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The Spectrum of Nocardia Lung Disease in Cystic Fibrosis

Mei-Zahav, Meir MD*†; Livnat, Galit MD; Bentur, Lea MD; Mussaffi, Huda MD*†; Prais, Dario MD*†; Stafler, Patrick MD*†; Bar-On, Ophir MD*†; Steuer, Guy MD*†; Blau, Hannah MB BS*†

The Pediatric Infectious Disease Journal: August 2015 - Volume 34 - Issue 8 - p 909–911
doi: 10.1097/INF.0000000000000759
Brief Reports
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We reviewed all cases of Nocardia infection in cystic fibrosis patients at 2 centers. Eight of 200 patients had Nocardia in sputum. Four developed severe lung disease, including 3 with associated allergic bronchopulmonary aspergillosis; 4 remained clinically stable. Nocardia is often associated with significant lung disease in cystic fibrosis, possibly associated with allergic bronchopulmonary aspergillosis or steroids.

From the *The Kathy and Lee Graub Cystic Fibrosis Center, Pulmonary Institute, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and Pediatric Pulmonology Unit, Meyer Children’s Hospital, Rambam Medical Center, The Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel.

Accepted for publication February 18, 2015.

M.M.Z. and G.L. contribute equally to this study.

The authors have no funding or conflicts of interest to disclose.

Address for correspondence: Hannah Blau, MB BS, The Kathy and Lee Graub Cystic Fibrosis Center, Pulmonary Institute, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel. E-mail: hblau@post.tau.ac.il

Nocardiosis in cystic fibrosis (CF) is possibly associated with increasing length of survival, chronic antibiotic therapy, a changing pulmonary microbiome or improving diagnosis.1

Pulmonary Nocardia infection in CF patients was first described 20 years ago. Its role as a causative agent for either acute or chronic pulmonary disease is debated, and a recent report suggested that no treatment is required.1 In our experience, Nocardia infection in CF can sometimes lead to inexorable pulmonary deterioration and even lung transplantation.

We did a retrospective chart review from 2002 through2013, at 2 CF centers in Israel: the Graub CF Center at Schneider Children’s Medical Center of Israel and the CF Center at Meyer Children’s Hospital, Rambam Medical Center. All patients met the CF Foundation Consensus Panel criteria for CF diagnosis. Sputum was acquired at least twice annually for Ziehl–Neelsen staining and culture on blood agar for 3 weeks. If found positive, cultures were subsequently taken at every clinic visit, that is, every 1–2 months. We considered Nocardia to be eradicated if 3 consecutive sputum cultures were negative.

The study was approved by the hospitals’ ethics committees.

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RESULTS

We reviewed charts of 200 CF patients aged 2 months to 63 years. Eight (4%) had at least 1 positive sputum culture for Nocardia. Findings are summarized in Table 1.

TABLE 1

TABLE 1

Two patterns of Nocardia infection were observed: (1) patients 1–4 experienced a complicated clinical course with respiratory deterioration leading to the decision to treat the infection; patients 1–3 also had pulmonary nodules consistent with Nocardia lung disease on chest computerized tomography (CT); (2) patients 5–8 had a more gradual deterioration in their pulmonary disease. In patients 5 and 8, no other pathogens were identified despite pulmonary symptoms. This led to the decision to treat the Nocardia. In patient 6, there was an associated decrease in lung function, which improved once Nocardia was eradicated. Only patient 7 had no treatment as there appeared to be no associated clinical decline.

When Nocardia was repeatedly cultured, with clinical symptoms but without an aggressive course, trimethoprim–sulfamethoxazole (TMP/SMX) single drug therapy was instituted. In cases with a more fulminant clinical course, particularly when resistance to TMP/SMX was shown on susceptibility studies, multidrug therapy including intravenous (IV) meropenem or oral linezolid was instituted for several months.

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Case Presentations

Patient 1, a 55-year-old female, was diagnosed with CF at 41 years with diffuse bronchiectasis, recurrent major hemoptysis and chronic Pseudomonas aeruginosa infection. Following institution of CF care, forced expiratory volume at 1 second (FEV1) increased from 45% to 75% predicted. One year before CF diagnosis, she developed allergic bronchopulmonary aspergillosis (ABPA) treated with prolonged oral steroids. At 42 years, Nocardia asteroides was cultured from her sputum and persisted for 6 years. She was initially stable on TMP/SMX, inhaled amikacin and amoxycilin–clavulanate therapy but at 43 years pulmonary symptoms worsened, with fever, 10 kg weight loss, a white cell count of 28,000/mL and a drop in FEV1 from 75% to 41% predicted. Chest CT showed a new 2.5 cm nodule, and bronchoalveolar lavage revealed a bacterial index of >100 bacilli/high power field on Ziehl–Neelsen staining and heavy growth of Nocardia. There was no evidence of ABPA. IV ceftazidime for 3 months resulted in clinical improvement and resolution of the nodule but symptoms recurred on cessation of therapy, with a concomitant increased growth of Nocardia. Linezolid therapy led to stabilization but was stopped because of peripheral neuropathy. IV ceftazidime and oral TMP/SMX led to gradual improvement. FEV1 rose to 70% predicted, and Nocardia was eradicated at 48 years.

Patient 2 is a 29-year-old female who had chronic P. aeruginosa infection and FEV1 of 55% predicted preceding Nocardia infection at 24 years. Over the following 4 years, there was inexorable clinical decline leading to eventual lung transplantation. Initially, TMP/SMX therapy was effective but was discontinued because of severe allergy. Frequent courses of IV meropenem and amikacin as well as oral linezolid for 3 months resulted in only transient improvement. She had recurrent febrile episodes and developed respiratory failure requiring BIPAP ventilation. Pulmonary nodules were present on chest imaging and large areas of consolidation appeared on chest radiograph and CT scan (Fig. 1A and B). There was heavy growth of multiresistant Nocardia cyriacigeorgica, susceptible only to TMP/SMX, linezolid and tigecycline. Tigecycline caused severe nausea without clinical improvement. FEV1 dropped to 25% predicted. At 28 years, she underwent bilateral lung transplantation.

FIGURE 1

FIGURE 1

Patient 3, a 29-year-old male, diagnosed with CF in infancy had an FEV1 85% predicted and intermittent P. aeruginosa infection. Nocardia was identified at 21 years and was treated with TMP/SMX. Chest CT revealed scattered bronchiectasis with no pulmonary nodules. Two years later, he had increased symptoms, FEV1 decreased to 53% predicted, and Nocardia infection persisted. Following only transient improvement with TMP/SMX, ciprofloxacin and inhaled tobramycin therapy, he required IV meropenem for 4 months when cultures became negative for Nocardia. He then developed ABPA, but IV pulse steroids and voriconazole with meropenem brought minimal improvement. Nocardia recurred and nodules on chest CT were consistent with Nocardia lung disease. Steroids were replaced with omalizumab. Linezolid therapy for 15 months led to clinical improvement but was discontinued because of peripheral neuropathy. Subsequent long-term TMP/SMX and ciprofloxacin did not eradicate Nocardia.

Patient 4, a 12-year-old boy, developed chronic ABPA treated with pulse steroids and voriconazole at 6 years. At 9 years, pulmonary exacerbation with a drop in FEV1 from 52% to 34% predicted did not respond to therapy for ABPA or antibiotics. Bronchoalveolar lavage was positive for Nocardia and Stenotrophomonas maltophilia. Chest CT demonstrated diffuse bronchiectasis and patchy infiltrates. TMP/SMX therapy resulted in severe neutropenia. Following IV meropenem for 3 months, he gained 2.5 kg, FEV1 increased to 51% predicted and Nocardia was eradicated.

Patient 5, a 15-year-old girl, developed CF-related diabetes at 10 years with subsequent decline in FEV1 from 59% to 46% predicted. Nocardia was cultured with no other pathogen found. A 7-month course of TMP/SMX resulted in gradual decrease in pulmonary symptoms, rise in FEV1 to 60% predicted and eradication of Nocardia.

Patients 6 and 7 are brothers. Patient 6 is 17 years old, with chronic P. aeruginosa and aspergillus airway infection and on chest CT, widespread bronchiectasis without nodular infiltrates. Since 10 years, sputum cultures have been intermittently positive for Nocardia but became persistently positive with an associated decrease in FEV1 from 85% to 70% predicted at 16 years. Following prolonged oral TMP/SMX and IV meropenem, Nocardia was eradicated, and FEV1 increased from 70% to 90% predicted. Patient 7, aged 19 years, had chronic P. aeruginosa since infancy. Sputum cultures were intermittently positive for Nocardia over the past 18 months with no associated symptoms or change in lung function. He received no specific therapy.

Patient 8 is a 13-year-old boy who at the age of 10 years had a sputum culture positive for Nocardia with a decrease in FEV1 from 101% to 88% of predicted. Chest CT demonstrated ground glass opacities with no nodules. He was treated with TMP/SMX for 4 months, with only 1 additional positive culture for Nocardia.

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DISCUSSION

This case series presents a broad spectrum of Nocardia lung disease in CF. The potential for severe progressive lung disease, either from the onset of infection or after years of colonization, has not been highlighted previously.

TMP/SMZ is the treatment of choice for Nocardia, although resistance is increasing.1 Carbapenems, linezolid and tigecycline are still usually active against pathogenic Nocardia species, and multiple drug therapy is recommended in the immune-compromised host including posttransplantation or with disseminated disease for at least 12 months.2,3

There is a dilemma regarding the necessity for therapy when Nocardia is isolated in CF sputum. Although some suggest that no treatment is required,1,4 infection was treated in our series when associated with clinical deterioration. We used TMP/SMZ as first-line therapy but prolonged multidrug therapy according to susceptibility testing and clinical response for severe CF related Nocardia lung disease. A similar debate regarding the significance of nontuberculous mycobacteria (NTM) in CF arose previously. The potential of Mycobacterium abscessus for virulence and persistence is now well described.5

Immune dysregulation may play a part in prolonged Nocardia infection in CF. In a murine model, Nocardia infection was found to modulate T-lymphocyte responses, and when production of interferon-γ decreased, bacterial load increased and chronicity of infection was favored.6 It appears that interferon-γ production is a major mechanism for suppressing Nocardia pathogenicity. This may be attenuated in CF, and the shift from this TH1 response to a predominantly TH2 response as found in ABPA might play a role in the transition from colonization to aggressive Nocardia infection. We previously described an association between ABPA and NTM infection in CF,7,8 possibly associated with the downregulation of TH1 cells and related cytokines crucial for NTM eradication. Nocardia infection has been described with prior ABPA in non-CF patients,9 but we are the first to describe this association in CF. Prolonged steroid therapy, known to be a risk factor for Nocardia,10 may well have been the predisposing factor for pulmonary nocardiosis in our patients with CF and ABPA.

This study is limited by its retrospective nature and small patient cohort. It is difficult or even impossible to separate the effect of Nocardia from that of other pathogens over time periods of 3–7 years, as was the case in our patients with CF. Nevertheless, typical nodules on chest CT, improvement with anti-Nocardia treatment in the face of failed therapy aimed at other organisms or lack of other organisms in sputum, support its pathogenicity in many of the cases described here.

We suggest that CF patients with Nocardia infection, particularly those with ABPA or steroid therapy, be observed closely. Aggressive multidrug therapy should be instituted early when there is clinical progression and no response to TMP/SMX. Microbiologic surveillance, both routine and during unexplained deterioration, may be important. Prospective multicenter studies are recommended.

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REFERENCES

1. Thorn ST, Brown MA, Yanes JJ, et al. Pulmonary nocardiosis in cystic fibrosis. J Cyst Fibros. 2009;8:316–320
2. Corti M.. Nocardiosis: a review. Int J Infect Dis. 2003;7:243–250
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5. Leung JM, Olivier KN.. Nontuberculous mycobacteria: the changing epidemiology and treatment challenges in cystic fibrosis. Curr Opin Pulm Med. 2013;19:662–669
6. Rosas-Taraco AG, Perez-Liñan AR, Bocanegra-Ibarias P, et al. Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice. Infect Immun. 2012;80:2493–2499
7. Bar-On O, Mussaffi H, Mei-Zahav M, et al. Increasing nontuberculous mycobacteria infection in cystic fibrosis. J Cyst Fibros. 2015;14:53–62
8. Mussaffi H, Rivlin J, Shalit I, et al. Nontuberculous mycobacteria in cystic fibrosis associated with allergic bronchopulmonary aspergillosis and steroid therapy. Eur Respir J. 2005;25:324–328
9. Sharma B, Ghosh G, Kamble U, et al. Allergic bronchopulmonary aspergillosis complicated by nocardiosis. Case Rep Pulmonol. 2012;2012:1–5
10. Peleg AY, Husain S, Qureshi ZA, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis. 2007;44:1307–1314
Keywords:

nocardiosis; cystic fibrosis; aspergillus; lung transplant; steroids

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