Legionella Jordanis in Hematopoietic SCT Patients Radiographically Mimicking Invasive Mold Infection

ORIGINAL ARTICLE Legionella jordanis in hematopoietic SCT patients radiographically mimicking invasive mold infection

This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

R Meyer1, U Rappo2, M Glickman2, SK Seo2, K Sepkowitz2, J Eagan3 and TN Small1

1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and 3Infection Control, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Opportunistic pulmonary infections are a major cause of tions, occurring early or late in the post-transplant course, post-transplant morbidity and mortality. Among these range from pulmonary edema, hemorrhage, engraftment infections, Aspergillus is a common cause of fatal syndrome, bronchiolitis obliterans, GVHD to, most pneumonia. Owing to the precarious clinical condition of commonly, infection. Since the advent of chemoprophy- many patients who acquire invasive mold infections, laxis against Pneumocystis carinii and preemptive or clinicians often treat them on the basis of radiographic prophylactic strategies against CMV, currently the most findings, such as the halo sign. However, in patients who common infectious organisms include invasive mold, do not respond to treatment or who have uncommon adenovirus and bacterial pathogens.2–4 Pulmonary infec- presentations, bronchoscopy or lung biopsy looking for tions are often treated empirically, presumptively diag- other pathogens should be considered. This study describes nosed based on clinical signs and symptoms, radiographic two cases in which the radiographic halo signs character- findings and noninvasive microbiological results, including istic of Aspergillus were in fact due to Legionella jordanis, assessment of DNA or RNA viremia, b-D-glucan and a pathogen that has been culture proven only in Aspergillus galactomannan Ag. Although bronchoscopy two patients previously (both of whom had underlying and biopsy would ideally be undertaken, thrombocytopenia lung pathology) and diagnosed by serologic evidence in and unstable hemodynamic and pulmonary status often several other patients. In immunocompromised patients, preclude their safe undertaking in this patient population. Legionella can present as a cavitary lesion. Thus, Nevertheless, aggressive pursuit of infected tissue for presumptive treatment for this organism should be pathology and culture has the potential to clarify the considered in post-transplant patients who do not have a infecting organism and reduce empiric antimicrobial classic presentation for invasive fungal infection and/or therapy. We describe two cases in which classic presenta- who fail to respond to conventional treatment. These cases tions suggested invasive mold. Instead, biopsy results illustrate the importance of obtaining tissue cultures to indicated Legionella jordanis. differentiate among the wide variety of pathogens present in this patient population. Bone Marrow Transplantation (2011) 46, 1099–1103; doi:10.1038/bmt.2011.94 Patients and methods Keywords: opportunistic infections; Legionella; invasive fungal infection The first patient was a 30-year-old West-Indian man with Ph chromosome-positive CML who underwent a 5/6 HLA- mismatched unrelated BMT, T cell depleted with the T10B9 MoAb and complement.5 His cytoreduction consisted of TBI, cytarabine and CY. He received cyclosporine Introduction and corticosteroids for GVHD prophylaxis as described previously.5 The patient developed biopsy-proven skin Pulmonary complications occur in nearly half of all GVHD on day þ 31, which was treated successfully with patients undergoing hematopoietic SCT.1 These complica- topical and systemic steroids and the anti-IL-2 receptor, daclizumab. On transplant day 69, the patient was hospitalized owing to fever, cough and 12-pound weight loss. Chest radiograph Correspondence: Dr R Meyer, Department of Pediatrics, Memorial showed a focal nodular density in the superior segment of Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. the right lower lobe (Figure 1). A chest computed E-mail: [email protected] tomography (CT) scan demonstrated a single 3-cm round Received 19 January 2011; accepted 17 February 2011 mass (Figure 2). The patient was treated with ticarcillin/ Legionella jordanis in HSCT patients R Meyer et al 1100

Figure 3 Follow-up chest CT showing lung nodule with central cavitation (performed on hospital day 10). Figure 1 Chest radiograph with right lower lobe focal nodular density (performed on hospital day 1).

Figure 2 Chest CT that conﬁrmed a 3 Â 3cm2 right lower lobe mass (performed on hospital day 2).

Figure 4 Chest CT on readmission, showing increased numbers of right clavulanate and amikacin, continued on itraconazole, and lower lobe nodules, mostly cavitary. amphotericin B deoxycholate was added owing to concern regarding subtherapeutic serum itraconazole levels. A random measurement of the itraconazole level on hospital amphotericin B. Two weeks following admission, he day 9 was o0.5 mcg/mL, prompting a 33% increase in underwent a right-sided video-assisted thoracoscopic itraconazole dose. Bronchoscopy performed on hospital surgery (VATS) with right lower lobe wedge resection. day 6 (day þ 75) was non-diagnostic. The patient had Pathology showed interstitial pneumonitis. The biopsy was resolution of fever and cough, and a chest CT scan negative for granulomas or viral inclusions, but showed performed 1 week after initiation of broad-spectrum rare bacillary forms on modified Steiner stain. Immunoper- therapy showed the presence of a smaller pulmonary oxidase stains for CMV, EBV, adenovirus and toxoplas- nodule (1.7 cm) with central cavitation (Figure 3). The mosis were negative. Special stains for acid-fast bacteria patient was discharged on hospital day 21 to complete an and fungi were negative. Culture grew L. jordanis. Urine additional week of double antifungal coverage. Legionella Ag was negative. In light of these findings, At 48 h after discharge, the patient was readmitted with antimicrobial therapy was modified to include azithromy- fever, lethargy and cough, and crackles in the right mid- cin. Further history revealed that the patient took frequent axilla and lung base. WBC count on admission was long showers at home and in the hospital. Unfortunately, 3.9 cells/mm3, with absolute neutrophil and lymphocyte the patient subsequently developed CMV viremia and counts of 3.5 and 0.1 cells/mm3, respectively. Lymphoid multiple small central nervous system lesions suggestive of phenotyping showed a circulating CD4 cell count of 4/mL. cerebral toxoplasmosis and/or aspergillus, as well as new His chest CT scan showed an increase in the number and bilateral alveolar infiltrates and pleural effusions. Despite size of right lower lobe pulmonary nodules, many of which broad-spectrum antimicrobial therapy, diuresis and oxygen were cavitary (Figure 4). His serum cryptococcal Ag was support, his respiratory status deteriorated. He died on day negative. The patient was continued on itraconazole; his 149 post hematopoietic stem cell transplant (HSCT). His amphotericin B deoxycholate was changed to liposomal family declined autopsy.

Bone Marrow Transplantation Legionella jordanis in HSCT patients R Meyer et al 1101

Figure 5 Right middle lobe opacity noted on portable chest X-ray.

Figure 6 Chest CT demonstrating cavitary lesion. The second patient is a 17-year-old boy with Fanconi anemia who received an 8/10 HLA-matched unrelated T-cell-depleted transplant for myelodysplastic syndrome with clonal evolution. His cytoreduction consisted of single low-dose TBI, fludarabine and low-dose CY as described previously.6 His graft rejection prophylaxis consisted of pre-transplant rabbit anti-thymocyte globulin and short- course tacrolimus with rapid taper. His cytoreduction was truncated secondary to respiratory and hemodynamic decompensation of unknown etiology. His post-transplant course was complicated by vancomycin-resistant Entero- coccus bacteremia on day þ 8 post HSCT and EBV (peak copy number was 535 000 copies/mL on day þ 62). His EBV viremia was treated successfully with five doses of rituximab. On day 104 post transplant, the patient presented with Figure 7 Gram-negative bacillus (later identified as L. jordanis) isolated from needle aspiration of cavitary lung lesion ( Â 1000, courtesy of Fitzroy acute onset of right-sided pleuritic chest pain following a Edwards). minor car accident. On physical examination, he was afebrile, tachycardic. His lungs were clear, he was not tachypneic and his oxygen saturation was normal on room infiltration and epithelioid histiocytes consistent with air. His chest X-ray demonstrated a right middle-lobe granulomatous inflammation. He was treated with levo- opacification (Figure 5). CT scan showed a subpleural floxacin for 3 weeks, following which CT scan showed parenchymal opacification with a suggestion of peripheral resolution of lesions. The patient is now 20 months ground glass halo, felt to be consistent with a fungal post-transplant, clinically well, with an absolute CD4, infection (Figure 6). He had a normal WBC count, Hb, CD8 and CD19 cell count of 161, 642 and 222 cells/mL, mild thrombocytopenia, normal electrolytes, elevated liver respectively. His PHA response is 85% of the lower limit of enzymes and an elevated sedimentation rate of 41 mm/h. normal. His admission medications included low-dose tacrolimus, micafungin, pentamidine prophylaxis and weekly hyper- immune CMV Ig. He was started on linezolid, cefepime, Discussion liposomal amphotericin B and continued on micafungin. His blood culture grew coagulase-negative staphylococcus, These two cases emphasize the need for definitive diagnosis after which his central line was removed. in patients with nodular infiltrates, particularly cavitary, in Owing to the patient’s lack of fever or cough, and whom other supporting laboratory findings such as immunodeficiency (CD4 count 140 cells/mL, T-cell prolif- Aspergillus galactomannan and/or b-D-glucan assay are erative response o10% of the lower limit of normal and negative, particularly if there is lack of response to anti- absence of circulating B cells), the patient underwent a fungal therapy. In addition, it emphasizes the potential role needle biopsy of his lung lesion. Purulent material was of L. jordanis as a pulmonary pathogen in immunocom- drained from the lesion, which grew L. jordanis on buffered promised patients. In both cases, patients presented with charcoal yeast extract agar (Figure 7). The identity of the lesions on chest CT scan that were suggestive of invasive organism was confirmed at the Centers for Disease Control pulmonary aspergillosis. In a study of 235 patients with by 98% homology in the macrophage infectivity potentia- invasive pulmonary aspergillosis,8 94% had at least tor genes.7 Legionella urinary Ag was negative. Pathology one pulmonary macronodule and 61% had a halo sign of the fluid revealed many histiocytes, granulocytic (a macronodule surrounded by ground glass opacity

Bone Marrow Transplantation Legionella jordanis in HSCT patients R Meyer et al 1102 representing a discrete nodule with infarction and coagu- species that reacted with antisera for both L. jordanis and lative necrosis surrounded by alveolar hemorrhage). L. bozemanii group 2 were isolated from showerheads in Aspergillosis is the most common cause of the halo sign in two rooms where the patient had resided. Molecular typing immunocompromised individuals, although this sign has was not performed on the patient’s isolate and the been described in patients with Pseudomonas aeruginosa showerhead isolates, so it is unclear from where the patient and Zygomycetes species.8,9 Because pulmonary aspergil- acquired this organism. In response to these findings, losis carries a high morbidity and mortality, the halo sign is monthly thermal-chlorine disinfection was instituted, but often used as a surrogate for early infection. Patients who 19% of the showerheads remained positive for Legionella. are treated based on the presence of a halo sign have A copper–silver ionization unit was then installed; monthly better survival (79 vs 53%) and response to treatment (52 follow-up for 1 year revealed no isolation of Legionella. vs 29%) than patients without halo signs.8 However, Our institution’s water system continues to be monitored L. pneumophila can often present as ground glass opacities routinely.18 Of note, there were 43 cases of Legionella next to discrete areas of consolidation on chest CT scan.8,9 reported in NYC in June 2009 and 58 cases in July 2009.19 L. jordanis was first isolated in 1978 from the Jordan All of these cases except ours were L. pneumophila River in Indiana following an outbreak of Legionnaire’s serogroup 1, diagnosed mostly by Legionella urine Ag.20 disease in that region. The same researchers isolated a These cases illustrate the importance of tissue diagnosis second strain 2 years later from a sewage plant in in unusual or refractory infections. A retrospective analysis Georgia.10 Since that time there have been only two case of 174 patients following HSCT showed that fiberoptic reports of culture-proven human infection with L. jordanis, bronchoscopy was diagnostic in 42.1% of patients and none of which have been described in HSCT recipients.11,12 changed the management in 31.6% of patients (including The two culture-proven reports of L. jordanis in the the patient profiled in our first case). Although this study literature were in patients who were not immunocompro- was performed to assess the utility of bronchoscopy in the mised at baseline, although they had evidence of underlying diagnosis of CMV and pneumocystis carinii (PCP) infec- lung disease. One patient was a 79-year-old man with tion, it instead revealed the broader spectrum of infection progressive hyaline membrane disease and focal necrotizing in post-HSCT patients and the need for definitive pneumonitis.11 The second patient was a 53-year-old man diagnosis.1 with chronic cough and a ‘tree-in-bud’ finding on chest In summary, we describe two cases of culture-proven CT.12 Although neither of these patients had cavitary L. jordanis, the first described in HSCT recipients. In lesions, there is evidence that other types of Legionella, patients deemed too unstable to undergo bronchoalveolar including L. pneumophila, are more likely to cause lavage (BAL) and/or lung biopsy, treatment for this cavitation in immunocompromised individuals.13 Addition- organism should be considered. ally, cavitary Legionella infection is more common in patients on steroid therapy; for example, there is a reported case of L. bozemanii cavitary lesion in a pediatric patient Conflict of interest undergoing allogeneic SCT.14 This case expands our knowledge of the role of L. jordanis as a pathogen in The authors declare no conflict of interest. immunocompromised hosts, especially its ability to cause cavitary lesions and its possible growth with the disconti- nuation of trimethoprim-sulfamethoxazole in the setting References of HSCT. Although there are two cases of culture-proven 1 Feinstein MB, Mokhtari M, Ferreiro R, Stover D, Jakubowski L. jordanis in the literature, there are additional cases that A. Fiberoptic bronchoscopy in allogeneic bone marrow are suggestive of L. jordanis based on fourfold increase in transplantation: findings in the era of serum cytomegalovirus titers to at least 1:128. In general, there is a low level of antigen surveillance. Chest 2001; 120: 1094–1100. seroprevalence to Legionella species in healthy popula- 2 Yen KT, Lee AS, Krowka MJ, Burger CD. Pulmonary complications in bone marrow transplantation: a practical tions.15 Other features may also help support a serologic approach to diagnosis and treatment. Clin Chest Med 2004; 25: diagnosis. For example, a 19-year-old woman diagnosed by 189–201. serology in Israel also had L. jordanis cultured from her 3 Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell 16 showerhead. However, a 78-year-old smoker in Thailand transplantation: an overview of infection risks and epidemiol- diagnosed by serology had slightly elevated levels of other ogy. Infect Dis Clin North Am 2010; 24: 257–272. Legionella titers, although titers to L. jordanis were the 4 Mori T, Kato J. Cytomegalovirus infection/disease after most significant. There is also evidence that pseudomonal hematopoietic stem cell transplantation. Int J Hematol 2010; infection can elevate Legionella titers, thereby making 91: 588–595. serologic testing less helpful in diagnosis.17 Additionally, 5 Casper J, Camitta B, Truitt R, Baxter-Lowe LA, Bunin N, serologic testing is often not helpful in patients who have Lawton C et al. Unrelated bone marrow donor transplants for Blood undergone HSCT and have not yet achieved full immune children with leukemia or myelodysplasia. 1995; 85: 2354–2363. reconstitution. 6 Chaudhury S, Auerbach AD, Kernan NA, Small TN, Prockop L. jordanis has only been described in water sources, and SE, Scaradavou A et al. Fludarabine-based cytoreductive there has been concern for nosocomial transmission of this regimen and T-cell-depleted grafts from alternative donors for organism. At the time of presentation, the first patient had the treatment of high-risk patients with Fanconi anaemia. Br J been out of the hospital for 6 weeks. However, Legionella Haematol 2008; 140: 644–655.

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