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jirovecii</span> &#40;NPJ&#41; is due to the reactivation of a latent infection in an immunocompromised patient&#44; current data show that it is a <span class="elsevierStyleItalic">de novo</span> infection&#46; Nevertheless&#44; colonisation by <span class="elsevierStyleItalic">P&#46; jirovecii</span> has been shown to exist in certain susceptible populations&#44; although the clinical implications of this finding are unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Once it has been acquired&#44; <span class="elsevierStyleItalic">P&#46; jirovecii</span> passes through a complicated life-cycle&#46; It has two predominant forms&#44; trophic and cystic&#44; of which the first type represents 90&#37; of the total number of <span class="elsevierStyleItalic">P&#46; jirovecii</span> organisms during infection&#46; Trophic forms are united by interdigitations to the cellular membrane of the type I pneumocyte in the alveolar epithelium&#44; permitting the close unification of both membranes without breaking the alveolar cell or penetrating it&#46; The interaction of <span class="elsevierStyleItalic">P&#46; jirovecii</span> with the pneumocyte and alveolar macrophages triggers a cascade of cellular responses in <span class="elsevierStyleItalic">P&#46; jirovecii</span> itself as well as in the lung cells&#58; <span class="elsevierStyleItalic">P&#46; jirovecii</span> is stimulated to proliferate&#44; at the same time that the alveolar macrophages commence phagocytosis of <span class="elsevierStyleItalic">P&#46; jirovecii</span> and its destruction&#44; and the alveolar cells release proinflammatory cytokines and chemokines that promote the recruitment and activation of neutrophils and T lymphocytes&#46; T CD4&#43; lymphocytes encharged with coordinating the inflammatory response of the host&#44; recruiting and activating additional immune effecter cells &#40;monocytes and macrophages&#41; which will be responsible for eliminating <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; In immunocompetent individuals the infection is eliminated with minimum inflammation and lung damage&#46; However&#44; in immunocompromised hosts a hyperinflammatory response is trigged that is unable to eliminate <span class="elsevierStyleItalic">P&#46; jirovecii</span> but which causes lung damage and affects gas interchange&#46; This causes NPJ&#44; the chief manifestation of this infection&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical manifestations</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">P&#46; jirovecii</span> has a special tropism for the lungs&#44; and its dissemination in the rest of an infected organism is exceptional&#46; Interstitial pneumonia is the main disease caused by <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; The most common symptoms are the appearance of a dry cough&#44; dyspnoea&#44; fever&#44; tachycardia and tachypnea&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In pulmonary auscultation the presence of fine rales stands out&#44; and in thoracic X-ray there is tenuous bilateral interstitial infiltrate&#46; High resolution computed tomography &#40;HRCT&#41; shows higher sensitivity in detecting NPJ than simple X-ray imaging&#44; showing the characteristic areas of ground glass opacity in peri-hiliar distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Generally high levels of lactate dehydrogenase &#40;LDH&#41; are detected&#44; with a fall in serum albumin and CD4&#43; counts &#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#46; Due to damage in the alveolar epithelium the blood gases are altered&#44; detecting hypoxemia and&#47;or respiratory failure in arterial gasometry&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In immunocompromised patients without HIV&#44; the infection usually runs a more acute course&#44; manifesting with fewer systemic symptoms but with greater respiratory repercussion &#40;a higher level of respiratory failure and tachypnea&#41;&#44; and in broncoalveolar washing a lower concentration of organisms is detected&#44; although with a higher neutrophil count<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and&#44; in general&#44; the condition tends to be more severe&#44; with a longer stay in intensive care units and higher rates of mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;12</span></a> This higher mortality has been associated with low PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> coefficients&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> with the need for mechanical ventilation&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> hypoalbuminemia&#44; male sex&#44; advanced age and medical care in private hospitals&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The magnitude of the problem</span><p id="par0040" class="elsevierStylePara elsevierViewall">This infection is often lethal&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The mortality rate is close to 100&#37; without treatment&#44; and it varies from 5&#37; to 40&#37; in treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The rate of mortality due to NPJ in patients without HIV currently stands at from 39&#46;4&#37; to 59&#46;1&#37;&#44; a figure far higher than the 6&#37;&#8211;7&#37; recorded in HIV&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The individuals at the greatest risk of NPJ are patients with HIV&#44; especially those with CD4&#43; counts &#60;200&#47;mm&#59;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> those who have received organ transplants or haematopoietic cells&#59;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> premature infants who require mechanical ventilation&#59; patients with primary immunodeficiencies that affect T lymphocyte functioning<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and patients who receive oncological chemotherapy or are treated with immunosuppressor drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The use of antiretroviral drugs to treat HIV infection together with prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span> following the recommendations of clinical practice guides<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> have drastically reduced the incidence of NPJ in developed countries in patients with AIDS&#44; from rates of 70&#37;&#8211;80&#37; before implementing these measures&#44; to fewer than one case per 100 persons-year&#46; On the contrary&#44; an increase in incidence has been observed in immunocompromised patients without HIV&#58; rates of incidence vary depending on the disease&#44; but they may reach 44&#46;6 cases per 100&#44;000 patients&#47;year in those who have received transplants&#44; &#62;45 cases per 100&#44;000 patients&#47;year in haematological neoplasias&#44; 53&#46;6 cases per 100&#44;000 patients&#47;year in inflammatory myopathies&#44; 71&#46;9 cases per100&#44;000 patients&#47;year in vasculitis associated with anti-neutrophil cytoplasm antibodies &#40;ANCA&#41; and 93&#46;2 cases per 100&#44;000 patients&#47;year in patients with panarteritis nodosa &#40;PAN&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Guides for the prophylaxis of NPJ have recently been published for patients with haematological diseases and organ transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Nevertheless&#44; to date no guide for the prophylaxis of NPJ has been published for patients with RD&#38;SA under immunosuppressor treatment&#46; Several authors have expressed the advisability of having these guides&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> as they would help to unify criteria which are currently very varied&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">As occurs in other pathologies&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> the risk of NPJ in patients with RD&#38;SA will be determined by the combination of different factors&#58; 1&#41; the disease&#59; 2&#41; the drugs used&#59; and 3&#41; the particular circumstances of each individual&#46; When deciding on the advisability of administering prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#44; it is also necessary to consider the potential toxicity of the treatment used for this&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> It has been suggested that a &#34;level of risk of NPJ&#34; higher than 3&#46;5&#37; should be the cut-off point for considering that the beneficial effect of prophylaxis is greater than the risk&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Finally&#44; it has to be taken into account that many of these factors will be modified over time&#44; so that continuous re-evaluation will be required of the risk&#47;benefit during the follow-up of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Risks associated with the disease</span><p id="par0060" class="elsevierStylePara elsevierViewall">The incidence of NPJ varies notably from some RD&#38;SA to others&#44; and it is higher in granulomatous vasculitis with polyangiitis &#40;VGP&#41;&#44; PAN&#44; systemic lupus erythematosus &#40;SLE&#41; and inflammatory myopathies&#44; making an individualised approach necessary&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">ANCA-associated vasculitis</span><p id="par0065" class="elsevierStylePara elsevierViewall">ANCA-associated vasculitis patients have a higher rate of NPJ incidence within RD&#38;SA &#40;8&#46;9 cases per every 1&#44;000 hospitalisations&#47;year in VGP&#44; 120&#47;10&#46;000 patients&#47;years&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;27&#44;28</span></a> with a very high mortality rate &#40;47&#37;&#8211;62&#46;5&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;15</span></a> The main factor associated with the development of NPJ in patients with VGP is lymphopenia&#58; lymphocyte levels under 800&#47;mm<span class="elsevierStyleSup">3</span> prior to treatment&#44; or below 600&#47;mm<span class="elsevierStyleSup">3</span> three months after the start of treatment&#44; were associated with the development of NPJ in a retrospective study&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Due to the high incidence of NPJ in these patients during induction treatment&#44; the European guide for the management of ANCA-associated vasculitis recommends prophylaxis with TMP-SMX in all of the patients treated with cyclophosphamide &#40;CFM&#41;&#44; and it mentions its usefulness in maintaining remission as it reduces the risk of relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Other authors recommend prophylaxis during induction even when other drugs are given&#44; such as rituximab&#44; on condition that the dose of corticoid is higher than 10<span class="elsevierStyleHsp" style=""></span>mg&#44; as well as with lymphocyte counts below 300&#47;mm&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Other types of vasculitis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The incidence of NPJ in PAN is 6&#46;5 cases per 1&#44;000 hospitalisations&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> with a mortality of 47&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In large vessel arteritis incidence is surprisingly low&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> in spite of the use of high doses of corticoids over prolonged periods of time&#46; None of the European management recommendations mentions NPJ prophylaxis&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Systemic lupus erythematosus &#40;SLE&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall">There is no uniform criterion for indicating NPJ prophylaxis in patients with SLE&#58; the overall incidence of this opportunist infection is lower than the level found in vasculitis-ANCA and inflammatory myopathies &#40;5&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> 1&#46;2 cases per 1&#44;000 hospitalisations&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> 8 cases per 10&#44;000 patients&#47;year<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#41;&#44; although rates of mortality are high &#40;20&#37;&#8211;45&#46;7&#37;&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;36</span></a> which more than justifies its treatment&#46; Numerous publications agree on the factors that predispose to the development of NPJ&#58; disease that is more active&#44; nephritis&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> the use of glucocorticoids &#40;GC&#41; at high doses&#44; treatment with cyclophosphamide<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and&#44; most especially&#44; lymphopenia&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29&#44;36</span></a> Taking the recommendations for prophylaxis in patients with HIV as a guide&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Lertnawapan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> recommend starting prophylaxis when total levels of lymphocytes fall below 750&#47;mm<span class="elsevierStyleSup">3</span> or when CD4&#43; &#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">There is special concern regarding the use of trimethoprim-sulfamethoxazole &#40;TMP-SMX&#41; in patients with SLE&#58; high rates of adverse reactions have been reported in from 27&#46;3&#37;&#8211;53&#37; of cases<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> &#40;cutaneous rash&#44; exacerbation of the SLE&#44; hepatic toxicity and myelosuppression&#41;&#44;which is more frequent in patients who are anti-Ro&#47;SS-A positive&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> although they are generally mild and do not require discontinuation of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;39</span></a> Nevertheless&#44; this factor should be taken into account when recommending prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; It would therefore be desirable to have guides&#44; recommendations or algorithms<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> that would help clinicians to reach decisions on an individualised basis&#58; unfortunately&#44; the European guides for the management of SLE do not include any recommendations on this subject&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Inflammatory myopathies</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patients with inflammatory myopathies have NPJ rates lower than those recorded for ANCA-associated vasculitis&#44; although higher than in SLE&#44; with figures that vary depending on the series from 2&#37; to 10&#37; of pacientes&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;41</span></a> and it is the cause in 27 cases of every 10&#44;000 hospitalisations&#47;year&#46; As occurred in the previous cases&#44; the rate of mortality is very high&#44; at from 33&#37; to 57&#46;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Lymphopenia is once again the predisposing factor&#44; so that some authors recommend starting prophylaxis when CD4&#43; lymphocyte counts are below 250&#47;mm&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rheumatoid arthritis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patients with rheumatoid arthritis &#40;RA&#41; are generally considered to be low risk for the development of NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Although the use of immunosuppressor drugs and biological agents increases the risk&#44; the figures are below 0&#46;1&#37;-0&#46;3&#37;&#44; with mortality rates that vary from 10&#37; to 28&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> There is also the additional risk of the MTX&#47;TMP-SMX combination&#46; Due to this&#44; and although systematic prophylaxis is not recommended&#44; some authors consider that certain preventive measures should be adopted&#44; such as the detection of <span class="elsevierStyleItalic">P&#46; jirovecii</span> carriers to implement treatment to eradicate it&#44; thereby avoiding any subsequent prophylaxis&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Drug associated risk</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Glucocorticoids</span><p id="par0100" class="elsevierStylePara elsevierViewall">GC are an essential part of the arsenal for the treatment of a large number of RD&#38;SA&#46; The association between GC and the development of NPJ has been clearly established&#44; considering it to be the main risk factor&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Several mechanisms interconnect to facilitate infection&#58; the prolonged use of GC causes a fall in T CD4&#43; lymphocytes&#44; in the blood as well as in the lungs<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> and&#44; although it has not been clearly determined&#44; it probably affects the functioning of alveolar macrophages&#44; hindering phagocytosis and the destruction of <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The risk of NPJ is dose and time-dependent&#44; and doses higher than 60<span class="elsevierStyleHsp" style=""></span>mg&#47;day of prednisone lead to higher risk&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> although daily doses of 16<span class="elsevierStyleHsp" style=""></span>mg for periods of eight weeks may be sufficient to induce NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Nevertheless&#44; it seems that another factor is necessary&#44; given that in ACG the risk is low in spite of high doses of GC over a prolonged period of time&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The type of disease&#44; concomitant use of cyclophosphamide and the presence of lymphopenia have all been shown to be additional predisposing factors for the development of NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Prophylaxis with TMP-SMX is highly effective&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> although in some studies this protective effect was only demonstrated when high doses of corticoids were used&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">There are not enough data in the literature to permit giving specific figures for dosage or treatment times over which prophylaxis should begin&#46; A dose of prednisone of 16&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day or higher has been suggested&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;46</span></a> as well as duration of treatment lasting eight weeks&#44; after which prophylaxis is indicated&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In spite of all these data&#44; curiously the EULRA recommendations on the use of GC do not mention either the risk or the advisability of prevention&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#8211;49</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Immunosuppressor drugs</span><p id="par0120" class="elsevierStylePara elsevierViewall">Although CFM has been implicated in the development of NPJ&#44; in a dose-dependent relationship&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> its effect may be associated with other immunosuppressor factors such as the use of GC&#46; Systematic prophylaxis is therefore not recommended&#44; and treatment has to be individualised depending on the presence of other predisposing factors&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The role of other immunosuppressor drugs &#40;methotrexate&#44; azathioprine and mycophenolate&#41; as predisposing factors for NPJ has not been clearly demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Biological agents</span><p id="par0130" class="elsevierStylePara elsevierViewall">There are currently no specific recommendations&#46; The British Society of Rheumatology registry of biological treatments found a higher incidence in patients treated with rituximab respecting those treated with drugs that inhibit tumour necrosis factor &#40;anti-TNF&#41; &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#59; CI 95&#37;&#58; 1&#46;4&#8211;7&#46;5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Given the low incidence in the majority of the series &#40;0&#46;03&#37;-0&#46;3&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> systematic prophylaxis is not recommended for all patients receiving biological treatment&#44; although it would be of interest to identify the subgroups at especial risk which could benefit from this prophylaxis&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Risk associated with individual factors</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Lymphopenia</span><p id="par0135" class="elsevierStylePara elsevierViewall">Lymphopenia has been shown to be one of the main predisposing factors for NPJ in patients with RD&#38;SA&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;15&#44;27&#44;29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;50&#44;53</span></a> The clinical practice guides for patients with HIV&#44; indicate starting prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span> when levels of CD4&#43; are below 200&#47;mm&#46;<span class="elsevierStyleSup">318</span> Several studies find counts of below 250&#47;mm<span class="elsevierStyleSup">3</span> in all of the patients who develop NPJ&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;54</span></a> Although the evidence is not so solid&#44; in patients with RD&#38;SA several authors recommend starting prophylaxis based on the same criterion&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Total lymphocyte levels prior to starting treatment have also be shown to be useful as a predictive factor&#58; in VGP&#44; NPJ is associated with pre-treatment lymphocyte levels below 800&#47;mm<span class="elsevierStyleSup">3</span>&#59;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Porges et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> find figures under 350&#47;mm<span class="elsevierStyleSup">3</span> identify all of the patients with SLE treated with GC and cytotoxic drugs in the risk of NPJ&#59; and in a heterogeneous group of connective tissue pathologies Ogawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> found an association between counts below 500&#47;mm<span class="elsevierStyleSup">3</span> two weeks before starting treatment with corticoids at doses higher than 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; Although it seems that absolute lymphopenia really is a predisposing factor for NPJ&#44; nobody has dared to set a cut-off point under which prophylaxis is indicated&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">The drug of choice for prophylaxis</span><p id="par0145" class="elsevierStylePara elsevierViewall">Different drugs have been tested in the prophylaxis of NPJ&#58; TMP&#47;SMX&#44; pentamidine&#44; atovaquone&#44; dapsone&#44; pyrimethamine and clindamycin&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> The best result was obtained with TMP&#47;SMX&#44; and this is why it is the recommended first-line drug&#46; Daily administration is equally effective as administration three days per week&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;58</span></a> When TMP-SMX is contraindicated the recommended second-line is pentamidine&#44; atovaquone or dapsone<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">It is important to take into account the interaction between TMP-SMX and methotrexate&#44; &#40;MTX&#41; as this association may cause severe cytopenia and myelosuppression&#44; even at low doses of MTX over a short time &#40;two days&#41; of treatment with TMP-SMX&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> This effect does not seem to arise with prophylactic doses of TMP-SMX&#44; although it must be taken into account&#46; The main side effects associated with the use of TMP&#47;SMX are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The duration of prophylaxis is controversial&#46; In ANCA-associated vasculitis it is suggested that it be discontinued when the immunosuppressant is suspended&#44; when the corticoid dose is lower than 20&#8722;10<span class="elsevierStyleHsp" style=""></span>mg of prednisone&#47;day&#44; or when B lymphocyte depletion halts after having used RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Prior to discontinuation other factors should be evaluated&#58; lymphopenia&#44; leucopoenia&#44; the CD4&#43; count and the dose of corticoid&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0160" class="elsevierStylePara elsevierViewall">There can be no doubt that the incidence of NPJ is higher in patients with certain RD&#38;SA&#44; often with a disastrous outcome&#46; Nor can there be any doubt as to the efficacy of prophylaxis in preventing it&#46; However&#44; there is no clear definition of the circumstances under which it is reasonable to apply the said prophylaxis&#46; This uncertainty is reflected in the result of different surveys of clinics&#44; where a wide range of criteria were detected&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Green et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> set the cut-off point at a risk of NPJ above 3&#46;5&#37; so that the risk&#47;benefit balance is favourable&#46; According to these authors&#44; patients with VGP would be included in this category&#44; while the other RD&#38;SA &#40;inflammatory myopathies&#44; SLE&#44; PAN&#44; scleroderma and RA&#41; should not receive prophylaxis as the balance would be unfavourable&#46; In their study Park et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> find an overall number necessary for harm &#40;NNH&#41; of 131 &#40;55&#8211;&#8734;&#41;&#44; as opposed to a number necessary to prevent a case of NPJ &#40;NNT&#41; of 52 &#40;33&#8211;124&#41;&#46; Stratifying according to diseases&#44; the NNT in patients with SLE &#40;43 &#40;28&#8211;85&#41;&#41; or PAM &#40;3 &#40;1&#46;6&#8211;39&#46;4&#41;&#41; was lower than the NNH&#44; which would justify prophylaxis&#46; This is not the case for the other diseases&#46; Nevertheless&#44; the actual situation is far more complex&#44; as the risk of NPJ will not only depend on the type of disease&#44; but also on its association with other predisposing factors&#46; A retrospective review of 21 cases of NPJ in patients with RD&#38;SA over a period of 20 years in an American hospital supports the theory that aetiology here is multifactorial&#44; with the participation of several factors &#40;high doses of corticoids&#44; the use of other immunosuppressor drugs&#44; lymphopenia or the coexistence of interstitial pulmonary disease&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> None of the 21 patients had received prophylaxis&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Different authors propose a very wide range of types of prophylaxis&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Wolfe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> classify NPJ risk factors into three categories&#58; established&#44; probable and possible &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; They suggest commencing prophylaxis&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#9702;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Always&#44; during induction treatment in VGP&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#9702;</span><p id="par0185" class="elsevierStylePara elsevierViewall">In other ANCA-associated vasculitis and in PAN&#58; during induction treatment or high dose corticoids&#44; on condition that there is lymphopenia &#40;&#60;500<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#41; or a low CD4&#43; count &#40;&#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#9702;</span><p id="par0190" class="elsevierStylePara elsevierViewall">In SLE and inflammatory myopathies&#58; when high doses of corticoids are being administered&#44; when there is also lymphopenia or a low CD4&#43; count and in SLE&#44; during immunosuppressor treatment or severe disease in case of inflammatory myopathy&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Ogawa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Chew et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> and Yale et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> base the start of prophylaxis on the corticoid dose given&#44; and they propose commencing it when the dose is above 10&#8722;30<span class="elsevierStyleHsp" style=""></span>mg of prednisone&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Stamp et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> administer prophylaxis to all of their patients treated with immunosuppressants and those with a history of NPJ&#44; as well as patients with persistent lymphopenia and CD4&#43; counts below 200&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Demoruelle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> propose reserving prophylaxis for patients with connective tissue pathologies who fulfil two or more of the following criteria&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#9702;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Steroids &#8805;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day for more than four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#9702;</span><p id="par0215" class="elsevierStylePara elsevierViewall">&#8805; Two disease-modifying drugs &#40;DMD&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#9702;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Total lymphocyte count &#8804; 350&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#9702;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Parenchymal lung disease&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Gupta et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> propose&#44; in patients with SLE treated with CFM&#44; administering prophylaxis only to those who have an additional risk factor&#58; severe leucopoenia&#44; severe lymphopenia&#44; high doses of corticoids&#44; hypocomplementemia&#44; active kidney disease or high activity scores &#40;SLEDAI&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> propose administering prophylaxis to patients with RD&#38;SA who receive high doses of immunosuppressant &#40;such as pulses of methyl-prednisolone&#41; and who have CD4&#43; counts lower than 250&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Sowden et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> propose determining CD4&#43; after one month of immunosuppressant only in patients who fulfil the following three criteria&#58; doses of prednisolone or equivalent above 15<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; planned duration of treatment longer than three months&#44; and total lymphocyte counts &#60;600&#47;mm<span class="elsevierStyleSup">3</span>&#46; In cases with CD4&#43; counts &#60;200&#44; prophylaxis would commence if the annual risk of <span class="elsevierStyleItalic">P&#46; jirovecii</span> is higher than 9&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Mansharamani et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> suggest use a CD4&#43; count lower than 300&#47;mm<span class="elsevierStyleSup">3</span> as the cut-off point to commence prophylaxis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Mori and Sugimoto<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> administer one tablet of TMP-SMX &#40;80<span class="elsevierStyleHsp" style=""></span>mg TMX plus 400<span class="elsevierStyleHsp" style=""></span>mg SMX&#41; per day during 5&#8211;7 days&#44; or two tablets three days a week for one week&#44; to all patients with RA prior to starting treatment&#46;</p></li></ul></p><p id="par0255" class="elsevierStylePara elsevierViewall">At the current time there are no data on which to decide which of these guidelines is the most effective in clinical practice&#44; and nor have any studies been designed to find predictive factors for the development of NPJ in patients with RD&#38;SA&#46;<span class="elsevierStyleSup">65</span> Taking its severity and the possibility of preventing it into account&#44; and awaiting studies that supply more solid and conclusive data&#44; it would be desirable to have recommendations that help clinicians to identify risk situations and apply prophylaxis more efficiently&#44; as this would doubtless have a highly favourable repercussion in our patients&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Financiering</span><p id="par0260" class="elsevierStylePara elsevierViewall">This research received no specific aid from public&#44; private or not-for-profit bodies&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0265" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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              "titulo" => "Lymphopenia"
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          "titulo" => "The drug of choice for prophylaxis"
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          "clase" => "keyword"
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            0 => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>"
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            0 => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>"
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            2 => "Enfermedad reum&#225;tica"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Infections&#44; including opportunistic infections&#44; are a major and frequent cause of morbidity and mortality in patients with systemic autoimmune and rheumatic diseases&#46; <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> pneumonia&#44; classically considered to be typical of HIV patients&#44; transplanted patients or patients treated with oncological chemotherapy&#44; is appearing increasingly frequently in these patients&#46; Therefore&#44; rheumatologists should know its mechanism of production&#44; clinical manifestations&#44; treatment and prophylaxis&#44; all of which are addressed in this review&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las infecciones&#44; entre ellas las oportunistas&#44; constituyen una causa importante y frecuente de morbilidad y mortalidad en los pacientes con enfermedades reum&#225;ticas y autoinmunes sist&#233;micas&#46; La neumon&#237;a por <span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#44; cl&#225;sicamente considerada propia de pacientes VIH&#44; trasplantados o tratados con quimioterapia oncol&#243;gica&#44; aparece cada vez con mayor frecuencia en estos pacientes&#46; Es por ello conveniente que los reumat&#243;logos conozcan su mecanismo de producci&#243;n&#44; manifestaciones cl&#237;nicas&#44; tratamiento y profilaxis&#44; aspectos todos ellos abordados en esta revisi&#243;n&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Vela Casasempere P&#44; Ruiz Torregrosa P&#44; Garc&#237;a Sevila R&#46; <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> en pacientes inmunocomprometidos con enfermedades reum&#225;ticas&#46; Reumatol Clin&#46; 2021&#59;17&#58;290&#8211;296&#46;</p>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">TMP&#47;SMX&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Trimethoprim 80<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sulfamethoxazole 400<span class="elsevierStyleHsp" style=""></span>mg oral per day&#44; trimethoprim 160<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sulfamethoxazole 800<span class="elsevierStyleHsp" style=""></span>mg oral 3 days&#47;week&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Second line</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Dapsone&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 mg&#47;kg&#47;day&#44; maximum 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Atovaquone&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">750<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">300<span class="elsevierStyleHsp" style=""></span>mg&#47; 4 weeks &#40;aerosol&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">NPJ prophylaxis regimes&#46;</p>"
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      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0055"
            "detalle" => "Table "
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        "tabla" => array:1 [
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              "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">Frequency&nbsp;\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">Manifestation&nbsp;\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">Predisposing factors&nbsp;\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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="5" align="left" valign="middle">Infrequent</td><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">Aseptic meningitis&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">HIV and RD&#38;SA&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">Delirium&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">Advanced age&#44; previous neurological damage&#44; infection&#44; metabolic disorder&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">Toxic epidermal necrolysis and other hypersensitivity reactions&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  " rowspan="5" align="left" valign="middle">Personal or family history</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">Acute interstitial nephritis&#44; hyponatremia&#44; tubulopathy&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">Thrombocytopenia&#44; aplasic anaemia&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 rowgroup " rowspan="4" align="left" valign="middle">Frequent</td><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">Cutaneous exanthem&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">Nausea&#44; vomiting&#44; diarrhoea&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">Cytochrome P450 system inhibitionInhibition of renal drug transport&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">Polymedication&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">Hyperpotasemia&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">Kidney failure&#59; diabetes&#59;High doses of TMP-SMX&#59; advanced age&#59; AIDSConcomitant use of&#58; ACE inhibitors&#44; NSAID&#44; spironolactone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2579501.png"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Side effects of TMP-SMX&#46;</p>"
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      ]
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        "etiqueta" => "Table 3"
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            "identificador" => "at0060"
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              "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">Established&nbsp;\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">Probable&nbsp;\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">Possible&nbsp;\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-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">Low T CD4&#43; lymphocytes&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">Glucocorticoids&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">Young age&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">Lymphopenia&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">Cyclophosphamide&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">Male sex&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">&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">Rituximab&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">Hispanic descent&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">&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">Methotrexate&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">Asiatic descent&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">&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">Anti-TNF&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">Private medical treatment&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">&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">Azathioprine&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">Interstitial lung disease&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">&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">&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">Caucasian descent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2579500.png"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Risk factors for the development of NPJ in patients with RD&#38;SA&#46; Modified from Wolf et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:64 [
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              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Infection-related morbidity and mortality in patients with connective tissue diseases&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;E&#46; Falagas"
                            1 => "K&#46;G&#46; Manta"
                            2 => "G&#46;I&#46; Betsi"
                            3 => "G&#46; Pappas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10067-006-0441-9"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Rheumatol&#46;"
                        "fecha" => "2007"
                        "volumen" => "26"
                        "numero" => "5"
                        "paginaInicial" => "663"
                        "paginaFinal" => "670"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17186117"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chapter 15 - Opportunistic Infections and Autoimmune Diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46; Faria"
                            1 => "C&#46; Pereira"
                            2 => "R&#46; Alves"
                            3 => "T&#46; Mendon&#231;a"
                            4 => "F&#46; Farinha"
                            5 => "C&#46; Vasconcelos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "editores" => "Y&#46;Shoenfeld, N&#46;Agmon-Levin, N&#46;R&#46;Rose"
                        "titulo" => "Infection and Autoimmunity &#40;Second Edition&#41; &#91;Internet&#93;"
                        "paginaInicial" => "251"
                        "paginaFinal" => "277"
                        "serieFecha" => "2015"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "http&#58;&#47;&#47;www&#46;sciencedirect&#46;com&#47;science&#47;article&#47;pii&#47;B9780444632692000180"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "P&#46; Garred"
                            1 => "A&#46; Voss"
                            2 => "H&#46;O&#46; Madsen"
                            3 => "P&#46; Junker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.gene.6363804"
                      "Revista" => array:7 [
                        "tituloSerie" => "Genes Immun&#46;"
                        "fecha" => "2001"
                        "volumen" => "2"
                        "numero" => "8"
                        "paginaInicial" => "442"
                        "paginaFinal" => "450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11781711"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Frequency of infection in patients with rheumatoid arthritis compared with controls&#58; A population-based study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46;F&#46; Doran"
                            1 => "C&#46;S&#46; Crowson"
                            2 => "G&#46;R&#46; Pond"
                            3 => "W&#46;M&#46; O&#8217;Fallon"
                            4 => "S&#46;E&#46; Gabriel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10524"
                      "Revista" => array:7 [
                        "tituloSerie" => "Arthritis Rheum&#46;"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "numero" => "9"
                        "paginaInicial" => "2287"
                        "paginaFinal" => "2293"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12355475"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span> Pneumonia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46; Catherinot"
                            1 => "F&#46; Lanternier"
                            2 => "M&#46;-E&#46;-E&#46; Bougnoux"
                            3 => "M&#46; Lecuit"
                            4 => "L&#46;-J&#46;-J&#46; Couderc"
                            5 => "O&#46; Lortholary"
                          ]
                        ]
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Review Article
Pneumocystis jirovecii in immunocompromised patients with rheumatic diseases
Pneumocystis jirovecii en pacientes inmunocomprometidos con enfermedades reumáticas
Paloma Vela Casasemperea,b,
Corresponding author
palomavela62@gmail.com

Corresponding author.
, Paloma Ruiz Torregrosac, Raquel García Sevilac
a Sección de Reumatología, Hospital General Universitario de Alicante, ISABIAL, Alicante, Spain
b Universidad Miguel Hernández, Alicante, Spain
c Servicio de Neumología, Hospital General Universitario de Alicante, Alicante, Spain
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    "titulo" => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span> in immunocompromised patients with rheumatic diseases"
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        "titulo" => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span> en pacientes inmunocomprometidos con enfermedades reum&#225;ticas"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Infections are a major and common cause of morbimortality in patients with rheumatic and systemic autoimmune diseases &#40;RD&#38;SA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> They include opportunistic infections among others&#44; defined as those caused by non-pathogenic organisms which become pathogenic when the immune system is altered&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> They are an increasingly severe problem&#44; due to the use of immunosuppressor agents to treat diseases&#44; as well as the increased susceptibility to infection caused by diseases themselves and the comorbidities associated with them&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#44; which was previously known as <span class="elsevierStyleItalic">Pneumocystis carinii</span>&#44; is a pathogenic&#44; opportunistic and extracellular fungus that belongs to the hemiascomicetes class&#46; It is in the <span class="elsevierStyleItalic">Pneumocystis</span> genus&#44; a complex group that is composed of many species with peculiar characteristics that differentiate them from other fungi&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Their cytoplasmatic membrane is mainly composed of cholesterol&#44; unlike those of other fungi which have membranes that contain ergosterol&#46; This is why standard antifungal drugs &#40;such as the azoles and polyenes&#41;&#44; are ineffective against <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#44; as they act on the ergosterol of the fungal membrane&#44; either directly &#40;amphotericin&#41; or indirectly&#44; inhibiting its synthesis &#40;azoles&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The new antifungal drugs &#40;echinocandins&#41;&#44; nevertheless&#44; interfere in the synthesis of 1&#44;3-&#946;-D glucan&#44; a specific constituent of the membrane of all fungi that is found in high quantities in the cystic form of <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#44; so that they would be a highly interesting member of the therapeutic arsenal&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Another peculiarity of <span class="elsevierStyleItalic">Pneumocystis</span> that is unique in mycology is their specificity for the selective invasion of a concrete host&#44; so that each mammal is affected by a different genetic variety&#46; Only <span class="elsevierStyleItalic">P&#46; jirovecii</span> is found in humans&#46; Lastly&#44; this fungus does not grow in artificial media&#44; so that diagnosis requires demonstration that it is present in sputum samples obtained by broncoalveolar washing&#44; or in tissue obtained by pulmonary biopsy&#44; using microscopy techniques &#40;preferentially with immunofluorescence&#41;&#44; or by techniques involving highly sensitive polymerase chain reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Although its exact transmission mechanism is unknown&#44; the most widely accepted hypothesis is that it passes from one person to another by the inhalation of particles in the air&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Exposure to <span class="elsevierStyleItalic">P&#46; jirovecii</span> in humans is highly common&#44; as is shown by the fact that in developed countries more than 80&#37; of children have developed antibodies against <span class="elsevierStyleItalic">P&#46; jirovecii</span> before they are four years old&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Although the theory used to be that pneumonia caused by <span class="elsevierStyleItalic">P&#46; jirovecii</span> &#40;NPJ&#41; is due to the reactivation of a latent infection in an immunocompromised patient&#44; current data show that it is a <span class="elsevierStyleItalic">de novo</span> infection&#46; Nevertheless&#44; colonisation by <span class="elsevierStyleItalic">P&#46; jirovecii</span> has been shown to exist in certain susceptible populations&#44; although the clinical implications of this finding are unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Once it has been acquired&#44; <span class="elsevierStyleItalic">P&#46; jirovecii</span> passes through a complicated life-cycle&#46; It has two predominant forms&#44; trophic and cystic&#44; of which the first type represents 90&#37; of the total number of <span class="elsevierStyleItalic">P&#46; jirovecii</span> organisms during infection&#46; Trophic forms are united by interdigitations to the cellular membrane of the type I pneumocyte in the alveolar epithelium&#44; permitting the close unification of both membranes without breaking the alveolar cell or penetrating it&#46; The interaction of <span class="elsevierStyleItalic">P&#46; jirovecii</span> with the pneumocyte and alveolar macrophages triggers a cascade of cellular responses in <span class="elsevierStyleItalic">P&#46; jirovecii</span> itself as well as in the lung cells&#58; <span class="elsevierStyleItalic">P&#46; jirovecii</span> is stimulated to proliferate&#44; at the same time that the alveolar macrophages commence phagocytosis of <span class="elsevierStyleItalic">P&#46; jirovecii</span> and its destruction&#44; and the alveolar cells release proinflammatory cytokines and chemokines that promote the recruitment and activation of neutrophils and T lymphocytes&#46; T CD4&#43; lymphocytes encharged with coordinating the inflammatory response of the host&#44; recruiting and activating additional immune effecter cells &#40;monocytes and macrophages&#41; which will be responsible for eliminating <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; In immunocompetent individuals the infection is eliminated with minimum inflammation and lung damage&#46; However&#44; in immunocompromised hosts a hyperinflammatory response is trigged that is unable to eliminate <span class="elsevierStyleItalic">P&#46; jirovecii</span> but which causes lung damage and affects gas interchange&#46; This causes NPJ&#44; the chief manifestation of this infection&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical manifestations</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">P&#46; jirovecii</span> has a special tropism for the lungs&#44; and its dissemination in the rest of an infected organism is exceptional&#46; Interstitial pneumonia is the main disease caused by <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; The most common symptoms are the appearance of a dry cough&#44; dyspnoea&#44; fever&#44; tachycardia and tachypnea&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In pulmonary auscultation the presence of fine rales stands out&#44; and in thoracic X-ray there is tenuous bilateral interstitial infiltrate&#46; High resolution computed tomography &#40;HRCT&#41; shows higher sensitivity in detecting NPJ than simple X-ray imaging&#44; showing the characteristic areas of ground glass opacity in peri-hiliar distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Generally high levels of lactate dehydrogenase &#40;LDH&#41; are detected&#44; with a fall in serum albumin and CD4&#43; counts &#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#46; Due to damage in the alveolar epithelium the blood gases are altered&#44; detecting hypoxemia and&#47;or respiratory failure in arterial gasometry&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In immunocompromised patients without HIV&#44; the infection usually runs a more acute course&#44; manifesting with fewer systemic symptoms but with greater respiratory repercussion &#40;a higher level of respiratory failure and tachypnea&#41;&#44; and in broncoalveolar washing a lower concentration of organisms is detected&#44; although with a higher neutrophil count<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and&#44; in general&#44; the condition tends to be more severe&#44; with a longer stay in intensive care units and higher rates of mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;12</span></a> This higher mortality has been associated with low PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> coefficients&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> with the need for mechanical ventilation&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> hypoalbuminemia&#44; male sex&#44; advanced age and medical care in private hospitals&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The magnitude of the problem</span><p id="par0040" class="elsevierStylePara elsevierViewall">This infection is often lethal&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The mortality rate is close to 100&#37; without treatment&#44; and it varies from 5&#37; to 40&#37; in treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The rate of mortality due to NPJ in patients without HIV currently stands at from 39&#46;4&#37; to 59&#46;1&#37;&#44; a figure far higher than the 6&#37;&#8211;7&#37; recorded in HIV&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The individuals at the greatest risk of NPJ are patients with HIV&#44; especially those with CD4&#43; counts &#60;200&#47;mm&#59;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> those who have received organ transplants or haematopoietic cells&#59;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> premature infants who require mechanical ventilation&#59; patients with primary immunodeficiencies that affect T lymphocyte functioning<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and patients who receive oncological chemotherapy or are treated with immunosuppressor drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The use of antiretroviral drugs to treat HIV infection together with prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span> following the recommendations of clinical practice guides<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> have drastically reduced the incidence of NPJ in developed countries in patients with AIDS&#44; from rates of 70&#37;&#8211;80&#37; before implementing these measures&#44; to fewer than one case per 100 persons-year&#46; On the contrary&#44; an increase in incidence has been observed in immunocompromised patients without HIV&#58; rates of incidence vary depending on the disease&#44; but they may reach 44&#46;6 cases per 100&#44;000 patients&#47;year in those who have received transplants&#44; &#62;45 cases per 100&#44;000 patients&#47;year in haematological neoplasias&#44; 53&#46;6 cases per 100&#44;000 patients&#47;year in inflammatory myopathies&#44; 71&#46;9 cases per100&#44;000 patients&#47;year in vasculitis associated with anti-neutrophil cytoplasm antibodies &#40;ANCA&#41; and 93&#46;2 cases per 100&#44;000 patients&#47;year in patients with panarteritis nodosa &#40;PAN&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Guides for the prophylaxis of NPJ have recently been published for patients with haematological diseases and organ transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Nevertheless&#44; to date no guide for the prophylaxis of NPJ has been published for patients with RD&#38;SA under immunosuppressor treatment&#46; Several authors have expressed the advisability of having these guides&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> as they would help to unify criteria which are currently very varied&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">As occurs in other pathologies&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> the risk of NPJ in patients with RD&#38;SA will be determined by the combination of different factors&#58; 1&#41; the disease&#59; 2&#41; the drugs used&#59; and 3&#41; the particular circumstances of each individual&#46; When deciding on the advisability of administering prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#44; it is also necessary to consider the potential toxicity of the treatment used for this&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> It has been suggested that a &#34;level of risk of NPJ&#34; higher than 3&#46;5&#37; should be the cut-off point for considering that the beneficial effect of prophylaxis is greater than the risk&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Finally&#44; it has to be taken into account that many of these factors will be modified over time&#44; so that continuous re-evaluation will be required of the risk&#47;benefit during the follow-up of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Risks associated with the disease</span><p id="par0060" class="elsevierStylePara elsevierViewall">The incidence of NPJ varies notably from some RD&#38;SA to others&#44; and it is higher in granulomatous vasculitis with polyangiitis &#40;VGP&#41;&#44; PAN&#44; systemic lupus erythematosus &#40;SLE&#41; and inflammatory myopathies&#44; making an individualised approach necessary&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">ANCA-associated vasculitis</span><p id="par0065" class="elsevierStylePara elsevierViewall">ANCA-associated vasculitis patients have a higher rate of NPJ incidence within RD&#38;SA &#40;8&#46;9 cases per every 1&#44;000 hospitalisations&#47;year in VGP&#44; 120&#47;10&#46;000 patients&#47;years&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;27&#44;28</span></a> with a very high mortality rate &#40;47&#37;&#8211;62&#46;5&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;15</span></a> The main factor associated with the development of NPJ in patients with VGP is lymphopenia&#58; lymphocyte levels under 800&#47;mm<span class="elsevierStyleSup">3</span> prior to treatment&#44; or below 600&#47;mm<span class="elsevierStyleSup">3</span> three months after the start of treatment&#44; were associated with the development of NPJ in a retrospective study&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Due to the high incidence of NPJ in these patients during induction treatment&#44; the European guide for the management of ANCA-associated vasculitis recommends prophylaxis with TMP-SMX in all of the patients treated with cyclophosphamide &#40;CFM&#41;&#44; and it mentions its usefulness in maintaining remission as it reduces the risk of relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Other authors recommend prophylaxis during induction even when other drugs are given&#44; such as rituximab&#44; on condition that the dose of corticoid is higher than 10<span class="elsevierStyleHsp" style=""></span>mg&#44; as well as with lymphocyte counts below 300&#47;mm&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Other types of vasculitis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The incidence of NPJ in PAN is 6&#46;5 cases per 1&#44;000 hospitalisations&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> with a mortality of 47&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In large vessel arteritis incidence is surprisingly low&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> in spite of the use of high doses of corticoids over prolonged periods of time&#46; None of the European management recommendations mentions NPJ prophylaxis&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Systemic lupus erythematosus &#40;SLE&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall">There is no uniform criterion for indicating NPJ prophylaxis in patients with SLE&#58; the overall incidence of this opportunist infection is lower than the level found in vasculitis-ANCA and inflammatory myopathies &#40;5&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> 1&#46;2 cases per 1&#44;000 hospitalisations&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> 8 cases per 10&#44;000 patients&#47;year<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#41;&#44; although rates of mortality are high &#40;20&#37;&#8211;45&#46;7&#37;&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;36</span></a> which more than justifies its treatment&#46; Numerous publications agree on the factors that predispose to the development of NPJ&#58; disease that is more active&#44; nephritis&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> the use of glucocorticoids &#40;GC&#41; at high doses&#44; treatment with cyclophosphamide<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and&#44; most especially&#44; lymphopenia&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29&#44;36</span></a> Taking the recommendations for prophylaxis in patients with HIV as a guide&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Lertnawapan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> recommend starting prophylaxis when total levels of lymphocytes fall below 750&#47;mm<span class="elsevierStyleSup">3</span> or when CD4&#43; &#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">There is special concern regarding the use of trimethoprim-sulfamethoxazole &#40;TMP-SMX&#41; in patients with SLE&#58; high rates of adverse reactions have been reported in from 27&#46;3&#37;&#8211;53&#37; of cases<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> &#40;cutaneous rash&#44; exacerbation of the SLE&#44; hepatic toxicity and myelosuppression&#41;&#44;which is more frequent in patients who are anti-Ro&#47;SS-A positive&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> although they are generally mild and do not require discontinuation of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;39</span></a> Nevertheless&#44; this factor should be taken into account when recommending prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46; It would therefore be desirable to have guides&#44; recommendations or algorithms<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> that would help clinicians to reach decisions on an individualised basis&#58; unfortunately&#44; the European guides for the management of SLE do not include any recommendations on this subject&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Inflammatory myopathies</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patients with inflammatory myopathies have NPJ rates lower than those recorded for ANCA-associated vasculitis&#44; although higher than in SLE&#44; with figures that vary depending on the series from 2&#37; to 10&#37; of pacientes&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;41</span></a> and it is the cause in 27 cases of every 10&#44;000 hospitalisations&#47;year&#46; As occurred in the previous cases&#44; the rate of mortality is very high&#44; at from 33&#37; to 57&#46;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Lymphopenia is once again the predisposing factor&#44; so that some authors recommend starting prophylaxis when CD4&#43; lymphocyte counts are below 250&#47;mm&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rheumatoid arthritis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patients with rheumatoid arthritis &#40;RA&#41; are generally considered to be low risk for the development of NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Although the use of immunosuppressor drugs and biological agents increases the risk&#44; the figures are below 0&#46;1&#37;-0&#46;3&#37;&#44; with mortality rates that vary from 10&#37; to 28&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> There is also the additional risk of the MTX&#47;TMP-SMX combination&#46; Due to this&#44; and although systematic prophylaxis is not recommended&#44; some authors consider that certain preventive measures should be adopted&#44; such as the detection of <span class="elsevierStyleItalic">P&#46; jirovecii</span> carriers to implement treatment to eradicate it&#44; thereby avoiding any subsequent prophylaxis&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Drug associated risk</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Glucocorticoids</span><p id="par0100" class="elsevierStylePara elsevierViewall">GC are an essential part of the arsenal for the treatment of a large number of RD&#38;SA&#46; The association between GC and the development of NPJ has been clearly established&#44; considering it to be the main risk factor&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Several mechanisms interconnect to facilitate infection&#58; the prolonged use of GC causes a fall in T CD4&#43; lymphocytes&#44; in the blood as well as in the lungs<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> and&#44; although it has not been clearly determined&#44; it probably affects the functioning of alveolar macrophages&#44; hindering phagocytosis and the destruction of <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The risk of NPJ is dose and time-dependent&#44; and doses higher than 60<span class="elsevierStyleHsp" style=""></span>mg&#47;day of prednisone lead to higher risk&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> although daily doses of 16<span class="elsevierStyleHsp" style=""></span>mg for periods of eight weeks may be sufficient to induce NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Nevertheless&#44; it seems that another factor is necessary&#44; given that in ACG the risk is low in spite of high doses of GC over a prolonged period of time&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The type of disease&#44; concomitant use of cyclophosphamide and the presence of lymphopenia have all been shown to be additional predisposing factors for the development of NPJ&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Prophylaxis with TMP-SMX is highly effective&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> although in some studies this protective effect was only demonstrated when high doses of corticoids were used&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">There are not enough data in the literature to permit giving specific figures for dosage or treatment times over which prophylaxis should begin&#46; A dose of prednisone of 16&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day or higher has been suggested&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;46</span></a> as well as duration of treatment lasting eight weeks&#44; after which prophylaxis is indicated&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In spite of all these data&#44; curiously the EULRA recommendations on the use of GC do not mention either the risk or the advisability of prevention&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#8211;49</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Immunosuppressor drugs</span><p id="par0120" class="elsevierStylePara elsevierViewall">Although CFM has been implicated in the development of NPJ&#44; in a dose-dependent relationship&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> its effect may be associated with other immunosuppressor factors such as the use of GC&#46; Systematic prophylaxis is therefore not recommended&#44; and treatment has to be individualised depending on the presence of other predisposing factors&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The role of other immunosuppressor drugs &#40;methotrexate&#44; azathioprine and mycophenolate&#41; as predisposing factors for NPJ has not been clearly demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Biological agents</span><p id="par0130" class="elsevierStylePara elsevierViewall">There are currently no specific recommendations&#46; The British Society of Rheumatology registry of biological treatments found a higher incidence in patients treated with rituximab respecting those treated with drugs that inhibit tumour necrosis factor &#40;anti-TNF&#41; &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#59; CI 95&#37;&#58; 1&#46;4&#8211;7&#46;5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Given the low incidence in the majority of the series &#40;0&#46;03&#37;-0&#46;3&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> systematic prophylaxis is not recommended for all patients receiving biological treatment&#44; although it would be of interest to identify the subgroups at especial risk which could benefit from this prophylaxis&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Risk associated with individual factors</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Lymphopenia</span><p id="par0135" class="elsevierStylePara elsevierViewall">Lymphopenia has been shown to be one of the main predisposing factors for NPJ in patients with RD&#38;SA&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;15&#44;27&#44;29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;50&#44;53</span></a> The clinical practice guides for patients with HIV&#44; indicate starting prophylaxis against <span class="elsevierStyleItalic">P&#46; jirovecii</span> when levels of CD4&#43; are below 200&#47;mm&#46;<span class="elsevierStyleSup">318</span> Several studies find counts of below 250&#47;mm<span class="elsevierStyleSup">3</span> in all of the patients who develop NPJ&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;54</span></a> Although the evidence is not so solid&#44; in patients with RD&#38;SA several authors recommend starting prophylaxis based on the same criterion&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Total lymphocyte levels prior to starting treatment have also be shown to be useful as a predictive factor&#58; in VGP&#44; NPJ is associated with pre-treatment lymphocyte levels below 800&#47;mm<span class="elsevierStyleSup">3</span>&#59;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Porges et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> find figures under 350&#47;mm<span class="elsevierStyleSup">3</span> identify all of the patients with SLE treated with GC and cytotoxic drugs in the risk of NPJ&#59; and in a heterogeneous group of connective tissue pathologies Ogawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> found an association between counts below 500&#47;mm<span class="elsevierStyleSup">3</span> two weeks before starting treatment with corticoids at doses higher than 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; Although it seems that absolute lymphopenia really is a predisposing factor for NPJ&#44; nobody has dared to set a cut-off point under which prophylaxis is indicated&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">The drug of choice for prophylaxis</span><p id="par0145" class="elsevierStylePara elsevierViewall">Different drugs have been tested in the prophylaxis of NPJ&#58; TMP&#47;SMX&#44; pentamidine&#44; atovaquone&#44; dapsone&#44; pyrimethamine and clindamycin&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> The best result was obtained with TMP&#47;SMX&#44; and this is why it is the recommended first-line drug&#46; Daily administration is equally effective as administration three days per week&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;58</span></a> When TMP-SMX is contraindicated the recommended second-line is pentamidine&#44; atovaquone or dapsone<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">It is important to take into account the interaction between TMP-SMX and methotrexate&#44; &#40;MTX&#41; as this association may cause severe cytopenia and myelosuppression&#44; even at low doses of MTX over a short time &#40;two days&#41; of treatment with TMP-SMX&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> This effect does not seem to arise with prophylactic doses of TMP-SMX&#44; although it must be taken into account&#46; The main side effects associated with the use of TMP&#47;SMX are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The duration of prophylaxis is controversial&#46; In ANCA-associated vasculitis it is suggested that it be discontinued when the immunosuppressant is suspended&#44; when the corticoid dose is lower than 20&#8722;10<span class="elsevierStyleHsp" style=""></span>mg of prednisone&#47;day&#44; or when B lymphocyte depletion halts after having used RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Prior to discontinuation other factors should be evaluated&#58; lymphopenia&#44; leucopoenia&#44; the CD4&#43; count and the dose of corticoid&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0160" class="elsevierStylePara elsevierViewall">There can be no doubt that the incidence of NPJ is higher in patients with certain RD&#38;SA&#44; often with a disastrous outcome&#46; Nor can there be any doubt as to the efficacy of prophylaxis in preventing it&#46; However&#44; there is no clear definition of the circumstances under which it is reasonable to apply the said prophylaxis&#46; This uncertainty is reflected in the result of different surveys of clinics&#44; where a wide range of criteria were detected&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Green et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> set the cut-off point at a risk of NPJ above 3&#46;5&#37; so that the risk&#47;benefit balance is favourable&#46; According to these authors&#44; patients with VGP would be included in this category&#44; while the other RD&#38;SA &#40;inflammatory myopathies&#44; SLE&#44; PAN&#44; scleroderma and RA&#41; should not receive prophylaxis as the balance would be unfavourable&#46; In their study Park et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> find an overall number necessary for harm &#40;NNH&#41; of 131 &#40;55&#8211;&#8734;&#41;&#44; as opposed to a number necessary to prevent a case of NPJ &#40;NNT&#41; of 52 &#40;33&#8211;124&#41;&#46; Stratifying according to diseases&#44; the NNT in patients with SLE &#40;43 &#40;28&#8211;85&#41;&#41; or PAM &#40;3 &#40;1&#46;6&#8211;39&#46;4&#41;&#41; was lower than the NNH&#44; which would justify prophylaxis&#46; This is not the case for the other diseases&#46; Nevertheless&#44; the actual situation is far more complex&#44; as the risk of NPJ will not only depend on the type of disease&#44; but also on its association with other predisposing factors&#46; A retrospective review of 21 cases of NPJ in patients with RD&#38;SA over a period of 20 years in an American hospital supports the theory that aetiology here is multifactorial&#44; with the participation of several factors &#40;high doses of corticoids&#44; the use of other immunosuppressor drugs&#44; lymphopenia or the coexistence of interstitial pulmonary disease&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> None of the 21 patients had received prophylaxis&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Different authors propose a very wide range of types of prophylaxis&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Wolfe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> classify NPJ risk factors into three categories&#58; established&#44; probable and possible &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; They suggest commencing prophylaxis&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#9702;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Always&#44; during induction treatment in VGP&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#9702;</span><p id="par0185" class="elsevierStylePara elsevierViewall">In other ANCA-associated vasculitis and in PAN&#58; during induction treatment or high dose corticoids&#44; on condition that there is lymphopenia &#40;&#60;500<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#41; or a low CD4&#43; count &#40;&#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#9702;</span><p id="par0190" class="elsevierStylePara elsevierViewall">In SLE and inflammatory myopathies&#58; when high doses of corticoids are being administered&#44; when there is also lymphopenia or a low CD4&#43; count and in SLE&#44; during immunosuppressor treatment or severe disease in case of inflammatory myopathy&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Ogawa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Chew et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> and Yale et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> base the start of prophylaxis on the corticoid dose given&#44; and they propose commencing it when the dose is above 10&#8722;30<span class="elsevierStyleHsp" style=""></span>mg of prednisone&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Stamp et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> administer prophylaxis to all of their patients treated with immunosuppressants and those with a history of NPJ&#44; as well as patients with persistent lymphopenia and CD4&#43; counts below 200&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Demoruelle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> propose reserving prophylaxis for patients with connective tissue pathologies who fulfil two or more of the following criteria&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#9702;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Steroids &#8805;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day for more than four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#9702;</span><p id="par0215" class="elsevierStylePara elsevierViewall">&#8805; Two disease-modifying drugs &#40;DMD&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#9702;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Total lymphocyte count &#8804; 350&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#9702;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Parenchymal lung disease&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Gupta et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> propose&#44; in patients with SLE treated with CFM&#44; administering prophylaxis only to those who have an additional risk factor&#58; severe leucopoenia&#44; severe lymphopenia&#44; high doses of corticoids&#44; hypocomplementemia&#44; active kidney disease or high activity scores &#40;SLEDAI&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> propose administering prophylaxis to patients with RD&#38;SA who receive high doses of immunosuppressant &#40;such as pulses of methyl-prednisolone&#41; and who have CD4&#43; counts lower than 250&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Sowden et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> propose determining CD4&#43; after one month of immunosuppressant only in patients who fulfil the following three criteria&#58; doses of prednisolone or equivalent above 15<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; planned duration of treatment longer than three months&#44; and total lymphocyte counts &#60;600&#47;mm<span class="elsevierStyleSup">3</span>&#46; In cases with CD4&#43; counts &#60;200&#44; prophylaxis would commence if the annual risk of <span class="elsevierStyleItalic">P&#46; jirovecii</span> is higher than 9&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Mansharamani et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> suggest use a CD4&#43; count lower than 300&#47;mm<span class="elsevierStyleSup">3</span> as the cut-off point to commence prophylaxis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Mori and Sugimoto<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> administer one tablet of TMP-SMX &#40;80<span class="elsevierStyleHsp" style=""></span>mg TMX plus 400<span class="elsevierStyleHsp" style=""></span>mg SMX&#41; per day during 5&#8211;7 days&#44; or two tablets three days a week for one week&#44; to all patients with RA prior to starting treatment&#46;</p></li></ul></p><p id="par0255" class="elsevierStylePara elsevierViewall">At the current time there are no data on which to decide which of these guidelines is the most effective in clinical practice&#44; and nor have any studies been designed to find predictive factors for the development of NPJ in patients with RD&#38;SA&#46;<span class="elsevierStyleSup">65</span> Taking its severity and the possibility of preventing it into account&#44; and awaiting studies that supply more solid and conclusive data&#44; it would be desirable to have recommendations that help clinicians to identify risk situations and apply prophylaxis more efficiently&#44; as this would doubtless have a highly favourable repercussion in our patients&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Financiering</span><p id="par0260" class="elsevierStylePara elsevierViewall">This research received no specific aid from public&#44; private or not-for-profit bodies&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0265" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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            1 => "Immunosuppression"
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            3 => "Autoimmune disease"
            4 => "Prophylaxis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1362848"
          "palabras" => array:5 [
            0 => "<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>"
            1 => "Inmunosupresi&#243;n"
            2 => "Enfermedad reum&#225;tica"
            3 => "Enfermedad autoinmune"
            4 => "Profilaxis"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Infections&#44; including opportunistic infections&#44; are a major and frequent cause of morbidity and mortality in patients with systemic autoimmune and rheumatic diseases&#46; <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> pneumonia&#44; classically considered to be typical of HIV patients&#44; transplanted patients or patients treated with oncological chemotherapy&#44; is appearing increasingly frequently in these patients&#46; Therefore&#44; rheumatologists should know its mechanism of production&#44; clinical manifestations&#44; treatment and prophylaxis&#44; all of which are addressed in this review&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las infecciones&#44; entre ellas las oportunistas&#44; constituyen una causa importante y frecuente de morbilidad y mortalidad en los pacientes con enfermedades reum&#225;ticas y autoinmunes sist&#233;micas&#46; La neumon&#237;a por <span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#44; cl&#225;sicamente considerada propia de pacientes VIH&#44; trasplantados o tratados con quimioterapia oncol&#243;gica&#44; aparece cada vez con mayor frecuencia en estos pacientes&#46; Es por ello conveniente que los reumat&#243;logos conozcan su mecanismo de producci&#243;n&#44; manifestaciones cl&#237;nicas&#44; tratamiento y profilaxis&#44; aspectos todos ellos abordados en esta revisi&#243;n&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Vela Casasempere P&#44; Ruiz Torregrosa P&#44; Garc&#237;a Sevila R&#46; <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> en pacientes inmunocomprometidos con enfermedades reum&#225;ticas&#46; Reumatol Clin&#46; 2021&#59;17&#58;290&#8211;296&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0050"
            "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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">First line</th></tr></thead><tbody title="tbody"><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">TMP&#47;SMX&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">Trimethoprim 80<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sulfamethoxazole 400<span class="elsevierStyleHsp" style=""></span>mg oral per day&#44; trimethoprim 160<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sulfamethoxazole 800<span class="elsevierStyleHsp" style=""></span>mg oral 3 days&#47;week&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 " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Second line</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&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">2 mg&#47;kg&#47;day&#44; maximum 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&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">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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">750<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&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">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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">300<span class="elsevierStyleHsp" style=""></span>mg&#47; 4 weeks &#40;aerosol&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2579502.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">NPJ prophylaxis regimes&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0055"
            "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">Frequency&nbsp;\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">Manifestation&nbsp;\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">Predisposing factors&nbsp;\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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="5" align="left" valign="middle">Infrequent</td><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">Aseptic meningitis&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">HIV and RD&#38;SA&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">Delirium&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">Advanced age&#44; previous neurological damage&#44; infection&#44; metabolic disorder&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">Toxic epidermal necrolysis and other hypersensitivity reactions&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  " rowspan="5" align="left" valign="middle">Personal or family history</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">Acute interstitial nephritis&#44; hyponatremia&#44; tubulopathy&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">Thrombocytopenia&#44; aplasic anaemia&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 rowgroup " rowspan="4" align="left" valign="middle">Frequent</td><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">Cutaneous exanthem&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">Nausea&#44; vomiting&#44; diarrhoea&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">Cytochrome P450 system inhibitionInhibition of renal drug transport&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">Polymedication&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">Hyperpotasemia&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">Kidney failure&#59; diabetes&#59;High doses of TMP-SMX&#59; advanced age&#59; AIDSConcomitant use of&#58; ACE inhibitors&#44; NSAID&#44; spironolactone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2579501.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Side effects of TMP-SMX&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0060"
            "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">Established&nbsp;\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">Probable&nbsp;\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">Possible&nbsp;\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-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">Low T CD4&#43; lymphocytes&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">Glucocorticoids&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">Young age&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">Lymphopenia&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">Cyclophosphamide&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">Male sex&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">&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">Rituximab&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">Hispanic descent&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">&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">Methotrexate&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">Asiatic descent&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">&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">Anti-TNF&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">Private medical treatment&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">&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">Azathioprine&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">Interstitial lung disease&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">&nbsp;\t\t\t\t\t\t\n
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Idiomas
Reumatología Clínica (English Edition)
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¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?