Scientific Letter
Pulmonary Mycobacteriosis in a Patient Receiving Chronic Methotrexate Treatment
Micobacteriosis pulmonar en un paciente en tratamiento crónico con metotrexato
María Agustina Dal Molín-Vegliaa,b,c, Francisca Sánchez-Martíneza,b,c,d,f, Antonio Fernando Fernández-Alarzab,e, Marisol Domínguez-Álvarezb,c,f,g,
Corresponding author
a Servicios de Medicina Interna y Enfermedades Infecciosas, Hospital del Mar, Barcelona, Spain
b Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
c Universidad Autónoma de Barcelona (UAB), Barcelona, Spain
d Grupo de Estudio de las Infecciones por Micobacterias (GEIM) de la Sociedad Española de Enfermedades Infecciosas (SEIMC), Spain
e Servicio de Radiología, Hospital del Mar, Barcelona, Spain
f Servicio de Neumología, Hospital del Mar, Barcelona, Spain
g Centro de Investigación en red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISC III), Barcelona, Spain
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"identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Universidad Autónoma de Barcelona (UAB), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Grupo de Estudio de las Infecciones por Micobacterias (GEIM) de la Sociedad Española de Enfermedades Infecciosas (SEIMC), Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Radiología, Hospital del Mar, Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Neumología, Hospital del Mar, Barcelona, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Centro de Investigación en red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISC III), Barcelona, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Micobacteriosis pulmonar en un paciente en tratamiento crónico con metotrexato" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 563 "Ancho" => 1400 "Tamanyo" => 165494 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Chest CT: pulmonary consolidations in middle lobe, lingula, and both lower lobes. (B) Transbronchial biopsy of the right lung base: evidence of non-necrotizing granulomatous pneumonitis (hematoxylin-eosin staining, 4×).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We report the case of a 42-year-old man, Dutch national, resident in Spain for 11 years. He was an active smoker with a cumulative pack-year index of 15, and no other toxic habits, and reported no use of saunas or hot tubs. He had a diagnosis of pityriasis lichenoides, treated with 7.5<span class="elsevierStyleHsp" style=""></span>mg methotrexate weekly for the previous 5 years. He attended the emergency department with a 2-week history of 38<span class="elsevierStyleHsp" style=""></span>°C fever, myalgia, cough, expectoration of mucus, and dyspnea on moderate exertion. Initial clinical laboratory results showed 11,190 leukocytes/mm<span class="elsevierStyleSup">3</span> (70% neutrophils, 19% lymphocytes, 9% monocytes), C-reactive protein 11.2<span class="elsevierStyleHsp" style=""></span>mg/dl, and procalcitonin 0.56<span class="elsevierStyleHsp" style=""></span>ng/ml. Arterial blood gases were FiO<span class="elsevierStyleInf">2</span> 0.24, pH 7.48, PaCO<span class="elsevierStyleInf">2</span> 37<span class="elsevierStyleHsp" style=""></span>mmHg, PaO<span class="elsevierStyleInf">2</span> 87<span class="elsevierStyleHsp" style=""></span>mmHg and HCO<span class="elsevierStyleInf">3</span> 27<span class="elsevierStyleHsp" style=""></span>mmol/l. Chest X-ray revealed bilateral consolidations in the middle and lower fields. Urine antigen testing was negative for <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Legionella pneumophila</span> serogroup-1, and nasopharyngeal swabs for H1N1 virus, sputum smear microscopy and HIV serology were also negative. Community-acquired pneumonia with Fine score III<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> in an immunosuppressed patient was suspected, so antibiotic therapy with ceftriaxone and levofloxacin was started, and the patient was admitted to the respiratory medicine ward. Three days after admission, the patient's fever persisted with no clinical improvement, so the first bronchoscopy was performed, revealing a predominantly mononuclear cell count in the bronchoalveolar lavage (BAL): 58% macrophages, 60% lymphocytes, 3% neutrophils. Only adenovirus was identified by polymerase chain reaction (PCR), so cidofovir was added to the treatment. One week after hospitalization, the patient's failure to improve clinically and radiologically prompted the performance of a chest computed tomography (CT) which confirmed consolidation in both lung bases (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A), so a second bronchoscopy was performed and a transbronchial biopsy was obtained. Tests for anti-nuclear and anti-neutrophil cytoplasmic antibodies, rheumatoid and angiotensin-converting enzymes were all negative. Two days later, the patient presented clinical worsening with progressive consolidation and high oxygen requirements (PaO<span class="elsevierStyleInf">2</span>/FiO<span class="elsevierStyleInf">2</span>: 97<span class="elsevierStyleHsp" style=""></span>mmHg), so he was transferred to the Intensive Care Unit for monitoring and administration of high-flow oxygen therapy. Standard cultures of both bronchial aspirate and BAL grew saprophytic flora, and the sputum smear, galactomannan and study of viruses and parasites were all negative. BAL cytology showed persistent predominance of mononuclear cells. Transbronchial biopsy revealed non-necrotizing granulomas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Mycobacterial infection was suspected, although other etiologies such as sarcoidosis or pneumonitis associated with methotrexate could not be ruled out. Standard anti-tuberculosis treatment and methylprednisolone (1<span class="elsevierStyleHsp" style=""></span>mg/kg/day) were started. PCR testing (Real-Cycler TBM, Molecular Progeny) for <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> detection in BAL and the biopsy specimen was requested, both of which were negative. Having ruled out tuberculosis, a PCR was performed for non-tuberculous mycobacteria (NTM) (INNO-LIPA <span class="elsevierStyleItalic">Mycobacteria</span> v2, Innogenetics) on the first BAL sample, in which <span class="elsevierStyleItalic">Mycobacterium intracellulare</span> (<span class="elsevierStyleItalic">M. intracellulare</span>) and <span class="elsevierStyleItalic">Mycobacterium simiae (M. simiae)</span> were identified. Treatment was switched to rifampicin, ethambutol, azithromycin, and moxifloxacin, and rapid tapering of the corticosteroids began. Clinical and radiological improvement was observed, with oxygen saturation of 94% breathing room air at discharge. No microbiological confirmation was obtained from mycobacterial cultures in any of the respiratory samples tested. The patient continued treatment for 1 year, and remained asymptomatic with practically complete resolution of radiological changes.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The worldwide incidence and prevalence of pulmonary disease caused by NTM is increasing. It affects both immunosuppressed and immunocompetent individuals<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a>; in our case, a patient receiving chronic treatment with methotrexate.</p><p id="par0015" class="elsevierStylePara elsevierViewall">With regard to the mycobacteria identified in our patient, <span class="elsevierStyleItalic">M. simiae</span> is rarely associated with lung disease, suggesting that its isolation is due to environmental contamination.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a> Indeed, pseudo-outbreaks caused by contaminated hot water supplies have been reported.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a> Most cases have been described in the southern United States, Cuba, and Israel.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">3–5</span></a> Affected patients are primarily elderly immuno competent individuals with underlying lung disease, but disseminated infection can also occur in patients with advanced HIV infection (Aids).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> Treatment is complicated by the lack of correlation between <span class="elsevierStyleItalic">in vitro</span> susceptibility and the <span class="elsevierStyleItalic">in vivo</span> response, but must include clarithromycin in combination with other antimicrobials, such as fluoroquinolones and cotrimoxazole.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">3,6</span></a><span class="elsevierStyleItalic">M. intracellulare</span>, on the other hand, is included in the <span class="elsevierStyleItalic">Mycobacterium avium (M. avium)</span> complex. This species, unlike <span class="elsevierStyleItalic">M. avium</span>, is isolated more frequently in patients without HIV infection and presents with two main radiological patterns: fibrocavitary disease and nodular bronchiectasis.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a> Cases have been reported in the United States, Japan, Europe, and South Africa.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> It is resistant to chlorine and survives at high temperatures, so hot tubs or jacuzzis are associated with outbreaks.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a> Treatment must include a macrolide, rifampicin, ethambutol, and, if cavitary or disseminated lesions are observed, an injectable aminoglycoside during the induction phase is required.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Methotrexate has anti-proliferative and immunosuppressive activity, and is one of the therapeutic options for the treatment of pityriasis lichenoides.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> Chronic use can lead to immune changes that predispose to opportunistic infections.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">10–12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">This is the first report in the literature of mycobacterial infection caused by <span class="elsevierStyleItalic">M. simiae</span> and <span class="elsevierStyleItalic">M. intracellulare</span> during chronic treatment with methotrexate. Our patient met the ATS/IDSA criteria<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a> for the diagnosis of pulmonary disease caused by NTM, guided by the finding of granulomatous lesions in the biopsy and identification by molecular techniques. The patient also improved clinically and radiologically with treatment targeted at both microorganisms. However, the pathogenic role of <span class="elsevierStyleItalic">M. simiae</span> may be questionable, since previous studies have suggested that only 20% of isolates in respiratory samples are clinically relevant.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a> We cannot determine the influence that the initial treatment, including levofloxacin, may have had on the failure to grow <span class="elsevierStyleItalic">M. simiae and M. intracellulare</span> in the mycobacterial cultures, and the molecular biology techniques were objectively more sensitive for diagnosis.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In conclusion, NTM infections should be considered in the differential diagnosis of pneumonia in patients receiving immunosuppressive therapy.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Dal Molín-Veglia MA, Sánchez-Martínez F, Fernández-Alarza AF, Domínguez-Álvarez M. Micobacteriosis pulmonar en un paciente en tratamiento crónico con metotrexato. Arch Bronconeumol. 2018;54:225–226.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 563 "Ancho" => 1400 "Tamanyo" => 165494 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Chest CT: pulmonary consolidations in middle lobe, lingula, and both lower lobes. (B) Transbronchial biopsy of the right lung base: evidence of non-necrotizing granulomatous pneumonitis (hematoxylin-eosin staining, 4×).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A prediction rule to identify low-risk patients with community-acquired pneumonia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.J. Fine" 1 => "T.E. Auble" 2 => "D.M. Yealy" 3 => "B.H. Hanusa" 4 => "L.A. Weissfeld" 5 => "D.E. 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Yu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Tuberc Respir Dis" "fecha" => "2013" "volumen" => "75" "paginaInicial" => "28" "paginaFinal" => "31" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0130" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical relevance of <span class="elsevierStyleItalic">Mycobacterium simiae</span> in pulmonary samples" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J. Van Ingen" 1 => "M.J. Boeree" 2 => "P.N. Dekhuijzen" 3 => "D. van Soolingen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.00076107" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "106" "paginaFinal" => "109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18166593" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack342747" "titulo" => "Acknowledgements" "texto" => "<p id="par0035" class="elsevierStylePara elsevierViewall">We thank Dr. Lara Pijuan of the Pathology Department of the Hospital del Mar and Dr. Ana C. Siverio Parés of Microbiology Reference Laboratory of Catalonia.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005400000004/v2_201804150412/S1579212918300351/v2_201804150412/en/main.assets" "Apartado" => array:4 [ "identificador" => "49861" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005400000004/v2_201804150412/S1579212918300351/v2_201804150412/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212918300351?idApp=UINPBA00003Z" ]
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