PcP identified 5% of patients with systemic sclerosis, with a mortality rate of 17%.<a class="elsevierStyleCrossRef" href="#bib0360">18</a> A retrospective study of 585 patients with sarcoidosis who did not received prophylactic therapy for PcP showed that three (0.5%) of them developed PcP.<a class="elsevierStyleCrossRef" href="#bib0500">46</a> In addition, PcP has been sporadically reported in other autoimmune diseases, including cutaneous vasculitis, Behçet's disease, adult-onset Still disease, ankylosing spondylitis, Sjögren syndrome and polymyalgia rheumatica.<a class="elsevierStyleCrossRefs" href="#bib0330">12,25,47</a>Immunosuppressive therapies and Pneumocystis pneumoniaGlucocorticoids and conventional immunosuppressive drugsImmunosuppressive therapies used in autoimmune diseases, including GC, cyclophosphamide, methotrexate, azathioprine and biologic agents, mainly TNF-blockers and anti-CD20 agents, have been associated with PcP.<a class="elsevierStyleCrossRef" href="#bib0325">11</a> Of note, GC and all the other immunosuppressive agents can decrease total lymphocyte and CD4+ cell counts.<a class="elsevierStyleCrossRefs" href="#bib0340">14,39</a> Among these drugs, GC seem to be the common risk factor for PcP, since almost all patients receive GC prior to the infection onset.<a class="elsevierStyleCrossRefs" href="#bib0325">11,25,30</a> A study of 1092 patients with autoimmune diseases and 30 PcP cases found a mean interval between immunosuppression was started and PcP of 3.4 months (SD=2.5), a mean daily dose of prednisone of 31mg (SD=20) and 90% of patients receiving >15mg/day at the time of PcP diagnosis.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> In different studies, the daily dose that appears to confer risk of PcP has been reported >15mg/day.<a class="elsevierStyleCrossRefs" href="#bib0325">11,25,27,30</a>The use of any of the additional immunosuppressant agents (cyclophosphamide, methotrexate or azathioprine) during the first two weeks of GC therapy was found to be an independent risk factor for PcP.<a class="elsevierStyleCrossRef" href="#bib0420">30</a> Although the role of cyclophospamide as an independent factor contributing to the development of PcP is still controversial,<a class="elsevierStyleCrossRef" href="#bib0325">11</a> in ANCA-associated vasculitis, and particularly in GPA, PcP occurrence has been described associated to the use of high GC doses in addition to cyclophosphamide.<a class="elsevierStyleCrossRefs" href="#bib0410">28,29</a> In this regard, EULAR guidelines encourage prophylaxis during cyclophosphamide therapy in ANCA-associated vasculitis.<a class="elsevierStyleCrossRef" href="#bib0510">48</a> The use of methotrexate has been associated with the development of PcP in RA patients.<a class="elsevierStyleCrossRefs" href="#bib0475">41,42</a>Anti-TNF agentsAlthough P. jirovecii infection in patients treated with anti-TNF drugs have been repeatedly reported,<a class="elsevierStyleCrossRefs" href="#bib0465">39,49</a> the incidence of PcP is really low, as showed by two large French (0.009) and American (0.06) series of patients treated with TNF-inhibitors.<a class="elsevierStyleCrossRef" href="#bib0465">39</a> In 2007, the FDA Adverse Event Reporting System determined that the use of infliximab was associated with an incremented risk of P. jirovecii infection.<a class="elsevierStyleCrossRef" href="#bib0465">39</a> Most patients treated with TNF-inhibitors develop PcP after a mean of two infusions of infliximab<a class="elsevierStyleCrossRef" href="#bib0465">39</a> and within 26 weeks following the first injection of etanercept.<a class="elsevierStyleCrossRef" href="#bib0470">40</a> Although 27% of PcP patients on TNF-blockers died, mortality did not differ from PcP in other RA patients treated with different immunosuppressive drugs.<a class="elsevierStyleCrossRefs" href="#bib0360">18–20,39</a>RituximabRituximab is associated with the development of PcP in patients with lymphoproliferative and autoimmune diseases.<a class="elsevierStyleCrossRefs" href="#bib0315">9,14</a> While 11% of hematological patients receiving rituximab together with chemotherapy regimens may develop PcP, in a review of 516 patients with ANCA-associated vasculitis treated with rituximab, the occurrence of PcP has been reported of 1.2%.<a class="elsevierStyleCrossRef" href="#bib0340">14</a> PcP occurred from two to 32 months after the last rituximab infusion, equally in monotherapy or in combination with other immunosuppressive drugs. Mortality rate was of 33%.<a class="elsevierStyleCrossRef" href="#bib0340">14</a>The role of total lymphocyte and CD4+ counts on Pneumocystis pneumonia prophylaxis in autoimmune diseasesInternational guidelines recommend PcP prophylaxis for all HIV-infected persons with a CD4+ cell count <200cells/μl<a class="elsevierStyleCrossRef" href="#bib0375">21</a> and for all those with hematological conditions, including transplant recipients, children with well-defined primary immune deficiencies and patients treated with GC for more than four weeks, alemtuzumab or any combination of fludarabine, cyclophosphamide and rituximab.<a class="elsevierStyleCrossRef" href="#bib0380">22</a>Regarding patients with autoimmune diseases, several studies have addressed the recommendations of PcP prophylaxis based on total lymphocyte and/or CD4+ lymphocyte counts. A study identified a total lymphocyte count <500/μl after two weeks of the institution of GC as an independent risk factor for developing PcP.<a class="elsevierStyleCrossRef" href="#bib0420">30</a> Other authors have recommended PcP prophylaxis in patients with a total lymphocyte count <800/μl.<a class="elsevierStyleCrossRefs" href="#bib0430">32,44,50</a> Regarding CD4+ lymphocyte counts, a systematic review of 14 well-selected studies including 515 HIV-seronegative immunocompromised patients with PcP (144 of them with autoimmune or inflammatory conditions) found that a CD4+ cell count was <200/μl in 73% of patients. This cut-off value was considered a sensitive biomarker to identify non-HIV immunocompromised patients who are at risk for PcP.<a class="elsevierStyleCrossRef" href="#bib0335">13</a> Similarly, other studies on autoimmune diseases have pointed out a CD4+ cell count <200/μl as the value for which P. jirovecii prophylaxis is warranted,<a class="elsevierStyleCrossRefs" href="#bib0490">44,50</a> since the annual risk of PcP on these patients appears to be greater than 9%.<a class="elsevierStyleCrossRef" href="#bib0285">3</a>Despite all these considerations, in a daily basis, only 15% of physicians treating autoimmune diseases routinely consider lymphocyte counts, and 7.5% of them monitor CD4+ cell counts.<a class="elsevierStyleCrossRef" href="#bib0355">17</a>Duration of Pneumocystis pneumonia prophylaxis in autoimmune diseases based on CD4+ cell countsWhile discontinuation of primary PcP prophylaxis in HIV-infected patients on antiretroviral therapy appears to be safe in subjects with a negative viral load and a CD4+ cell count >100/μl,<a class="elsevierStyleCrossRefs" href="#bib0375">21,51</a> for hematological disorders, PcP prophylaxis cessation is recommended in cases in which immunosuppressive therapy has ended or the CD4+ cell count has increased to >200cells/μl.<a class="elsevierStyleCrossRef" href="#bib0380">22</a> In patients undergoing a kidney transplant, PcP prophylaxis is recommended between four and 12 months after transplantation.<a class="elsevierStyleCrossRef" href="#bib0335">13</a>In autoimmune diseases, some authors have proposed to discontinue prophylactic therapy when CD4+ cell counts are probed to be >200/μl, at least during 6 months.<a class="elsevierStyleCrossRef" href="#bib0445">35</a> As well as in patients with hematological malignancies or transplant recipients, in those with autoimmune diseases, it is advisable to raise awareness about the persistence of certain immunocompromised status, including a qualitative alteration in CD4+ lymphocytes, after cessation of immunosuppressive drugs.<a class="elsevierStyleCrossRef" href="#bib0445">35</a>Medications used for Pneumocystis pneumonia prophylaxis in autoimmune diseasesAs reported in cancer individuals on chemotherapy or undergoing bone marrow transplantation,<a class="elsevierStyleCrossRefs" href="#bib0310">8,10</a> in patients with autoimmune diseases, those who seem at risk of developing PcP are patients not receiving PcP prophylaxis.<a class="elsevierStyleCrossRefs" href="#bib0295">5,19,27,36,38,42,46</a>The efficacy of PcP prophylactic treatment for non–HIV immunocompromised patients, including those with autoimmune diseases requiring prolonged GC or other immunosuppressive drugs, was assessed by a 2007 systematic review and meta-analysis analyzing 12 randomized controlled trials and 1245 patients (50% children) on PcP prophylaxis.<a class="elsevierStyleCrossRef" href="#bib0530">52</a> TMP–SMX reduced by 91% the occurrence of PcP and significantly reduced PcP-related mortality. In addition, adverse events leading to treatment cessation were all reversible and only occurred in 3% of adults. Once the risk for severe adverse events is balanced, the authors recommended PcP prophylaxis in adult patients with an expected risk for PcP equal to or higher than 3.5% during the period of immunodeficiency.<a class="elsevierStyleCrossRef" href="#bib0530">52</a> Among patients with autoimmune diseases, these rates of risk were observed only in those with GPA.<a class="elsevierStyleCrossRef" href="#bib0530">52</a> Other conditions, such as PAN, SLE, systemic sclerosis and RA were associated with lower incidence rates in the analyzed cohorts.<a class="elsevierStyleCrossRef" href="#bib0530">52</a> Of note, in terms of efficacy, no differences were observed between once-daily and thrice-weekly administration of TMP–SMX.<a class="elsevierStyleCrossRef" href="#bib0530">52</a>A 2008 study of 1092 patients with autoimmune diseases and 30 with PcP, found that prophylaxis with TMP–SMX tended to reduce 1-year incidence of PcP in the whole group, but clearly reduced the occurrence of PcP in GPA patients receiving initial prednisone doses ≥60mg/day.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> This preventive effect was not observed in patients receiving lower doses.<a class="elsevierStyleCrossRef" href="#bib0395">25</a>Adverse effects associated with TMP-SMX have been reported in 3% to 21% of patients with autoimmune diseases, depending of the studies.<a class="elsevierStyleCrossRefs" href="#bib0395">25,52,53</a> Anyway, they seem to be lower than in HIV-infected patients.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> Among autoimmune diseases, adverse events have been described to be higher in patients with SLE (11%) and mixed connective tissue disease (33%),<a class="elsevierStyleCrossRef" href="#bib0535">53</a> since they occurred in 25% of patients carrying anti-RNP antibody (an autoimmune marker for mixed connective tissue disease).<a class="elsevierStyleCrossRef" href="#bib0535">53</a>The use of methotrexate in combination with full doses of TMP–SMX can cause severe cytopenias and bone marrow suppression because both drugs share the inhibition of dihydrofolate reductase as mechanism of action. However, this unsafe interaction does not seem to occur at prophylactic doses of TMP–SMX.<a class="elsevierStyleCrossRef" href="#bib0540">54</a>Other drugs used for PcP prophylaxis as an alternative to TMP–SMX include dapsone atovaquone and aerosolized pentamidine. Their recommended doses and main adverse effects are depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. However, these drugs have not been evaluated in patients with autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0325">11</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Proposed options for Pneumocystis pneumonia prophylaxis in autoimmune diseasesConsidering the different risk factors identified for PcP in immunocompromised patients with autoimmune diseases, several proposals for giving prophylactic therapy for P. jirovecii infection have been delineated. Among them, two groups of investigators recommend PcP prophylaxis in the next situations:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-If patients meet ≥2 of 4 of these risk factors: (a) prednisone (or equivalent) ≥20mg/day for >4 weeks; (b) current use of ≥2 immunosuppressive agents, including biologic agents; (c) absolute lymphocyte count <350cells/μl; and (d) having an underlying parenchymal lung disease.<a class="elsevierStyleCrossRef" href="#bib0540">54</a></li><li class="elsevierStyleListItem" id="lsti0010">-If patients have a CD4+ cell count <200/μl after one month of starting immunosuppressive therapy, only if they previously followed the three “screening criteria”: (a) GC dosage >15mg/day prednisolone (or equivalent); (b) GC treatment >3 months; and (c) a total lymphocyte count <600cells/μl.<a class="elsevierStyleCrossRef" href="#bib0285">3</a></li></ul>In the same sense, we advocate for considering PcP prophylaxis in any patient with an autoimmune disease in whom long-term (>3 months) treatment is expected, when: (a) receiving prednisone (or equivalent) >15mg/day together with cyclophosphamide; or (b) receiving prednisone (any dose) and other immunosuppressive (cytotoxic or biologic) agent different than cyclophosphamide, when total lymphocyte counts <800/μl or CD4+ cell counts <200/μl. It also seems reasonable to consider PcP prophylaxis cessation when prednisone doses achieve <15mg/day and the second immunosuppressant drug has been stopped, always in situations in which a recovery of total lymphocyte and CD4+ counts can be confirmed.Final considerationsDespite the increased risk of PcP in patients with autoimmune diseases, the overall incidence of P. jirovecii infection in this population remains relatively low. However, when PcP occurs in these patients, mortality is high, usually ranging between 30% and 50%. Almost all patients in whom PcP occurs do not receive any prophylactic treatment.Although there are no current consensus guidelines established to assist physicians in treating patients with autoimmune diseases for PcP prophylaxis, several risk factors for developing PcP have been identified and include: (a) the underlying disease (being GPA the autoimmune disease with the highest risk); (b) maintained GC therapy for >3 months with prednisone (or equivalent) doses of >15mg/day; (c) the use of an additional immunosuppressive agent, mainly cyclophosphamide, methotrexate, TNF-inhibitors and rituximab; (d) total lymphocyte counts <600/μl and/or CD4+ cell counts <200/μl.Currently, even physicians with experience in autoimmune diseases generally treat with prophylactic doses of SMX-TMP those patients they subjectively believe are at high risk for PcP. Although several recommendations have tried to address this matter, various unresolved issues about PcP prophylaxis in these patients need to be clarified. Large prospective studies focused in investigating and validating the clinical value balanced with the risk of adverse effects of PcP prophylaxis and its duration, together with the assessment of total lymphocytes and CD4+ cell counts as markers for guiding prophylaxis in patients with autoimmune diseases are needed in order to generate robust and consensus guidelines.Conflicts of interestAll authors have seen and approved the manuscript being submitted. On behalf of all co-authors, the corresponding author shall bear full responsibility for the submission, warrant that the article has not received prior publication and is not under consideration for publication elsewhere and also declare no financial disclosure or conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1207525" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1124529" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1124528" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres1207526" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1124527" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Pneumocystis pneumonia in systemic autoimmune diseases" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Pneumocystis pneumonia in systemic vasculitis" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Pneumocystis pneumonia in systemic lupus erythematosus" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Pneumocystis pneumonia in rheumatoid arthritis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Pneumocystis pneumonia in inflammatory myopathies, systemic sclerosis, sarcoidosis and other systemic autoimmune diseases" ] ] ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Immunosuppressive therapies and Pneumocystis pneumonia" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Glucocorticoids and conventional immunosuppressive drugs" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Anti-TNF agents" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Rituximab" ] ] ] 8 => array:3 [ "identificador" => "sec0055" "titulo" => "The role of total lymphocyte and CD4+ counts on Pneumocystis pneumonia prophylaxis in autoimmune diseases" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Duration of Pneumocystis pneumonia prophylaxis in autoimmune diseases based on CD4+ cell counts" ] ] ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Medications used for Pneumocystis pneumonia prophylaxis in autoimmune diseases" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Proposed options for Pneumocystis pneumonia prophylaxis in autoimmune diseases" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Final considerations" ] 12 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflicts of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-11-11" "fechaAceptado" => "2019-01-20" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1124529" "palabras" => array:8 [ 0 => "Pneumocystis jirovecii" 1 => "Pneumocystis pneumonia" 2 => "Autoimmune diseases" 3 => "PcP prophylaxis" 4 => "Immunosuppressive drugs" 5 => "Glucocorticoids" 6 => "Cyclophosphamide" 7 => "Biologic agents" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1124528" "palabras" => array:10 [ 0 => "ANCA" 1 => "GCA" 2 => "GC" 3 => "GPA" 4 => "PcP" 5 => "PAN" 6 => "RA" 7 => "SLE" 8 => "TMP–SMX" 9 => "TNF" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1124527" "palabras" => array:8 [ 0 => "Pneumocystis jirovecii" 1 => "Pneumocystis pneumonia" 2 => "Enfermedades autoinmunes" 3 => "Profilaxis de PcP" 4 => "Fármacos inmunodepresores" 5 => "Glucocorticoides" 6 => "Ciclofosfamida" 7 => "Agentes biológicos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Pneumocystis jirovecii (P. jirovecii) causes a potentially fatal pneumonia in immunocompromised individuals (Pneumocystis pneumonia or PcP), particularly in HIV-infected patients and those treated with immunosuppressive drugs, such as transplant patients and those with systemic autoimmune diseases. P. jirovecii colonization can be found in almost a third of patients with systemic autoimmune diseases. Although the incidence of PcP in such patients is usually low, mortality is quite high, ranging between 30% and 50% in the majority of autoimmune diseases. PcP development is almost always observed in patients not receiving prophylaxis for the infection. Despite the above, there are no clinical guidelines established for PcP prophylaxis in patients with autoimmune diseases treated with glucocorticoids, cytotoxic drugs, or more recently, biological agents. The objective of this review is to analyze the available data on the incidence of PcP and the effect of PcP prophylaxis in patients with autoimmune diseases that may be useful in clinical practice." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El hongo Pneumocystis jirovecii (P. jirovecii) es la causa de una neumonía (Pneumocystis pneumonia o PcP) potencialmente mortal en individuos inmunodeprimidos, sobre todo en pacientes infectados por el VIH, y en aquellos tratados con fármacos inmunodepresores, como los sometidos a trasplantes y los afectos de enfermedades autoinmunes sistémicas. En estos últimos, alrededor de un tercio de los casos puede estar colonizado por P. jirovecii y, aunque la incidencia de la PcP suele ser baja, la mortalidad de la misma es considerablemente alta, y oscila entre el 30 y el 50% en la mayoría de las enfermedades autoinmunes. El desarrollo de la PcP se observa casi siempre en pacientes que no reciben profilaxis para la infección. Aun así, no existen guías clínicas establecidas para la profilaxis de la PcP en pacientes afectos de enfermedades autoinmunes que son tratados con glucocorticoides, fármacos citotóxicos o más recientemente, con agentes biológicos. El objetivo de esta revisión es analizar los datos disponibles sobre la incidencia de la PcP y el efecto de la profilaxis para infección por P. jirovecii en los pacientes afectos de enfermedades autoinmunes que puedan ser útiles en la práctica clínica." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Usual doses \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main adverse effects \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First option</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trimethoprim–sulfamethoxazole(TMP/SMX) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 double strength (160mg TMP+800mg SMX) oral tablet/day or 3times/week, or1 single strength (80mg TMP+400mg SMX) oral tablet/day (orally) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nausea, abdominal pain, hypersensitivity reactions (rashes, fever), elevated creatinine, hyperkalemia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Second option</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dapsone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50mg twice/day or 100mg/day (orally) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, hemolysis, methemoglobinemia(G6PD deficiency must be checked prior to starting therapy) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atovaquone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">750mg twice/day or 1500mg orally once/day (orally) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nausea, diarrhea, rash, hepatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pentamidine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">300mg/month (aerosolized) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever, respiratory symptoms (cough, bronchospasm, pneumothorax), pancreatitis, arrhythmia, hypotension, hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2061136.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Antibiotic therapy for prophylaxis of Pneumocystis pneumonia." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib0275" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pneumocystis pneumonia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.F. 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Review

Pneumocystis jirovecii pneumonia prophylaxis in immunocompromised patients with systemic autoimmune diseases

Profilaxis de la neumonía por Pneumocystis jirovecii en pacientes inmunodeprimidos con enfermedades autoinmunes sistémicas

Beatriz P. Bragaa, Sergio Prieto-Gonzálezb, José Hernández-Rodríguezb,

Corresponding author

jhernan@clinic.ub.es

Corresponding author.

a Department of Internal Medicine, Hospital do Divino Espírito Santo de Ponta Delgada, São Miguel, Portugal

b Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pneumocystis jirovecii</span> &#40;<span class="elsevierStyleItalic">P&#46; jirovecii</span>&#41; is a ubiquitous fungus transmitted by the airborne route&#46; Immunocompetent adults may have asymptomatic lung colonization&#44; participating in the circulation of <span class="elsevierStyleItalic">P&#46; jirovecii</span> as an infective reservoir&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#8211;3</span></a><span class="elsevierStyleItalic">P&#46; jirovecii</span> causes <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia &#40;PcP&#41;&#44; a severe opportunistic and potentially life-threatening infection in immunocompromised individuals that rarely occurs in patients without immunodeficiency&#46; PcP usually presents with fever&#44; cough and dyspnea&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#8211;5</span></a> Typical chest X-ray features of PcP comprise diffuse and bilateral interstitial infiltrates&#44; and high-resolution computed tomography scan may demonstrate extensive ground glass opacities and cystic lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#44;4</span></a> Serum lactate dehydrogenase and beta-<span class="elsevierStyleSmallCaps">d</span>-glucan &#40;a cell wall component of most pathogenic fungi&#41; concentrations are elevated in PcP and usually associated with disease severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">6&#44;7</span></a> The definitive diagnosis of <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection or colonization requires identification of the organism by tinctorial staining&#44; fluorescent antibody staining or polymerase chain reaction-based assays of respiratory specimens &#40;induced sputum or bronchoalveolar lavage&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Trimethoprim&#8211;sulfamethoxazole &#40;TMP&#8211;SMX&#41; is the treatment of choice for PcP and also for PcP prophylaxis&#46; Therapy for an acute <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection should be initiated based upon the patient&#39;s risk&#44; clinical severity and suggestive complementary tests&#44; even if the diagnosis is only presumptive&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#8211;5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Apart from HIV-infected patients&#44; other individuals at substantial risk for PcP include hematopoietic cell and solid organ transplant recipients&#44; those with cancer &#40;particularly hematologic&#41;&#44; autoimmune diseases&#44; primary immunodeficiencies and severe malnutrition&#44; who are indeed on glucocorticoid &#40;GC&#41; therapy&#44; immunosuppressive or chemotherapeutic agents&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#44;6&#44;8&#8211;10</span></a> Therefore&#44; patients with systemic autoimmune diseases suffer from a primary dysfunction of the immune system and also from an induced or secondary immunodeficiency because of the use of GC and other immunosuppressive agents&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> Suppression of cell-mediated immunity with low CD4&#43; counts and alterations in lung surfactant have been suggested as some of the mechanisms by which GC and other drugs predispose to the development of PcP&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Patients with autoimmune diseases comprise 25&#37;&#8211;28&#37; of non-HIV cases who develop PcP&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">12&#44;13</span></a><span class="elsevierStyleItalic">P&#46; jirovecii</span> asymptomatic lung colonization can be found in 16&#37;&#8211;29&#37; of them&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">14&#8211;16</span></a> However&#44; <span class="elsevierStyleItalic">P&#46; jirovecii</span> colonization does not imply a direct development of an overt infection in patients with autoimmune diseases&#44;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">14&#44;15</span></a> as demonstrated in a cohort of patients with different autoimmune conditions prospectively followed during one year&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">15</span></a> Anyway&#44; the incidence of PcP in non-HIV immunosuppressed patients is increasing as more people are receiving GC and other immunosuppressive medications&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#44;6&#44;17</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In patients with autoimmune diseases&#44; PcP typically occurs abruptly with fulminant respiratory failure&#44; usually requiring intensive care unit admission and intubation&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">1&#44;6</span></a> Remarkably&#44; PcP in non-HIV patients exhibits higher mortality rates &#40;27&#37;&#8211;62&#37;&#41; than in those with HIV infection &#40;4&#37;&#8211;15&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">4&#44;6&#44;9&#44;12&#44;13&#44;18&#8211;20</span></a> Concurrent respiratory infections &#40;mainly by different bacteria&#44; aspergillus and cytomegalovirus&#41; have been found in 34&#37;&#8211;50&#37; of patients with autoimmune diseases and may complicate patients&#8217;recovery&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">3&#44;4&#44;11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Although there are guidelines for prophylaxis of <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection in HIV-infected patients&#44; hematological and solid organs cancer or transplant&#44;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">21&#8211;23</span></a> there are no specific consensus guidelines for patients with autoimmune diseases receiving immunosuppressive drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">20&#44;24&#44;25</span></a> In real life&#44; a survey of 727 US rheumatologists with experience in autoimmune diseases revealed that two-thirds of them prescribed PcP prophylaxis for patients with granulomatosis with polyangiitis &#40;GPA or Wegener&#41;&#44; more than one-third for systemic lupus erythematosus &#40;SLE&#41;&#44; polyarteritis nodosa &#40;PAN&#41; and other systemic vasculitides&#44; 17&#37; for inflammatory myopathies and 6&#37; for rheumatoid arthritis &#40;RA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">17</span></a> Prophylaxis was prescribed to only 12&#46;5&#37; of patients on GC monotherapy&#44; regardless of the dose&#46; However&#44; 75&#37; of professionals would recommend PcP prophylaxis to patients treated with cyclophosphamide&#44; and 50&#37;&#44; to patients treated with a combination of prednisone and other immunosuppressive agents&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">17</span></a> Similarly&#44; 50&#37; of SLE patients treated with cyclophosphamide received PcP prophylaxis in a large series&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">26</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">This review tries to shed light on the reported occurrence of PcP in the different autoimmune diseases and the current evidence for PcP prophylactic treatment of patients with autoimmune diseases receiving any type of immunosuppressive agents &#40;GC&#44; cytotoxic or biologic agents&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035"><span class="elsevierStyleItalic">Pneumocystis</span> pneumonia in systemic autoimmune diseases</span><p id="par0040" class="elsevierStylePara elsevierViewall">A recent observational study of 1092 patients with different autoimmune diseases found an incidence rate of PcP of 2&#46;37 &#40;95&#37;CI&#58; 1&#46;59&#8211;3&#46;41&#41;&#47;100 person-years&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> Overall&#44; reported mortality rates are usually high&#44; ranging from 30&#37; for RA to 62&#37; for GPA&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#44;19</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040"><span class="elsevierStyleItalic">Pneumocystis</span> pneumonia in systemic vasculitis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The incidence and mortality of PcP vary among the different forms of systemic vasculitis&#46; In small-vessel vasculitides&#44; PcP has been more frequently reported in patients with antineutrophil cytoplasmic antibody &#40;ANCA&#41;-associated vasculitis&#44; particularly in those with GPA&#44; mostly during remission induction regimens&#44;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">27&#44;28</span></a> but also several months even years after the treatment onset&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">29</span></a> While sporadic cases of PcP have been reported in microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis &#40;Churg&#8211;Strauss&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">12&#44;25&#44;27&#44;29</span></a> in patients with GPA non-receiving prophylactic drugs&#44; the occurrence of PcP is of 12&#37;&#8211;20&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">19&#44;27</span></a> Indeed&#44; PcP can also occur in GPA patients preventively treated for PcP&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">27&#44;30</span></a> Mortality due to PcP in GPA patients is specially high&#44; ranging in most studies from 25&#37; to 62&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#8211;20&#44;27&#44;28</span></a> Although with discrepancies among investigators&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> the use of cyclophosphamide has been considered a relevant risk factor for developing PcP in ANCA-associated vasculitis&#44; particularly in GPA&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">3&#44;11&#44;28&#44;29</span></a> Other risk factors identified include a low lymphocyte count before and during therapy and GC use &#62;1 month at doses &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleItalic">P&#46; jirovecii</span> infection has been sporadically reported in other small-vessel vasculitis&#44; such as cryoglobulinemic vasculitis and IgA vasculitis &#40;Henoch&#8211;Schonlein&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">20&#44;25&#44;31</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In PAN&#44; a medium-vessel vasculitis&#44; few studies have reported a concomitant PcP&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">12&#44;18&#44;25&#44;32</span></a> although when present mortality is as high as 48&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">18</span></a> Among large-vessel vasculitis&#44; no cases of PcP have been found in patients with Takayasu&#39;s arteritis<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">11&#44;27</span></a> and it appears to be rare in patients with GCA&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;12&#44;33</span></a> Kermani et al&#46; analyzed 7543 patients with GCA and only 7 &#40;0&#46;1&#37;&#41; of them developed PcP&#44; with a median time from GCA to PcP diagnosis of 4 months&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> All patients were on high doses of prednisone &#40;a median of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; at the time of PcP and none of them were on specific prophylaxis&#46; The mortality rate was of 29&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> By contrast&#44; a study of 62 consecutive diagnosed GCA patients revealed that four &#40;6&#46;5&#37;&#41; of them developed PcP and all four patients were concomitantly receiving GC and methotrexate&#44; without receiving prophylactic drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">34</span></a> Mortality similarly occurred in 25&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">34</span></a> However&#44; no cases of PcP have been reported in clinical trials about GCA&#44; even in the absence of any PcP prophylactic approach&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">27</span></a> Therefore&#44; despite of the use of initial high doses of GC and their long-term administration in GCA&#44; current data available do not support any strong recommendation for the routine use of PcP prophylaxis in GCA patients&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">35</span></a> Nevertheless&#44; preventive therapy could be reserved for patients treated with GC and methotrexate&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045"><span class="elsevierStyleItalic">Pneumocystis</span> pneumonia in systemic lupus erythematosus</span><p id="par0055" class="elsevierStylePara elsevierViewall">A 2007 systematic review including 2120 SLE patients found a 5&#37; incidence of PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">19</span></a> However&#44; in 2008&#44; a 10-year period study of 76&#44;156 patients with SLE treated with cyclophosphamide&#44; in which prophylaxis was given to 50&#37; of them&#44; showed a lower frequency of PcP &#40;0&#46;16&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">26</span></a> Other study in 2013 analyzed the occurrence of PcP in 2013 hospitalized patients with SLE &#40;without PcP prophylaxis&#41; and similarly found a low prevalence of 0&#46;3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">36</span></a> Although PcP occurrence in SLE appears to be low&#44; mortality rates are remarkably high&#44; ranging from 32&#37; to 46&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#44;19&#44;26</span></a> The authors of the larger studies concluded that routine prophylaxis against PcP was not supported&#44; but suggested that it could be considered in cases with severe leukopenia&#47;lymphopenia or in those with severe disease activity&#44; usually requiring higher GC doses&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">26&#44;36</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050"><span class="elsevierStyleItalic">Pneumocystis</span> pneumonia in rheumatoid arthritis</span><p id="par0060" class="elsevierStylePara elsevierViewall">A systematic review of 4977 patients with RA found that 1&#37; of them developed PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">19</span></a> This proportion seems to be lower in larger studies&#44; such as in a British prospective observational cohort of 19&#44;282 RA patients that found 24 &#40;0&#46;12&#37;&#41; cases of PcP &#40;all of them received either rituximab or anti-tumor necrosis factor &#91;TNF&#93; therapy&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">37</span></a> or in a nationwide Japanese multicenter study including 18&#44;668 RA patients and 60 &#40;0&#46;32&#37;&#41; cases of PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">38</span></a> None of them were taking prophylactic drugs for PcP&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">37&#44;38</span></a> A 6-year review of the FDA Adverse Event Reporting System on infliximab-treated patients found 84 cases &#40;49 with RA&#41; of PcP following infliximab therapy&#46; Despite the concomitant administration with traditional immunosuppressive medications&#44; the authors concluded that infliximab is associated with PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleItalic">P&#46; jirovecii</span> infection has been also described in RA patients treated with etanercept&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">40</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">These studies identified several factors increasing the risk for developing PcP&#44; such as and age &#8805;65 years&#44; the presence of lung disease and the use of GC&#44; methotrexate and TNF inhibitors&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">38&#44;40&#8211;42</span></a> Mortality rate in patients with RA and PcP was about 30&#37; in most studies&#44; including those receiving biologic agents&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#8211;20&#44;39</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055"><span class="elsevierStyleItalic">Pneumocystis</span> pneumonia in inflammatory myopathies&#44; systemic sclerosis&#44; sarcoidosis and other systemic autoimmune diseases</span><p id="par0070" class="elsevierStylePara elsevierViewall">PcP has rarely been reported in inflammatory myopathies&#46; A recent study of 204 patients with dermatomyositis&#44; polymyositis and sporadic inclusion body myositis with a long-term follow-up found only one &#40;0&#46;5&#37;&#41; case who had developed PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">43</span></a> In other studies&#44; PcP occurrence ranged from 0&#37; to 11&#37; of patients with inflammatory myopathies&#44; particularly affecting those patients with interstitial lung disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">12&#44;19&#44;43&#44;44</span></a> In a series of four patients with dermatomyositis and PcP&#44; three &#40;75&#37;&#41; of them died&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">45</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">No studies about prevalence of PcP in systemic sclerosis have been found&#46; A series of 223 patients with autoimmune diseases and PcP identified 5&#37; of patients with systemic sclerosis&#44; with a mortality rate of 17&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">18</span></a> A retrospective study of 585 patients with sarcoidosis who did not received prophylactic therapy for PcP showed that three &#40;0&#46;5&#37;&#41; of them developed PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">46</span></a> In addition&#44; PcP has been sporadically reported in other autoimmune diseases&#44; including cutaneous vasculitis&#44; Beh&#231;et&#39;s disease&#44; adult-onset Still disease&#44; ankylosing spondylitis&#44; Sj&#246;gren syndrome and polymyalgia rheumatica&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">12&#44;25&#44;47</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunosuppressive therapies and <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Glucocorticoids and conventional immunosuppressive drugs</span><p id="par0080" class="elsevierStylePara elsevierViewall">Immunosuppressive therapies used in autoimmune diseases&#44; including GC&#44; cyclophosphamide&#44; methotrexate&#44; azathioprine and biologic agents&#44; mainly TNF-blockers and anti-CD20 agents&#44; have been associated with PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> Of note&#44; GC and all the other immunosuppressive agents can decrease total lymphocyte and CD4&#43; cell counts&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">14&#44;39</span></a> Among these drugs&#44; GC seem to be the common risk factor for PcP&#44; since almost all patients receive GC prior to the infection onset&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">11&#44;25&#44;30</span></a> A study of 1092 patients with autoimmune diseases and 30 PcP cases found a mean interval between immunosuppression was started and PcP of 3&#46;4 months &#40;SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;5&#41;&#44; a mean daily dose of prednisone of 31<span class="elsevierStyleHsp" style=""></span>mg &#40;SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41; and 90&#37; of patients receiving &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day at the time of PcP diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> In different studies&#44; the daily dose that appears to confer risk of PcP has been reported &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">11&#44;25&#44;27&#44;30</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The use of any of the additional immunosuppressant agents &#40;cyclophosphamide&#44; methotrexate or azathioprine&#41; during the first two weeks of GC therapy was found to be an independent risk factor for PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">30</span></a> Although the role of cyclophospamide as an independent factor contributing to the development of PcP is still controversial&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> in ANCA-associated vasculitis&#44; and particularly in GPA&#44; PcP occurrence has been described associated to the use of high GC doses in addition to cyclophosphamide&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">28&#44;29</span></a> In this regard&#44; EULAR guidelines encourage prophylaxis during cyclophosphamide therapy in ANCA-associated vasculitis&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">48</span></a> The use of methotrexate has been associated with the development of PcP in RA patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">41&#44;42</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Anti-TNF agents</span><p id="par0090" class="elsevierStylePara elsevierViewall">Although <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection in patients treated with anti-TNF drugs have been repeatedly reported&#44;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">39&#44;49</span></a> the incidence of PcP is really low&#44; as showed by two large French &#40;0&#46;009&#41; and American &#40;0&#46;06&#41; series of patients treated with TNF-inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">39</span></a> In 2007&#44; the FDA Adverse Event Reporting System determined that the use of infliximab was associated with an incremented risk of <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">39</span></a> Most patients treated with TNF-inhibitors develop PcP after a mean of two infusions of infliximab<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">39</span></a> and within 26 weeks following the first injection of etanercept&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">40</span></a> Although 27&#37; of PcP patients on TNF-blockers died&#44; mortality did not differ from PcP in other RA patients treated with different immunosuppressive drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#8211;20&#44;39</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Rituximab</span><p id="par0095" class="elsevierStylePara elsevierViewall">Rituximab is associated with the development of PcP in patients with lymphoproliferative and autoimmune diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">9&#44;14</span></a> While 11&#37; of hematological patients receiving rituximab together with chemotherapy regimens may develop PcP&#44; in a review of 516 patients with ANCA-associated vasculitis treated with rituximab&#44; the occurrence of PcP has been reported of 1&#46;2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">14</span></a> PcP occurred from two to 32 months after the last rituximab infusion&#44; equally in monotherapy or in combination with other immunosuppressive drugs&#46; Mortality rate was of 33&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">The role of total lymphocyte and CD4&#43; counts on <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia prophylaxis in autoimmune diseases</span><p id="par0100" class="elsevierStylePara elsevierViewall">International guidelines recommend PcP prophylaxis for all HIV-infected persons with a CD4&#43; cell count &#60;200<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> and for all those with hematological conditions&#44; including transplant recipients&#44; children with well-defined primary immune deficiencies and patients treated with GC for more than four weeks&#44; alemtuzumab or any combination of fludarabine&#44; cyclophosphamide and rituximab&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">22</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Regarding patients with autoimmune diseases&#44; several studies have addressed the recommendations of PcP prophylaxis based on total lymphocyte and&#47;or CD4&#43; lymphocyte counts&#46; A study identified a total lymphocyte count &#60;500&#47;&#956;l after two weeks of the institution of GC as an independent risk factor for developing PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">30</span></a> Other authors have recommended PcP prophylaxis in patients with a total lymphocyte count &#60;800&#47;&#956;l&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">32&#44;44&#44;50</span></a> Regarding CD4&#43; lymphocyte counts&#44; a systematic review of 14 well-selected studies including 515 HIV-seronegative immunocompromised patients with PcP &#40;144 of them with autoimmune or inflammatory conditions&#41; found that a CD4&#43; cell count was &#60;200&#47;&#956;l in 73&#37; of patients&#46; This cut-off value was considered a sensitive biomarker to identify non-HIV immunocompromised patients who are at risk for PcP&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">13</span></a> Similarly&#44; other studies on autoimmune diseases have pointed out a CD4&#43; cell count &#60;200&#47;&#956;l as the value for which <span class="elsevierStyleItalic">P&#46; jirovecii</span> prophylaxis is warranted&#44;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">44&#44;50</span></a> since the annual risk of PcP on these patients appears to be greater than 9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">3</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Despite all these considerations&#44; in a daily basis&#44; only 15&#37; of physicians treating autoimmune diseases routinely consider lymphocyte counts&#44; and 7&#46;5&#37; of them monitor CD4&#43; cell counts&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">17</span></a></p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Duration of <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia prophylaxis in autoimmune diseases based on CD4&#43; cell counts</span><p id="par0115" class="elsevierStylePara elsevierViewall">While discontinuation of primary PcP prophylaxis in HIV-infected patients on antiretroviral therapy appears to be safe in subjects with a negative viral load and a CD4&#43; cell count &#62;100&#47;&#956;l&#44;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">21&#44;51</span></a> for hematological disorders&#44; PcP prophylaxis cessation is recommended in cases in which immunosuppressive therapy has ended or the CD4&#43; cell count has increased to &#62;200<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">22</span></a> In patients undergoing a kidney transplant&#44; PcP prophylaxis is recommended between four and 12 months after transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">13</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In autoimmune diseases&#44; some authors have proposed to discontinue prophylactic therapy when CD4&#43; cell counts are probed to be &#62;200&#47;&#956;l&#44; at least during 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">35</span></a> As well as in patients with hematological malignancies or transplant recipients&#44; in those with autoimmune diseases&#44; it is advisable to raise awareness about the persistence of certain immunocompromised status&#44; including a qualitative alteration in CD4&#43; lymphocytes&#44; after cessation of immunosuppressive drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">35</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Medications used for <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia prophylaxis in autoimmune diseases</span><p id="par0125" class="elsevierStylePara elsevierViewall">As reported in cancer individuals on chemotherapy or undergoing bone marrow transplantation&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">8&#44;10</span></a> in patients with autoimmune diseases&#44; those who seem at risk of developing PcP are patients not receiving PcP prophylaxis&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;19&#44;27&#44;36&#44;38&#44;42&#44;46</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The efficacy of PcP prophylactic treatment for non&#8211;HIV immunocompromised patients&#44; including those with autoimmune diseases requiring prolonged GC or other immunosuppressive drugs&#44; was assessed by a 2007 systematic review and meta-analysis analyzing 12 randomized controlled trials and 1245 patients &#40;50&#37; children&#41; on PcP prophylaxis&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> TMP&#8211;SMX reduced by 91&#37; the occurrence of PcP and significantly reduced PcP-related mortality&#46; In addition&#44; adverse events leading to treatment cessation were all reversible and only occurred in 3&#37; of adults&#46; Once the risk for severe adverse events is balanced&#44; the authors recommended PcP prophylaxis in adult patients with an expected risk for PcP equal to or higher than 3&#46;5&#37; during the period of immunodeficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> Among patients with autoimmune diseases&#44; these rates of risk were observed only in those with GPA&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> Other conditions&#44; such as PAN&#44; SLE&#44; systemic sclerosis and RA were associated with lower incidence rates in the analyzed cohorts&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> Of note&#44; in terms of efficacy&#44; no differences were observed between once-daily and thrice-weekly administration of TMP&#8211;SMX&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A 2008 study of 1092 patients with autoimmune diseases and 30 with PcP&#44; found that prophylaxis with TMP&#8211;SMX tended to reduce 1-year incidence of PcP in the whole group&#44; but clearly reduced the occurrence of PcP in GPA patients receiving initial prednisone doses &#8805;60<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> This preventive effect was not observed in patients receiving lower doses&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Adverse effects associated with TMP-SMX have been reported in 3&#37; to 21&#37; of patients with autoimmune diseases&#44; depending of the studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">25&#44;52&#44;53</span></a> Anyway&#44; they seem to be lower than in HIV-infected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> Among autoimmune diseases&#44; adverse events have been described to be higher in patients with SLE &#40;11&#37;&#41; and mixed connective tissue disease &#40;33&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">53</span></a> since they occurred in 25&#37; of patients carrying anti-RNP antibody &#40;an autoimmune marker for mixed connective tissue disease&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">53</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The use of methotrexate in combination with full doses of TMP&#8211;SMX can cause severe cytopenias and bone marrow suppression because both drugs share the inhibition of dihydrofolate reductase as mechanism of action&#46; However&#44; this unsafe interaction does not seem to occur at prophylactic doses of TMP&#8211;SMX&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">54</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Other drugs used for PcP prophylaxis as an alternative to TMP&#8211;SMX include dapsone atovaquone and aerosolized pentamidine&#46; Their recommended doses and main adverse effects are depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; However&#44; these drugs have not been evaluated in patients with autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Proposed options for <span class="elsevierStyleItalic">Pneumocystis</span> pneumonia prophylaxis in autoimmune diseases</span><p id="par0155" class="elsevierStylePara elsevierViewall">Considering the different risk factors identified for PcP in immunocompromised patients with autoimmune diseases&#44; several proposals for giving prophylactic therapy for <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection have been delineated&#46; Among them&#44; two groups of investigators recommend PcP prophylaxis in the next situations&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0160" class="elsevierStylePara elsevierViewall">If patients meet &#8805;2 of 4 of these risk factors&#58; &#40;a&#41; prednisone &#40;or equivalent&#41; &#8805;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day for &#62;4 weeks&#59; &#40;b&#41; current use of &#8805;2 immunosuppressive agents&#44; including biologic agents&#59; &#40;c&#41; absolute lymphocyte count &#60;350<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l&#59; and &#40;d&#41; having an underlying parenchymal lung disease&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">54</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0165" class="elsevierStylePara elsevierViewall">If patients have a CD4&#43; cell count &#60;200&#47;&#956;l after one month of starting immunosuppressive therapy&#44; only if they previously followed the three &#8220;screening criteria&#8221;&#58; &#40;a&#41; GC dosage &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day prednisolone &#40;or equivalent&#41;&#59; &#40;b&#41; GC treatment &#62;3 months&#59; and &#40;c&#41; a total lymphocyte count &#60;600<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">3</span></a></p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">In the same sense&#44; we advocate for considering PcP prophylaxis in any patient with an autoimmune disease in whom long-term &#40;&#62;3 months&#41; treatment is expected&#44; when&#58; &#40;a&#41; receiving prednisone &#40;or equivalent&#41; &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day together with cyclophosphamide&#59; or &#40;b&#41; receiving prednisone &#40;any dose&#41; and other immunosuppressive &#40;cytotoxic or biologic&#41; agent different than cyclophosphamide&#44; when total lymphocyte counts &#60;800&#47;&#956;l or CD4&#43; cell counts &#60;200&#47;&#956;l&#46; It also seems reasonable to consider PcP prophylaxis cessation when prednisone doses achieve &#60;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day and the second immunosuppressant drug has been stopped&#44; always in situations in which a recovery of total lymphocyte and CD4&#43; counts can be confirmed&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Final considerations</span><p id="par0175" class="elsevierStylePara elsevierViewall">Despite the increased risk of PcP in patients with autoimmune diseases&#44; the overall incidence of <span class="elsevierStyleItalic">P&#46; jirovecii</span> infection in this population remains relatively low&#46; However&#44; when PcP occurs in these patients&#44; mortality is high&#44; usually ranging between 30&#37; and 50&#37;&#46; Almost all patients in whom PcP occurs do not receive any prophylactic treatment&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Although there are no current consensus guidelines established to assist physicians in treating patients with autoimmune diseases for PcP prophylaxis&#44; several risk factors for developing PcP have been identified and include&#58; &#40;a&#41; the underlying disease &#40;being GPA the autoimmune disease with the highest risk&#41;&#59; &#40;b&#41; maintained GC therapy for &#62;3 months with prednisone &#40;or equivalent&#41; doses of &#62;15<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#59; &#40;c&#41; the use of an additional immunosuppressive agent&#44; mainly cyclophosphamide&#44; methotrexate&#44; TNF-inhibitors and rituximab&#59; &#40;d&#41; total lymphocyte counts &#60;600&#47;&#956;l and&#47;or CD4&#43; cell counts &#60;200&#47;&#956;l&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Currently&#44; even physicians with experience in autoimmune diseases generally treat with prophylactic doses of SMX-TMP those patients they subjectively believe are at high risk for PcP&#46; Although several recommendations have tried to address this matter&#44; various unresolved issues about PcP prophylaxis in these patients need to be clarified&#46; Large prospective studies focused in investigating and validating the clinical value balanced with the risk of adverse effects of PcP prophylaxis and its duration&#44; together with the assessment of total lymphocytes and CD4&#43; cell counts as markers for guiding prophylaxis in patients with autoimmune diseases are needed in order to generate robust and consensus guidelines&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0190" class="elsevierStylePara elsevierViewall">All authors have seen and approved the manuscript being submitted&#46; On behalf of all co-authors&#44; the corresponding author shall bear full responsibility for the submission&#44; warrant that the article has not received prior publication and is not under consideration for publication elsewhere and also declare no financial disclosure or conflict of interest&#46;</p></span></span>"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
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          "titulo" => "Pneumocystis pneumonia in systemic autoimmune diseases"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Pneumocystis pneumonia in systemic vasculitis"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Pneumocystis pneumonia in systemic lupus erythematosus"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Pneumocystis pneumonia in rheumatoid arthritis"
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              "identificador" => "sec0030"
              "titulo" => "Pneumocystis pneumonia in inflammatory myopathies&#44; systemic sclerosis&#44; sarcoidosis and other systemic autoimmune diseases"
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          "identificador" => "sec0035"
          "titulo" => "Immunosuppressive therapies and Pneumocystis pneumonia"
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            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Glucocorticoids and conventional immunosuppressive drugs"
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              "identificador" => "sec0045"
              "titulo" => "Anti-TNF agents"
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            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Rituximab"
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          "identificador" => "sec0055"
          "titulo" => "The role of total lymphocyte and CD4&#43; counts on Pneumocystis pneumonia prophylaxis in autoimmune diseases"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Duration of Pneumocystis pneumonia prophylaxis in autoimmune diseases based on CD4&#43; cell counts"
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          "identificador" => "sec0065"
          "titulo" => "Medications used for Pneumocystis pneumonia prophylaxis in autoimmune diseases"
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        10 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Proposed options for Pneumocystis pneumonia prophylaxis in autoimmune diseases"
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        11 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Final considerations"
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        12 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-11-11"
    "fechaAceptado" => "2019-01-20"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1124529"
          "palabras" => array:8 [
            0 => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>"
            1 => "<span class="elsevierStyleItalic">Pneumocystis</span> pneumonia"
            2 => "Autoimmune diseases"
            3 => "PcP prophylaxis"
            4 => "Immunosuppressive drugs"
            5 => "Glucocorticoids"
            6 => "Cyclophosphamide"
            7 => "Biologic agents"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1124528"
          "palabras" => array:10 [
            0 => "ANCA"
            1 => "GCA"
            2 => "GC"
            3 => "GPA"
            4 => "PcP"
            5 => "PAN"
            6 => "RA"
            7 => "SLE"
            8 => "TMP&#8211;SMX"
            9 => "TNF"
          ]
        ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1124527"
          "palabras" => array:8 [
            0 => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>"
            1 => "<span class="elsevierStyleItalic">Pneumocystis</span> pneumonia"
            2 => "Enfermedades autoinmunes"
            3 => "Profilaxis de PcP"
            4 => "F&#225;rmacos inmunodepresores"
            5 => "Glucocorticoides"
            6 => "Ciclofosfamida"
            7 => "Agentes biol&#243;gicos"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Pneumocystis jirovecii</span> &#40;<span class="elsevierStyleItalic">P&#46; jirovecii</span>&#41; causes a potentially fatal pneumonia in immunocompromised individuals &#40;<span class="elsevierStyleItalic">Pneumocystis</span> pneumonia or PcP&#41;&#44; particularly in HIV-infected patients and those treated with immunosuppressive drugs&#44; such as transplant patients and those with systemic autoimmune diseases&#46; <span class="elsevierStyleItalic">P&#46; jirovecii</span> colonization can be found in almost a third of patients with systemic autoimmune diseases&#46; Although the incidence of PcP in such patients is usually low&#44; mortality is quite high&#44; ranging between 30&#37; and 50&#37; in the majority of autoimmune diseases&#46; PcP development is almost always observed in patients not receiving prophylaxis for the infection&#46; Despite the above&#44; there are no clinical guidelines established for PcP prophylaxis in patients with autoimmune diseases treated with glucocorticoids&#44; cytotoxic drugs&#44; or more recently&#44; biological agents&#46; The objective of this review is to analyze the available data on the incidence of PcP and the effect of PcP prophylaxis in patients with autoimmune diseases that may be useful in clinical practice&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El hongo <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> &#40;<span class="elsevierStyleItalic">P&#46; jirovecii</span>&#41; es la causa de una neumon&#237;a &#40;<span class="elsevierStyleItalic">Pneumocystis</span> pneumonia o PcP&#41; potencialmente mortal en individuos inmunodeprimidos&#44; sobre todo en pacientes infectados por el VIH&#44; y en aquellos tratados con f&#225;rmacos inmunodepresores&#44; como los sometidos a trasplantes y los afectos de enfermedades autoinmunes sist&#233;micas&#46; En estos &#250;ltimos&#44; alrededor de un tercio de los casos puede estar colonizado por <span class="elsevierStyleItalic">P&#46; jirovecii</span> y&#44; aunque la incidencia de la PcP suele ser baja&#44; la mortalidad de la misma es considerablemente alta&#44; y oscila entre el 30 y el 50&#37; en la mayor&#237;a de las enfermedades autoinmunes&#46; El desarrollo de la PcP se observa casi siempre en pacientes que no reciben profilaxis para la infecci&#243;n&#46; Aun as&#237;&#44; no existen gu&#237;as cl&#237;nicas establecidas para la profilaxis de la PcP en pacientes afectos de enfermedades autoinmunes que son tratados con glucocorticoides&#44; f&#225;rmacos citot&#243;xicos o m&#225;s recientemente&#44; con agentes biol&#243;gicos&#46; El objetivo de esta revisi&#243;n es analizar los datos disponibles sobre la incidencia de la PcP y el efecto de la profilaxis para infecci&#243;n por <span class="elsevierStyleItalic">P&#46; jirovecii</span> en los pacientes afectos de enfermedades autoinmunes que puedan ser &#250;tiles en la pr&#225;ctica cl&#237;nica&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Usual doses&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main adverse effects&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">First option</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Trimethoprim&#8211;sulfamethoxazole&#40;TMP&#47;SMX&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 double strength &#40;160<span class="elsevierStyleHsp" style=""></span>mg TMP<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>800<span class="elsevierStyleHsp" style=""></span>mg SMX&#41; oral tablet&#47;day or 3<span class="elsevierStyleHsp" style=""></span>times&#47;week&#44; or1 single strength &#40;80<span class="elsevierStyleHsp" style=""></span>mg TMP<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>400<span class="elsevierStyleHsp" style=""></span>mg SMX&#41; oral tablet&#47;day &#40;orally&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Nausea&#44; abdominal pain&#44; hypersensitivity reactions &#40;rashes&#44; fever&#41;&#44; elevated creatinine&#44; hyperkalemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Second option</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dapsone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">50<span class="elsevierStyleHsp" style=""></span>mg twice&#47;day or 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;orally&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Anemia&#44; hemolysis&#44; methemoglobinemia&#40;G6PD deficiency must be checked prior to starting therapy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Atovaquone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">750<span class="elsevierStyleHsp" style=""></span>mg twice&#47;day or 1500<span class="elsevierStyleHsp" style=""></span>mg orally once&#47;day &#40;orally&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nausea&#44; diarrhea&#44; rash&#44; hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pentamidine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">300<span class="elsevierStyleHsp" style=""></span>mg&#47;month &#40;aerosolized&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Fever&#44; respiratory symptoms &#40;cough&#44; bronchospasm&#44; pneumothorax&#41;&#44; pancreatitis&#44; arrhythmia&#44; hypotension&#44; hypoglycemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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      "titulo" => "References"
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          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:54 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Pneumocystis</span> pneumonia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;F&#46; Thomas Jr&#46;"
                            1 => "A&#46;H&#46; Limper"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra032588"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2004"
                        "volumen" => "350"
                        "paginaInicial" => "2487"
                        "paginaFinal" => "2498"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15190141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Pneumocystis</span> colonization is highly prevalent in the autopsied lungs of the general population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "C&#46;A&#46; Ponce"
                            1 => "M&#46; Gallo"
                            2 => "R&#46; Bustamante"
                            3 => "S&#46;L&#46; Vargas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/649868"
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