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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">A 69 year-old woman was admitted to hospital due to fever&#46; She was from the South of Morocco and had been living in Spain for four years&#46; She had a ten-year medical history of hypertension and type 2 diabetes mellitus&#46; Nine months before admission&#44; she received a kidney allograft from a deceased donor&#44; due to end-stage renal disease&#46;</span></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common cause of fever in renal transplant patients is infection&#46; However&#44; many other factors may be responsible&#44; such as allograft rejection&#44; drug hypersensitivity&#44; and malignancy&#46; Acute rejection occurs more frequently during the first six months after transplantation&#46; Post-transplant lymphoproliferative disorders &#40;PTLD&#41; occur mainly within the first year&#46; Most infections after transplantation occur on a relatively consistent timeline&#44; reflecting the interplay of risk factors and the net state of immunosuppression&#46; The majority of infections occurring later than six months after transplantation are basically the common community-acquired infections encountered in patients with chronic conditions &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Urinary infection is frequent&#44; especially in diabetic women&#46; Other late manifestations may represent reactivated or chronic viral infections&#44; particularly cytomegalovirus &#40;CMV&#41;&#46; Finally&#44; patients with acute or chronic rejection and over-immunosuppression are at high risk of life-threatening infection by opportunistic pathogens&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Pretransplant anti-HLA panel reactive antibodies were 52&#37;&#46; She was seropositive for CMV&#46; Immunosuppression comprised tacrolimus&#44; mycophenolate mofetil and steroids&#46; Prophylaxis with intravenous cefuroxime &#40;2 days&#41;&#44; oral cotrimoxazole &#40;9 months&#41;&#44; and intravenous ganciclovir &#40;10 days&#41;&#44; followed by oral valganciclovir &#40;3 months&#41; was administered&#46; At hospital discharge creatinine clearance was 71<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Four months after transplantation&#44; a biopsy-proven acute vascular rejection &#40;grade IIB according to the Banff classification&#41; was established&#46; It was successfully treated with thymoglobulin&#44; six sessions of plasmapheresis&#44; and human polyvalent immunoglobulin&#46; The patient developed several infections&#44; including</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Escherichia coli</span></span><span class="elsevierStyleBold">lower urinary tract infection&#44; varicella-zoster virus &#40;VZV&#41; monometameric cutaneous infection and a viral syndrome due to CMV&#46; At discharge&#44; her creatinine clearance was 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</span></p><p id="par0020" class="elsevierStylePara elsevierViewall">Given that pre-transplant panel reactive antibodies were above 50&#37;&#44; this patient should be considered as having high immunological risk&#46; Although the presence of donor-specific antibodies and C4d staining in the biopsy is not mentioned&#44; the information available suggests that she suffered from an acute antibody-mediated rejection&#46; Despite being successfully treated&#44; this episode of acute rejection reduced the glomerular filtration rate by 21<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Moreover&#44; during admission there were infections related to immunosuppression&#44; namely VZV cutaneous infection and a late CMV viral syndrome&#46; CMV has been shown to raise rates of allograft rejection and other opportunistic infections&#46; The current fever episode could be due to recurrence of acute humoral rejection or&#44; either alternatively or concomitantly&#44; to complications related to over-immunosuppression&#44; mainly PTLD and infection&#46; My infectious disease differential diagnosis includes CMV reactivation&#44; tuberculosis and other opportunistic infections&#46; I would inquire about the results of screening for latent tuberculosis infection prior to transplantation and findings on chest radiography&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">On admission&#44; examination showed the patient to be severely ill&#46; Axillary temperature was 39<span class="elsevierStyleHsp" style=""></span>&#176;C and blood pressure was 150&#47;80<span class="elsevierStyleHsp" style=""></span>mmHg&#46; Pulmonary auscultation revealed mild bibasal crackles&#46; The rest of the physical examination was unremarkable&#46; Hematological laboratory tests showed hemoglobin 13<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; white-cell count 2&#44;600 per mm</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">3</span></span><span class="elsevierStyleBold">&#40;neutrophils 76&#37;&#44; lymphocytes 10&#37;&#41;&#44; and platelets 132&#44;000 per mm</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">3</span></span><span class="elsevierStyleBold">&#46; Abnormal serum laboratory results were creatinine 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and lactate dehydrogenase 399 U&#47;L &#40;normal range&#44; 90-230 U&#47;L&#41;&#46;</span><a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a><span class="elsevierStyleBold">shows the patient&#39;s chest radiography&#46; An abdomen ultrasound revealed atrophic native kidneys&#44; without any other pathologic findings&#44; even in the renal allograft&#46; Urine culture grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">E&#46; coli</span></span><span class="elsevierStyleBold">&#40;&#62;10</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">5</span></span><span class="elsevierStyleBold">colony-forming units&#47;mL&#41;&#46; Despite antibiotic treatment for urinary infection&#44; the patient remained febrile and her general condition worsened&#46;</span></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The presence of fever and creatinine increase raises the possibility of a new acute rejection episode&#46; However&#44; the information provided is more suggestive of a renal dysfunction due to poor clinical condition&#46; Rather than a urinary infection&#44; the lack of response to antibiotic therapy suggests <span class="elsevierStyleItalic">E&#46; coli</span> asymptomatic bacteriuria&#44; which is common in women with diabetes mellitus and patients with kidney transplant&#46; The chest radiography showed a right lower lobe infiltrate&#44; associated with a pleural reaction&#44; and some small-calcified lesions&#46; The concurrence of high fever&#44; a lung infiltrate and crackles heard during auscultation suggests that the patient may have a pulmonary infection&#46; The absence of lymphadenopathies on both chest radiography and abdominal ultrasound makes the diagnosis of PTLD unlikely&#46; The chest radiological pattern would be unusual for <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia and&#44; since the patient was receiving cotrimoxazole prophylaxis&#44; this diagnosis can be ruled out&#46; Although leukopenia may be drug-related&#44; the occurrence of CMV viremia should be ruled out by antigenemia or polymerase chain reaction &#40;PCR&#41;&#46; The finding of calcified lesions on chest radiography may indicate past tuberculosis infection&#46; In this regard&#44; the possibility of tuberculosis reactivation should be strongly considered&#46; Other conditions that should be ruled out include nocardiosis and fungal infection&#44; especially aspergillosis&#46; The two latter infections frequently cause pulmonary nodules that are not observed on chest radiography&#46; Nevertheless&#44; a computed tomography &#40;CT&#41; of the chest could be useful to identify lesions missed on plain radiography&#46; At this juncture&#44; it would be appropriate to perform a bronchoscopy with bronchoalveolar lavage &#40;BAL&#41;&#46; Samples should be submitted for direct microscopic examination&#44; cytological analysis&#44; galactomannan detection&#44; and bacterial&#44; viral&#44; fungal&#44; and mycobacterial cultures&#46; Moreover&#44; blood&#44; urine&#44; and stool samples should be obtained and processed for specific mycobacterial cultures&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Blood cultures were repeatedly negative&#46; CMV antigenemia was also negative&#46; Three sputum and urine specimens were negative for acid-fast bacilli&#46; A tuberculin skin test &#40;TST&#41; was nonreactive&#46; Fundoscopic examination was normal&#46; The patient developed a progressive respiratory failure&#44; precluding bronchoscopy with BAL&#46; Thoracoabdominal CT was performed&#46;</span><a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a><span class="elsevierStyleBold">shows chest CT findings&#46; CT revealed no significant abdominal abnormalities&#46;</span></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The negativity of several blood cultures provides further evidence against the presence of bacterial infections&#46; In addition&#44; the negative antigenemia makes the diagnosis of CMV disease unlikely&#46; CT of the chest shows a patchy airspace consolidation in the medium field of the right lung&#44; some calcified mediastinal small nodules&#44; two centimetric nodules&#44; and a tree-in-bud bilateral pattern with small centrilobular nodules&#46; Both the clinical picture and CT findings are suggestive of endobronchial spread of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>&#44; although the diagnosis of aspergillosis cannot be totally ruled out&#46; As the sensitivity of acid-fast bacilli sputum and urine smears is low&#44; the negativity of these tests does not rule out tuberculosis&#46; Similarly&#44; it is well known that TST has a low efficacy due to false-negative results after transplantation&#46; At this point&#44; in a patient with progressive respiratory failure&#44; I would perform a percutaneous CT-guided needle aspiration of the left lung subpleural nodule&#46; The samples should be properly processed&#46; Meanwhile&#44; I would start antituberculosis treatment and voriconazole to cover <span class="elsevierStyleItalic">Aspergillus</span>&#46; Voriconazole dose should be adjusted to obtain trough levels within the therapeutic range &#40;1 to 5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46; Close monitoring of the levels of immunosuppressive drugs is important due to the significant risk of pharmacokinetic interactions&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Empirical antituberculosis treatment with isoniazid&#44; rifabutin&#44; pyrazinamide and ethambutol was initiated&#46; Double dose of tacrolimus was administered&#46; The patient became afebrile in two days&#46; Her general clinical condition also presented a significant improvement&#44; meaning that a bronchoscopy with BAL could be performed&#46; Cytological analysis was negative for malignant cells&#46; Gram and acid-fast staining as well as bacterial and viral cultures were negative in BAL smears&#46; Toluidine blue staining for</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">P&#46; jiroveci</span></span><span class="elsevierStyleBold">was negative&#46; PCR test for</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">M&#46; tuberculosis</span></span><span class="elsevierStyleBold">was also negative&#46; BAL culture grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Aspergillus terreus</span></span><span class="elsevierStyleBold">&#46;</span></p><p id="par0050" class="elsevierStylePara elsevierViewall">Isolation of <span class="elsevierStyleItalic">A&#46; terreus</span> from BAL has a high predictive value for invasive infection in severely immunocompromised patients&#46; Invasive aspergillosis is an uncommon but extremely serious complication in renal allograft recipients&#46; Prompt administration of appropriate antifungal therapy is essential to a successful outcome&#44; as is reduction of the overall level of immune suppression&#44; particularly corticosteroids&#46; Most isolates of <span class="elsevierStyleItalic">A&#46; terreus</span> are resistant <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> to amphotericin B&#46; Therefore&#44; an antifungal triazole such as voriconazole should be used&#46; The negativity of acid-fast bacilli smear and PCR results from BAL does not rule out the diagnosis of active tuberculosis&#46; Dual infection is not uncommon among immunocompromised hosts with pulmonary infiltrates&#46; Interestingly&#44; the patient became afebrile and her clinical condition improved soon after antituberculosis treatment was initiated&#46; In this patient from a developing country&#44; I would be concerned about the possibility of drug-resistant tuberculosis&#46; So&#44; pending the results of the L&#246;wenstein culture and susceptibility tests&#44; I would maintain the four-drug antituberculous therapy&#46; I am particularly worried about pharmacokinetic interactions and nephrotoxicity&#46; Isoniazid is a CYP3A4 inhibitor and may increase tacrolimus exposure&#46; Rifabutin&#44; like rifampin&#44; induces CYP3A4 and decreases tacrolimus levels&#44; although rifabutin is a less potent inducer of microsomal P450 enzymes&#46; In any case&#44; as the net effect favors rifabutin&#44; it is advisable to increase the tacrolimus dose and to monitor blood levels closely&#46; Voriconazole is a CYP3A4 inhibitor&#46; It has been suggested that when voriconazole is initiated&#44; the tacrolimus dose should be reduced by 50&#37;&#46; Therefore&#44; I would adjust rifabutin&#44; pyrazinamide and ethambutol doses to renal function and I would monitor tacrolimus blood level twice a week&#46; I would also maintain a degree of hydration sufficient to prevent hyperuricemia-induced renal dysfunction&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">The patient remained afebrile and her respiratory function improved progressively&#46; Oral steroids were tapered&#46; Due to the favorable clinical response&#44; treatment with four antituberculosis drugs was maintained&#46; Serum testing for galactomannan antigen was repeatedly negative&#46; Caspofungin was started due to the suspicion of an invasive infection caused by</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">A terreus</span></span><span class="elsevierStyleBold">&#46; Despite the increase in tacrolimus dose&#44; the blood level of this drug was 3 ng&#47;mL 6 days after the start of antituberculosis treatment&#46; Serum creatinine level increased to 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and creatinine clearance fell to 16<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</span></p><p id="par0060" class="elsevierStylePara elsevierViewall">Galactomannan testing has been demonstrated to be a useful tool for early diagnosis of invasive aspergillosis in neutropenic patients&#46; The performance characteristics of serum galactomannan assay are less well defined in other populations&#46; In solid organ transplant &#40;SOT&#41; recipients the sensitivity of the test is about 50&#37;&#46; Therefore&#44; the repeatedly negative galactomannan result would not change my decision to administer antifungal therapy to this patient&#46; Caspofungin is approved for use in patients with probable or proven invasive aspergillosis that is refractory to or intolerant of other therapies&#46; Caspofungin is usually well tolerated and has fewer drug interactions than voriconazole&#46; Nevertheless&#44; it can reduce the area under the curve of tacrolimus by &#8764;20&#37;&#46; On the other hand&#44; inducers of drug clearance such as rifabutin may significantly reduce caspofungin concentrations&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Differential diagnosis of acute renal allograft dysfunction in this patient may be broad&#44; taking into account the limited data available&#46; Clinical information of urinary volume and weight gain in combination with analytical data in serum and urine would be useful&#46; In the absence of fever and urinary symptoms&#44; bacterial pyelonephritis may be practically ruled out&#46; Antituberculosis therapy may be a cause of interstitial nephritis in native kidney although it is only rarely described in renal recipients receiving concomitant steroid treatment&#46; Pyrazinamide-related hyperuricemia may cause renal dysfunction&#46; Low tacrolimus levels and concomitant steroid dose reduction may put this patient at risk to acute rejection&#46; Therefore I would promptly increase the tacrolimus dose and carefully review clinical and analytical data&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Daily dose of tacrolimus was increased&#46; Pyrazinamide was discontinued because of creatinine clearance below 20<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Levofloxacin was added to the antituberculosis treatment&#46; A new bronchoscopy with transbronchial biopsy of one of the nodular lesions was performed&#46; The histological examination showed a negligible amount of lung parenchyma without abnormalities&#46; Neither granulomas nor filamentous fungi were observed&#46; Serum creatinine level decreased to 1&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; Blood levels of tacrolimus were maintained between 9 and 12 ng&#47;mL&#46; Thereafter&#44; the following liver function test abnormalities appeared&#58; total bilirubin 2&#46;27<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;normal range&#44; 0&#46;20-1&#46;10&#41;&#59; aspartate aminotransferase 807 U&#47;L &#40;normal range&#44; 5-45&#41;&#59; alaline aminotransferase 225 U&#47;L &#40;normal range&#44; 5-45&#41;&#59; alkaline phosphatase 660 U&#47;L &#40;normal range&#44; 40-130&#41;&#59; &#947;-glutamyl transpeptidase 362 U&#47;L &#40;normal range&#44; 8-61&#41;&#46; The patient was asymptomatic and receiving steroids&#44; tacrolimus&#44; mycophenolate mofetil&#44; caspofungin&#44; isoniazid&#44; rifabutin&#44; ethambutol&#44; and levofloxacin&#46;</span></p><p id="par0075" class="elsevierStylePara elsevierViewall">The improvement of renal function after pyrazinamide discontinuation suggests that pyrazinamide-related hyperuricemia was the most likely cause of the renal dysfunction&#46; More importantly&#44; liver function test results suggest severe antituberculosis drug-induced hepatotoxicity&#46; Isoniazid is a well-known cause of liver injury during antituberculosis treatment&#46; Moreover&#44; the patient had been receiving pyrazinamide&#44; which has increasingly been recognized as a significant cause of hepatotoxicity&#46; Rifabutin is associated with a lower potential for hepatotoxicity than isoniazid or pyrazinamide&#46; For their part&#44; levofloxacin and particularly ethambutol rarely cause liver injury&#46; Hepatotoxicity is the most serious adverse effect of antituberculosis treatment and can be a life-threatening complication&#46; Therefore&#44; at this point&#44; I would immediately stop all the antituberculosis drugs and closely monitor tacrolimus levels&#46; When alaline aminotransferase returns to less than twice the upper limit of normal&#44; I would restart the antituberculosis drugs one at a time&#59; first ethambutol&#44; second levofloxacin&#44; and finally rifabutin&#46; While awaiting the results of the L&#246;wenstein culture&#44; I would not administer isoniazid and pyrazinamide&#44; since these drugs are the most frequently associated with hepatotoxicity&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Treatment with isoniazid and rifabutin was stopped and pyrazinamide was reinitiated&#46; The patient&#39;s general condition improved greatly and she was able to walk around the ward without any help&#46; A few days later she was discharged&#46; Although the diagnosis of tuberculosis was not microbiologically documented&#44; treatment with ethambutol&#44; levofloxacin and pyrazinamide was maintained&#46; As rifabutin was not longer administered&#44; oral voriconazole was given instead of caspofungin&#46; Tacrolimus dose was adjusted appropriately&#46;</span></p><p id="par0085" class="elsevierStylePara elsevierViewall">Taking into account the fever resolution and the clear improvement on clinical condition&#44; it is reasonable to maintain antituberculosis treatment and antifungal therapy while awaiting the final microbiological results&#46; However&#44; I would reintroduce rifabutin instead of pyrazinamide&#46; First&#44; at the usual doses&#44; rifabutin hepatotoxicity is uncommon&#46; Second&#44; the absence of any disproportionate increase in bilirubin and alkaline phosphatase in liver function tests argue against rifabutin hepatotoxicity&#46; Third&#44; a regimen containing neither isoniazid nor a rifamycin should be administered for at least 18-24 months to lessen the risk of relapse&#46; Introduction of voriconazole will increase tacrolimus exposure and put this patient at risk of calcineurin inhibitor-related hyperuricemia and acute nephroxicity&#46; Thus&#44; the tacrolimus dose should be reduced and its levels carefully monitored&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">One month after the first bronchocopy was performed&#44; the BAL sample grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">M&#46; tuberculosis</span></span><span class="elsevierStyleBold">susceptible to all antituberculosis drugs&#46; Treatment with voriconazole was discontinued&#46; The patient completed a total of 18 months under triple antituberculosis treatment&#46; A new CT&#44; 60 days after admission&#44; revealed resolution of lung infiltrates&#46; Liver enzymes remained within the normal range for the rest of the treatment period&#46; Serum creatinine remained stable around 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and creatinine clearance remained around 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; After 3 years of follow-up the patient remains in good health&#46;</span></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Commentary</span><p id="par0095" class="elsevierStylePara elsevierViewall">Tuberculosis is one of the most significant opportunistic infections affecting SOT recipients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Toxicity of the treatment and interactions with immunosuppressive drugs makes clinical decisions very difficult in this context&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Clinicians in charge of this patient had to adopt challenging decisions before they had a microbiologically confirmed diagnosis&#46; First one was to initiate empirical antituberculous treatment based on suggestive clinical&#44; epidemiological and radiological data&#46; In Spain&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> the incidence of tuberculosis in renal transplant recipients has been estimated to be 358 cases per 10<span class="elsevierStyleSup">5</span> per year&#44; but much higher figures have been reported in developing countries&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The second crucial decision was to continue antituberculous treatment based on clinical response&#44; despite microbiological preliminary results were against this diagnosis &#40;negative tuberculin PPD test&#44; negative PCR and negative acid-fast stain&#41;&#46; As the discussant pointed out&#44; in some cases the diagnosis of tuberculosis is made solely on the basis of respond to therapy<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; This choice was even harder to adopt because the available microbiologic results pointed to other life-threatening opportunistic infections such as aspergillosis&#46; Although the isolation of <span class="elsevierStyleItalic">A&#46; terreus</span> from BAL cannot discriminate between colonization and infection&#44; it has a high predictive value for invasive disease in immunocompromised hosts&#46; The patient fulfilled criteria for probable invasive fungal disease according to revised definitions&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The decision to initiate an empirical treatment<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> must be based on the probability of the infection&#44; its severity and the therapeutic threshold of the treatment&#46; In this scenario&#44; it was considered prudent to initiate antifungal treatment despite the clinical respond to empirical antituberculous treatment&#46; The patient presented a high risk for hepatotoxicity of antituberculous drugs<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and for difficult to manage interactions between first choice antituberculous&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9</span></a> antifungal<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and immunosuppressive drugs&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The third clinically relevant decision was to adjust treatment when adverse effects and interactions developed&#46; In this clinical context the treating physicians were dealing not only with the possibility of two severe opportunistic infections&#44; but with the necessity of preserving the allograft&#44; given the poor prognosis of elderly patients under dialysis&#46; Once the decision of initiating an empirical treatment has been adopted&#44; the development of adverse effects or interactions should be a criterion to search for the most beneficial combination of drugs&#44; rather than to taper off them&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; despite continuing improvements in microbiological and imaging methods&#44; clinicians still have to face puzzling cases in which therapeutic decisions have to be based on the clinical respond to drug administration&#46; Maintaining this decision&#44; despite side effects of the drugs administered&#44; might be the key for a favorable outcome&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronology of infections after solid organ transplantation&#46; Adapted from Fishman JA<span class="elsevierStyleSup">2</span>&#46; HSV &#8211; herpes simplex virus&#59; CMV &#8211; cytomegalovirus&#59; EBV &#8211; Ebstein-Barr virus&#59; VZV &#8211; varicella-zoster virus&#59; PTLD &#8211; postransplant lymphoproliferative disorders&#46;</p>"
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Conferencia clínico-patológica
Fever in a kidney transplant recipient: No Facts and Many Interactions
Fiebre en un receptor de trasplante renal: ninguna evidencia y muchas interacciones
F. López-Medranoa,
Autor para correspondencia
flmedrano@yahoo.es

Corresponding author.
, J. Carratalàb, J.M. Cruzadoc, M.J. Gutiérrezd, J.M. Aguadoa
a Infectious Diseases Unit, University Hospital 12 de Octubre, Madrid, Spain
b Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, Barcelona, Spain
c Department of Nephrology, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, Barcelona, Spain
d Department of Nephrology, University Hospital 12 de Octubre, Madrid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">A 69 year-old woman was admitted to hospital due to fever&#46; She was from the South of Morocco and had been living in Spain for four years&#46; She had a ten-year medical history of hypertension and type 2 diabetes mellitus&#46; Nine months before admission&#44; she received a kidney allograft from a deceased donor&#44; due to end-stage renal disease&#46;</span></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common cause of fever in renal transplant patients is infection&#46; However&#44; many other factors may be responsible&#44; such as allograft rejection&#44; drug hypersensitivity&#44; and malignancy&#46; Acute rejection occurs more frequently during the first six months after transplantation&#46; Post-transplant lymphoproliferative disorders &#40;PTLD&#41; occur mainly within the first year&#46; Most infections after transplantation occur on a relatively consistent timeline&#44; reflecting the interplay of risk factors and the net state of immunosuppression&#46; The majority of infections occurring later than six months after transplantation are basically the common community-acquired infections encountered in patients with chronic conditions &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Urinary infection is frequent&#44; especially in diabetic women&#46; Other late manifestations may represent reactivated or chronic viral infections&#44; particularly cytomegalovirus &#40;CMV&#41;&#46; Finally&#44; patients with acute or chronic rejection and over-immunosuppression are at high risk of life-threatening infection by opportunistic pathogens&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Pretransplant anti-HLA panel reactive antibodies were 52&#37;&#46; She was seropositive for CMV&#46; Immunosuppression comprised tacrolimus&#44; mycophenolate mofetil and steroids&#46; Prophylaxis with intravenous cefuroxime &#40;2 days&#41;&#44; oral cotrimoxazole &#40;9 months&#41;&#44; and intravenous ganciclovir &#40;10 days&#41;&#44; followed by oral valganciclovir &#40;3 months&#41; was administered&#46; At hospital discharge creatinine clearance was 71<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Four months after transplantation&#44; a biopsy-proven acute vascular rejection &#40;grade IIB according to the Banff classification&#41; was established&#46; It was successfully treated with thymoglobulin&#44; six sessions of plasmapheresis&#44; and human polyvalent immunoglobulin&#46; The patient developed several infections&#44; including</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Escherichia coli</span></span><span class="elsevierStyleBold">lower urinary tract infection&#44; varicella-zoster virus &#40;VZV&#41; monometameric cutaneous infection and a viral syndrome due to CMV&#46; At discharge&#44; her creatinine clearance was 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</span></p><p id="par0020" class="elsevierStylePara elsevierViewall">Given that pre-transplant panel reactive antibodies were above 50&#37;&#44; this patient should be considered as having high immunological risk&#46; Although the presence of donor-specific antibodies and C4d staining in the biopsy is not mentioned&#44; the information available suggests that she suffered from an acute antibody-mediated rejection&#46; Despite being successfully treated&#44; this episode of acute rejection reduced the glomerular filtration rate by 21<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Moreover&#44; during admission there were infections related to immunosuppression&#44; namely VZV cutaneous infection and a late CMV viral syndrome&#46; CMV has been shown to raise rates of allograft rejection and other opportunistic infections&#46; The current fever episode could be due to recurrence of acute humoral rejection or&#44; either alternatively or concomitantly&#44; to complications related to over-immunosuppression&#44; mainly PTLD and infection&#46; My infectious disease differential diagnosis includes CMV reactivation&#44; tuberculosis and other opportunistic infections&#46; I would inquire about the results of screening for latent tuberculosis infection prior to transplantation and findings on chest radiography&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">On admission&#44; examination showed the patient to be severely ill&#46; Axillary temperature was 39<span class="elsevierStyleHsp" style=""></span>&#176;C and blood pressure was 150&#47;80<span class="elsevierStyleHsp" style=""></span>mmHg&#46; Pulmonary auscultation revealed mild bibasal crackles&#46; The rest of the physical examination was unremarkable&#46; Hematological laboratory tests showed hemoglobin 13<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; white-cell count 2&#44;600 per mm</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">3</span></span><span class="elsevierStyleBold">&#40;neutrophils 76&#37;&#44; lymphocytes 10&#37;&#41;&#44; and platelets 132&#44;000 per mm</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">3</span></span><span class="elsevierStyleBold">&#46; Abnormal serum laboratory results were creatinine 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and lactate dehydrogenase 399 U&#47;L &#40;normal range&#44; 90-230 U&#47;L&#41;&#46;</span><a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a><span class="elsevierStyleBold">shows the patient&#39;s chest radiography&#46; An abdomen ultrasound revealed atrophic native kidneys&#44; without any other pathologic findings&#44; even in the renal allograft&#46; Urine culture grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">E&#46; coli</span></span><span class="elsevierStyleBold">&#40;&#62;10</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">5</span></span><span class="elsevierStyleBold">colony-forming units&#47;mL&#41;&#46; Despite antibiotic treatment for urinary infection&#44; the patient remained febrile and her general condition worsened&#46;</span></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The presence of fever and creatinine increase raises the possibility of a new acute rejection episode&#46; However&#44; the information provided is more suggestive of a renal dysfunction due to poor clinical condition&#46; Rather than a urinary infection&#44; the lack of response to antibiotic therapy suggests <span class="elsevierStyleItalic">E&#46; coli</span> asymptomatic bacteriuria&#44; which is common in women with diabetes mellitus and patients with kidney transplant&#46; The chest radiography showed a right lower lobe infiltrate&#44; associated with a pleural reaction&#44; and some small-calcified lesions&#46; The concurrence of high fever&#44; a lung infiltrate and crackles heard during auscultation suggests that the patient may have a pulmonary infection&#46; The absence of lymphadenopathies on both chest radiography and abdominal ultrasound makes the diagnosis of PTLD unlikely&#46; The chest radiological pattern would be unusual for <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia and&#44; since the patient was receiving cotrimoxazole prophylaxis&#44; this diagnosis can be ruled out&#46; Although leukopenia may be drug-related&#44; the occurrence of CMV viremia should be ruled out by antigenemia or polymerase chain reaction &#40;PCR&#41;&#46; The finding of calcified lesions on chest radiography may indicate past tuberculosis infection&#46; In this regard&#44; the possibility of tuberculosis reactivation should be strongly considered&#46; Other conditions that should be ruled out include nocardiosis and fungal infection&#44; especially aspergillosis&#46; The two latter infections frequently cause pulmonary nodules that are not observed on chest radiography&#46; Nevertheless&#44; a computed tomography &#40;CT&#41; of the chest could be useful to identify lesions missed on plain radiography&#46; At this juncture&#44; it would be appropriate to perform a bronchoscopy with bronchoalveolar lavage &#40;BAL&#41;&#46; Samples should be submitted for direct microscopic examination&#44; cytological analysis&#44; galactomannan detection&#44; and bacterial&#44; viral&#44; fungal&#44; and mycobacterial cultures&#46; Moreover&#44; blood&#44; urine&#44; and stool samples should be obtained and processed for specific mycobacterial cultures&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Blood cultures were repeatedly negative&#46; CMV antigenemia was also negative&#46; Three sputum and urine specimens were negative for acid-fast bacilli&#46; A tuberculin skin test &#40;TST&#41; was nonreactive&#46; Fundoscopic examination was normal&#46; The patient developed a progressive respiratory failure&#44; precluding bronchoscopy with BAL&#46; Thoracoabdominal CT was performed&#46;</span><a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a><span class="elsevierStyleBold">shows chest CT findings&#46; CT revealed no significant abdominal abnormalities&#46;</span></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The negativity of several blood cultures provides further evidence against the presence of bacterial infections&#46; In addition&#44; the negative antigenemia makes the diagnosis of CMV disease unlikely&#46; CT of the chest shows a patchy airspace consolidation in the medium field of the right lung&#44; some calcified mediastinal small nodules&#44; two centimetric nodules&#44; and a tree-in-bud bilateral pattern with small centrilobular nodules&#46; Both the clinical picture and CT findings are suggestive of endobronchial spread of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>&#44; although the diagnosis of aspergillosis cannot be totally ruled out&#46; As the sensitivity of acid-fast bacilli sputum and urine smears is low&#44; the negativity of these tests does not rule out tuberculosis&#46; Similarly&#44; it is well known that TST has a low efficacy due to false-negative results after transplantation&#46; At this point&#44; in a patient with progressive respiratory failure&#44; I would perform a percutaneous CT-guided needle aspiration of the left lung subpleural nodule&#46; The samples should be properly processed&#46; Meanwhile&#44; I would start antituberculosis treatment and voriconazole to cover <span class="elsevierStyleItalic">Aspergillus</span>&#46; Voriconazole dose should be adjusted to obtain trough levels within the therapeutic range &#40;1 to 5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46; Close monitoring of the levels of immunosuppressive drugs is important due to the significant risk of pharmacokinetic interactions&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Empirical antituberculosis treatment with isoniazid&#44; rifabutin&#44; pyrazinamide and ethambutol was initiated&#46; Double dose of tacrolimus was administered&#46; The patient became afebrile in two days&#46; Her general clinical condition also presented a significant improvement&#44; meaning that a bronchoscopy with BAL could be performed&#46; Cytological analysis was negative for malignant cells&#46; Gram and acid-fast staining as well as bacterial and viral cultures were negative in BAL smears&#46; Toluidine blue staining for</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">P&#46; jiroveci</span></span><span class="elsevierStyleBold">was negative&#46; PCR test for</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">M&#46; tuberculosis</span></span><span class="elsevierStyleBold">was also negative&#46; BAL culture grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Aspergillus terreus</span></span><span class="elsevierStyleBold">&#46;</span></p><p id="par0050" class="elsevierStylePara elsevierViewall">Isolation of <span class="elsevierStyleItalic">A&#46; terreus</span> from BAL has a high predictive value for invasive infection in severely immunocompromised patients&#46; Invasive aspergillosis is an uncommon but extremely serious complication in renal allograft recipients&#46; Prompt administration of appropriate antifungal therapy is essential to a successful outcome&#44; as is reduction of the overall level of immune suppression&#44; particularly corticosteroids&#46; Most isolates of <span class="elsevierStyleItalic">A&#46; terreus</span> are resistant <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> to amphotericin B&#46; Therefore&#44; an antifungal triazole such as voriconazole should be used&#46; The negativity of acid-fast bacilli smear and PCR results from BAL does not rule out the diagnosis of active tuberculosis&#46; Dual infection is not uncommon among immunocompromised hosts with pulmonary infiltrates&#46; Interestingly&#44; the patient became afebrile and her clinical condition improved soon after antituberculosis treatment was initiated&#46; In this patient from a developing country&#44; I would be concerned about the possibility of drug-resistant tuberculosis&#46; So&#44; pending the results of the L&#246;wenstein culture and susceptibility tests&#44; I would maintain the four-drug antituberculous therapy&#46; I am particularly worried about pharmacokinetic interactions and nephrotoxicity&#46; Isoniazid is a CYP3A4 inhibitor and may increase tacrolimus exposure&#46; Rifabutin&#44; like rifampin&#44; induces CYP3A4 and decreases tacrolimus levels&#44; although rifabutin is a less potent inducer of microsomal P450 enzymes&#46; In any case&#44; as the net effect favors rifabutin&#44; it is advisable to increase the tacrolimus dose and to monitor blood levels closely&#46; Voriconazole is a CYP3A4 inhibitor&#46; It has been suggested that when voriconazole is initiated&#44; the tacrolimus dose should be reduced by 50&#37;&#46; Therefore&#44; I would adjust rifabutin&#44; pyrazinamide and ethambutol doses to renal function and I would monitor tacrolimus blood level twice a week&#46; I would also maintain a degree of hydration sufficient to prevent hyperuricemia-induced renal dysfunction&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">The patient remained afebrile and her respiratory function improved progressively&#46; Oral steroids were tapered&#46; Due to the favorable clinical response&#44; treatment with four antituberculosis drugs was maintained&#46; Serum testing for galactomannan antigen was repeatedly negative&#46; Caspofungin was started due to the suspicion of an invasive infection caused by</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">A terreus</span></span><span class="elsevierStyleBold">&#46; Despite the increase in tacrolimus dose&#44; the blood level of this drug was 3 ng&#47;mL 6 days after the start of antituberculosis treatment&#46; Serum creatinine level increased to 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and creatinine clearance fell to 16<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</span></p><p id="par0060" class="elsevierStylePara elsevierViewall">Galactomannan testing has been demonstrated to be a useful tool for early diagnosis of invasive aspergillosis in neutropenic patients&#46; The performance characteristics of serum galactomannan assay are less well defined in other populations&#46; In solid organ transplant &#40;SOT&#41; recipients the sensitivity of the test is about 50&#37;&#46; Therefore&#44; the repeatedly negative galactomannan result would not change my decision to administer antifungal therapy to this patient&#46; Caspofungin is approved for use in patients with probable or proven invasive aspergillosis that is refractory to or intolerant of other therapies&#46; Caspofungin is usually well tolerated and has fewer drug interactions than voriconazole&#46; Nevertheless&#44; it can reduce the area under the curve of tacrolimus by &#8764;20&#37;&#46; On the other hand&#44; inducers of drug clearance such as rifabutin may significantly reduce caspofungin concentrations&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Differential diagnosis of acute renal allograft dysfunction in this patient may be broad&#44; taking into account the limited data available&#46; Clinical information of urinary volume and weight gain in combination with analytical data in serum and urine would be useful&#46; In the absence of fever and urinary symptoms&#44; bacterial pyelonephritis may be practically ruled out&#46; Antituberculosis therapy may be a cause of interstitial nephritis in native kidney although it is only rarely described in renal recipients receiving concomitant steroid treatment&#46; Pyrazinamide-related hyperuricemia may cause renal dysfunction&#46; Low tacrolimus levels and concomitant steroid dose reduction may put this patient at risk to acute rejection&#46; Therefore I would promptly increase the tacrolimus dose and carefully review clinical and analytical data&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Daily dose of tacrolimus was increased&#46; Pyrazinamide was discontinued because of creatinine clearance below 20<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Levofloxacin was added to the antituberculosis treatment&#46; A new bronchoscopy with transbronchial biopsy of one of the nodular lesions was performed&#46; The histological examination showed a negligible amount of lung parenchyma without abnormalities&#46; Neither granulomas nor filamentous fungi were observed&#46; Serum creatinine level decreased to 1&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; Blood levels of tacrolimus were maintained between 9 and 12 ng&#47;mL&#46; Thereafter&#44; the following liver function test abnormalities appeared&#58; total bilirubin 2&#46;27<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;normal range&#44; 0&#46;20-1&#46;10&#41;&#59; aspartate aminotransferase 807 U&#47;L &#40;normal range&#44; 5-45&#41;&#59; alaline aminotransferase 225 U&#47;L &#40;normal range&#44; 5-45&#41;&#59; alkaline phosphatase 660 U&#47;L &#40;normal range&#44; 40-130&#41;&#59; &#947;-glutamyl transpeptidase 362 U&#47;L &#40;normal range&#44; 8-61&#41;&#46; The patient was asymptomatic and receiving steroids&#44; tacrolimus&#44; mycophenolate mofetil&#44; caspofungin&#44; isoniazid&#44; rifabutin&#44; ethambutol&#44; and levofloxacin&#46;</span></p><p id="par0075" class="elsevierStylePara elsevierViewall">The improvement of renal function after pyrazinamide discontinuation suggests that pyrazinamide-related hyperuricemia was the most likely cause of the renal dysfunction&#46; More importantly&#44; liver function test results suggest severe antituberculosis drug-induced hepatotoxicity&#46; Isoniazid is a well-known cause of liver injury during antituberculosis treatment&#46; Moreover&#44; the patient had been receiving pyrazinamide&#44; which has increasingly been recognized as a significant cause of hepatotoxicity&#46; Rifabutin is associated with a lower potential for hepatotoxicity than isoniazid or pyrazinamide&#46; For their part&#44; levofloxacin and particularly ethambutol rarely cause liver injury&#46; Hepatotoxicity is the most serious adverse effect of antituberculosis treatment and can be a life-threatening complication&#46; Therefore&#44; at this point&#44; I would immediately stop all the antituberculosis drugs and closely monitor tacrolimus levels&#46; When alaline aminotransferase returns to less than twice the upper limit of normal&#44; I would restart the antituberculosis drugs one at a time&#59; first ethambutol&#44; second levofloxacin&#44; and finally rifabutin&#46; While awaiting the results of the L&#246;wenstein culture&#44; I would not administer isoniazid and pyrazinamide&#44; since these drugs are the most frequently associated with hepatotoxicity&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Treatment with isoniazid and rifabutin was stopped and pyrazinamide was reinitiated&#46; The patient&#39;s general condition improved greatly and she was able to walk around the ward without any help&#46; A few days later she was discharged&#46; Although the diagnosis of tuberculosis was not microbiologically documented&#44; treatment with ethambutol&#44; levofloxacin and pyrazinamide was maintained&#46; As rifabutin was not longer administered&#44; oral voriconazole was given instead of caspofungin&#46; Tacrolimus dose was adjusted appropriately&#46;</span></p><p id="par0085" class="elsevierStylePara elsevierViewall">Taking into account the fever resolution and the clear improvement on clinical condition&#44; it is reasonable to maintain antituberculosis treatment and antifungal therapy while awaiting the final microbiological results&#46; However&#44; I would reintroduce rifabutin instead of pyrazinamide&#46; First&#44; at the usual doses&#44; rifabutin hepatotoxicity is uncommon&#46; Second&#44; the absence of any disproportionate increase in bilirubin and alkaline phosphatase in liver function tests argue against rifabutin hepatotoxicity&#46; Third&#44; a regimen containing neither isoniazid nor a rifamycin should be administered for at least 18-24 months to lessen the risk of relapse&#46; Introduction of voriconazole will increase tacrolimus exposure and put this patient at risk of calcineurin inhibitor-related hyperuricemia and acute nephroxicity&#46; Thus&#44; the tacrolimus dose should be reduced and its levels carefully monitored&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">One month after the first bronchocopy was performed&#44; the BAL sample grew</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">M&#46; tuberculosis</span></span><span class="elsevierStyleBold">susceptible to all antituberculosis drugs&#46; Treatment with voriconazole was discontinued&#46; The patient completed a total of 18 months under triple antituberculosis treatment&#46; A new CT&#44; 60 days after admission&#44; revealed resolution of lung infiltrates&#46; Liver enzymes remained within the normal range for the rest of the treatment period&#46; Serum creatinine remained stable around 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and creatinine clearance remained around 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; After 3 years of follow-up the patient remains in good health&#46;</span></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Commentary</span><p id="par0095" class="elsevierStylePara elsevierViewall">Tuberculosis is one of the most significant opportunistic infections affecting SOT recipients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Toxicity of the treatment and interactions with immunosuppressive drugs makes clinical decisions very difficult in this context&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Clinicians in charge of this patient had to adopt challenging decisions before they had a microbiologically confirmed diagnosis&#46; First one was to initiate empirical antituberculous treatment based on suggestive clinical&#44; epidemiological and radiological data&#46; In Spain&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> the incidence of tuberculosis in renal transplant recipients has been estimated to be 358 cases per 10<span class="elsevierStyleSup">5</span> per year&#44; but much higher figures have been reported in developing countries&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The second crucial decision was to continue antituberculous treatment based on clinical response&#44; despite microbiological preliminary results were against this diagnosis &#40;negative tuberculin PPD test&#44; negative PCR and negative acid-fast stain&#41;&#46; As the discussant pointed out&#44; in some cases the diagnosis of tuberculosis is made solely on the basis of respond to therapy<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; This choice was even harder to adopt because the available microbiologic results pointed to other life-threatening opportunistic infections such as aspergillosis&#46; Although the isolation of <span class="elsevierStyleItalic">A&#46; terreus</span> from BAL cannot discriminate between colonization and infection&#44; it has a high predictive value for invasive disease in immunocompromised hosts&#46; The patient fulfilled criteria for probable invasive fungal disease according to revised definitions&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The decision to initiate an empirical treatment<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> must be based on the probability of the infection&#44; its severity and the therapeutic threshold of the treatment&#46; In this scenario&#44; it was considered prudent to initiate antifungal treatment despite the clinical respond to empirical antituberculous treatment&#46; The patient presented a high risk for hepatotoxicity of antituberculous drugs<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and for difficult to manage interactions between first choice antituberculous&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9</span></a> antifungal<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and immunosuppressive drugs&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The third clinically relevant decision was to adjust treatment when adverse effects and interactions developed&#46; In this clinical context the treating physicians were dealing not only with the possibility of two severe opportunistic infections&#44; but with the necessity of preserving the allograft&#44; given the poor prognosis of elderly patients under dialysis&#46; Once the decision of initiating an empirical treatment has been adopted&#44; the development of adverse effects or interactions should be a criterion to search for the most beneficial combination of drugs&#44; rather than to taper off them&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; despite continuing improvements in microbiological and imaging methods&#44; clinicians still have to face puzzling cases in which therapeutic decisions have to be based on the clinical respond to drug administration&#46; Maintaining this decision&#44; despite side effects of the drugs administered&#44; might be the key for a favorable outcome&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronology of infections after solid organ transplantation&#46; Adapted from Fishman JA<span class="elsevierStyleSup">2</span>&#46; HSV &#8211; herpes simplex virus&#59; CMV &#8211; cytomegalovirus&#59; EBV &#8211; Ebstein-Barr virus&#59; VZV &#8211; varicella-zoster virus&#59; PTLD &#8211; postransplant lymphoproliferative disorders&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Chest radiography showing a right lower lobe infiltrate &#40;arrow&#41;&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Computed tomography of the chest showing a patchy airspace consolidation in the medium field of the right lung &#40;arrow&#41;&#44; centimetric nodules &#40;star&#41;&#44; and a tree-in-bud bilateral pattern with small centrilobular nodules &#40;arrow heads&#41;&#46;</p>"
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                      "titulo" => "Mycobacterium tuberculosis infection in solid-organ transplant recipients&#58; impact and implications for management"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Singh"
                            1 => "D&#46;L&#46; Paterson"
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                    0 => array:1 [
                      "Revista" => array:7 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9827281"
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                      "titulo" => "Infection in solid-organ transplant recipients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;A&#46; Fishman"
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                      "doi" => "10.1056/NEJMra064928"
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                        "fecha" => "2007"
                        "volumen" => "357"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18094380"
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            2 => array:3 [
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              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tuberculosis after solid-organ transplant&#58; incidence&#44; risk factors&#44; and clinical characteristics in the RESITRA &#40;Spanish Network of Infection in Transplantation&#41; cohort"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Torre-Cisneros"
                            1 => "A&#46; Doblas"
                            2 => "J&#46;M&#46; Aguado"
                            3 => "R&#46; San Juan"
                            4 => "M&#46; Blanes"
                            5 => "M&#46; Montejo"
                          ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/599035"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2009"
                        "volumen" => "48"
                        "paginaInicial" => "1657"
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                      "titulo" => "Tuberculosis in solid-organ transplant recipients&#58; consensus statement of the group for the study of infection in transplant recipients &#40;GESITRA&#41; of the Spanish Society of Infectious Diseases and Clinical Microbiology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Aguado"
                            1 => "J&#46; Torre-Cisneros"
                            2 => "J&#46; Fortun"
                            3 => "N&#46; Benito"
                            4 => "Y&#46; Meije"
                            5 => "A&#46; Doblas"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/597590"
                      "Revista" => array:6 [
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                        "fecha" => "2009"
                        "volumen" => "48"
                        "paginaInicial" => "1276"
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              "etiqueta" => "5"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                      "titulo" => "Fever of unknown origin caused by tuberculosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;J&#46; Bofinger"
                            1 => "D&#46; Schlossberg"
                          ]
                        ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.idc.2007.08.001"
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                        "volumen" => "21"
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