Case reports Non-tuberculous mycobacterial lung infection

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					Thorax 2000;55:717–719                                                                                                             717



Case reports


                           Non-tuberculous mycobacterial lung infection
                           complicated by chronic necrotising pulmonary
                           aspergillosis
                           I Hafeez, M F Muers, S A Murphy, E G V Evans, R C Barton, P McWhinney



                           Abstract                                                   1997. Antimycobacterial drugs, itraconazole,
                           We report four cases of pulmonary myco-                    and prednisolone have been stopped.
                           bacterial disease (three due to Mycobac-
                           terium malmoense and one to Myco-
                                                                                      Case 2
                           bacterium avium intracellulare) compli-
                                                                                      In July 1997 a 76 year old man with a history of
                           cated by the development of chronic
                                                                                      moderate COPD and previously stable pulmo-
                           necrotising pulmonary aspergillosis. Dif-
                                                                                      nary function (FEV1/FVC 1.3/3.4) presented
                           ficulties with treatment and the potential
                                                                                      with worsening dyspnoea, a cough with puru-
                           benefits of steroids are discussed.
                           (Thorax 2000;55:717–719)                                   lent sputum, and weight loss (6 kg in less than
                                                                                      a year). His chest radiograph showed bilateral
                           Keywords: aspergillosis; chronic necrotising aspergillo-   upper lobe consolidation with cavitation and
                           sis; non-tuberculous mycobacteria; mycosis; cortico-       fibrosis. Sputum was smear positive for AAFB
                           steroids                                                   and, on culture, M malmoense (resistant to
                                                                                      rifampicin in vitro) was isolated. Quadruple
                           Case 1                                                     chemotherapy with rifabutin, ethambutol,
                           In October 1996 a 49 year old woman with                   clarithromycin, and ciprofloxacin was started.
                           chronic obstructive pulmonary disease                      However, three months later he was more dys-
St James’s University      (COPD) and a history of pulmonary tubercu-                 pnoeic, was producing copious quantities of
Hospital, Leeds LS9        losis, successfully treated with standard chemo-           purulent sputum, had lost more weight, and
7TF, UK                    therapy six years earlier, presented with cough            was persistently pyrexial. Radiologically there
I Hafeez
                           and dyspnoea. On examination she was unwell                had been marked deterioration. A fumigatus
Leeds General              and chest radiography showed left upper lobe               was cultured from the sputum and precipitins
Infirmary, Leeds            consolidation and cavitation. Her sputum was               were positive (1:16). A computed tomographic
LS1 3EX, UK                smear positive for acid and alcohol fast bacilli           (CT) scan of his chest showed extensive
M F Muers                  (AAFB) and treatment was started with                      consolidation, cavitation, and scarring in both
                           rifampicin, isoniazid, and pyrazinamide. Myco-             upper lobes. There was no eosinophilia and his
South Cleveland
Hospital,                  bacterium avium intracellulare was isolated from           serum IgE level was normal.
Middlesbrough,             a sputum culture eight weeks later and                        He was treated with intravenous amphoter-
Cleveland TS4 3BW,         treatment was changed to rifampicin, etham-                icin and oral itraconazole capsules (200 mg
UK                         butol (15 mg/kg), and clarithromycin.                      three times a day) but after three weeks of anti-
S A Murphy                    After initial improvement she deteriorated              fungal treatment he remained unwell. Pred-
                           both clinically and radiologically. Four months            nisolone (60 mg) was added with rapid im-
PHLS Mycology
Reference Laboratory,      after commencing treatment she had lost 8 kg               provement; he became afebrile and the sputum
General Infirmary,          in weight and the chest radiograph showed                  volume and purulence were reduced. Unfortu-
Leeds LS1 3EX, UK          increased consolidation and cavitation. As-                nately, he developed uveitis due to rifabutin,
E G V Evans                pergillus fumigatus was cultured from bronchial            and rifampicin was substituted. He remained
R C Barton                 washings and Aspergillus precipitins were posi-            stable for six months on maintenance treat-
                           tive (1:64). There was no obvious immunologi-              ment with rifampicin, ethambutol, clarithro-
Bradford Royal
Infirmary, Bradford         cal abnormality (immunoglobulins and CD4                   mycin, ciprofloxacin, itraconazole, and pred-
BD9 6RJ, UK                were normal) and the serum IgE level and                   nisolone. However, in April 1998 there was
P McWhinney                eosinophils were within normal limits.                     further clinical and radiological deterioration.
                              Itraconazole was started in a dose of 200 mg            His sputum was culture negative for Mycobac-
Correspondence to:         three times daily (suspension initially, capsules          teria but had a heavy growth of Aspergillus. No
Dr I Hafeez
email:                     later) but she continued to deteriorate, losing            other pathogens were isolated. He was treated
ihafeez@cableinet.co.uk    another 6 kg with further radiological deterio-            with intravenous amphotericin (Ambisome,
Received 20 May 1999
                           ration. Prednisolone (initially 60 mg/day and              Nexstar, Cambridge, UK) for three weeks with
Returned to authors        gradually reducing) was started which resulted             slight clinical improvement.
1 July 1999                in rapid clinical improvement. Two years                      In July 1998 his sputum remains positive for
Revised version received   following presentation she remains well. Her               Aspergillus although his radiographs are stable.
10 November 1999
Accepted for publication   sputum has remained culture negative for                   He remains on antimycobacterial drugs, itraco-
6 December 1999            Mycobacteria and Aspergillus spp since August              nazole, and prednisolone. However, we have


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718                                                                                  Hafeez, Muers, Murphy, et al


      had diYculty achieving therapeutic levels of         and radiological improvement. Itraconazole
      itraconazole in spite of high doses (300 mg          was discontinued in June 1998. She did not
      three times a day).                                  require any other treatment and remains well.

      Case 3
      A 66 year old man with long standing COPD            Discussion
      was referred in April 1992 with persistent right     The incidence of non-tuberculous mycobacte-
      upper zone shadowing on the chest radiograph.        rial pulmonary disease has increased in the last
      Bronchoscopic washings were positive for             few years.1 The organisms most frequently
      AAFB and culture grew M malmoense. He was            isolated in the UK are M xenopi, M avium
      started on treatment with isoniazid, rifampicin,     intracellulare (MAI), and M malmoense.2 3
      and ethambutol which were continued for a            Typically, as in the cases described, patients
      total of 14 months. His sputum had been              have pre-existing chronic lung disease and
      culture negative for AAFB during the last six        present with increased respiratory symptoms
      months of treatment, the chest radiograph            and deteriorating lung function and radiologi-
      improved, and treatment was stopped in               cal appearance.
      September 1993. In July 1994 his chest radio-           Current guidelines for treatment of MAI
      graph showed patchy consolidation in the right       pulmonary disease recommend a three (or
      mid zone and M malmoense was again isolated          more) drug regimen including ethambutol (E),
      from the sputum. Isoniazid, rifampicin, and          rifampicin (R), and clarithromycin (Cl) (or
      ethambutol were recommenced in October               azithromycin), continued for 12 months after
      1994. In February 1995 isoniazid was stopped         the sputum is culture negative.4 For M mal-
      and ciprofloxacin and clarithromycin were             moense isoniazid (H), E, and R are recom-
      added. By March 1996 his sputum was still            mended with the optional addition of
      culture positive for M malmoense and chest           streptomycin (SM) for the initial 3–6 months.4 5
      radiographs were worse. In September 1996 he         However, regimens including Cl and/or cipro-
      had a right upper lobectomy and antimycobac-         floxacin (Ci) are currently being evaluated by
      terial treatment was stopped. In February 1997       the British Thoracic Society.
      further right mid zone consolidation was                Because treatment is protracted and often
      observed on the chest radiograph. Rifampicin,        complicated by drug intolerance, response to
      ethambutol, ciprofloxacin, and clarithromycin         treatment may be diYcult to evaluate. How-
      were re-started but he continued to deteriorate      ever, as in our patients, a failure to respond to
      both clinically and radiologically. His sputum       antimycobacterial treatment or a relapse dur-
      grew both M malmoense and A fumigatus. The           ing treatment may be caused by concomitant
      serum IgE level was normal, there were no            infection with Aspergillus. In all four cases clini-
      eosinophils in the sputum, and no excess in the      cal and radiological deterioration was associ-
      blood. Serum precipitins for Aspergillus were        ated with isolation of A fumigatus from the spu-
      positive (titre 1:64). Despite a high dose of oral   tum and positive Aspergillus precipitins. It may
      itraconazole (200 mg three times daily) there        be appropriate to evaluate fully patients with
      was little clinical improvement. However, after      damaged lungs and non-tuberculous mycobac-
      adding prednisolone he improved rapidly. In          terial infection for coexisting Aspergillus infec-
      May 1998 he was clinically stable on four            tion at the start of the treatment. In the cases
      antimycobacterial drugs, itraconazole, and           reported here the stage at which Aspergillus
      corticosteroids. His sputum has remained cul-        infection was diagnosed was diVerent for each
      ture negative for AAFB and Aspergillus since         patient. Patient 1 deteriorated after four
      October 1997.                                        months of antimycobacterial treatment; patient
                                                           2 deteriorated steadily despite apparently com-
      Case 4                                               plying with all his treatment; patient 3 relapsed
      In July 1995 a 64 year old woman with severe         following 14 months of E, R, H (six months
      COPD (FEV1 0.4 l) presented with increasing          sputum negative)—despite reintroduction of
      dyspnoea and weight loss. The chest radio-           chemotherapy he remained persistently spu-
      graph showed left apical consolidation and           tum positive with M malmoense over a three
      cavitation. Sputum was smear positive for            year period; and in patient 4 clinical deteriora-
      AAFB so she was commenced on Rifater                 tion occurred within one month of completion
      (Hoechst Marion Roussel, Uxbridge, UK).              of antimycobacterial treatment. In patients 2
      However, M malmoense was isolated and treat-         and 3 the microbiological response to antimy-
      ment was changed to ethambutol, rifabutin,           cobacterial treatment occurred only when the
      isoniazid, and clarithromycin which resulted in      concurrent Aspergillus infection was also
      clinical and radiological improvement within         treated.
      three months.                                           Other recent case reports have identified
         Antimycobacterial treatment was stopped in        concomitant infection with Aspergillus spp as a
      October 1997 after two years. However, within        possible reason for failure to respond to
      one month of stopping she had become unwell          antimycobacterial chemotherapy. Bollert et al
      with persistent fever and new right upper lobe       reported co-infection by M malmoense and
      consolidation on the chest radiograph. Her           Aspergillus in three patients, all of whom died
      sputum remained culture negative for AAFB            despite antimycobacterial and antifungal treat-
      but A fumigatus was isolated and serum precip-       ment. Two of the three patients had evidence of
      itins were strongly positive (>1:64). Itracona-      an aspergilloma at post-mortem examination.6
      zole was commenced in a dose of 200 mg three         Similarly, Debieuvre et al reported a fatal case
      times daily, following which there was clinical      of M malmoense complicated by co-infection


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Non-tuberculous mycobacterial lung infections and aspergillosis                                                                                    719


                               with A fumigatus.7 Two other case reports have         failing to respond to itraconazole after attempts
                               described complex mycetomas complicating M             have been made to optimise bioavailability.12
                               kansasii and M xenopi infections.8 9                   Surgery may be an option in patients with focal
                                  The radiological appearances of our patients        disease and good lung function, but it may be
                               were in keeping with chronic necrotising               associated with significant mortality,22 in con-
                               pulmonary aspergillosis (CNPA) or semi-                trast to patients with haematological
                               invasive aspergillosis. CNPA is characteristi-         malignancy.23 Intralesional amphotericin may
                               cally an indolent cavitating process in the lungs      be used when cavities are present.24
                               caused by invasion by Aspergillus spp.10–12 As            Although the role of corticosteroids in treat-
                               seen in our patients, constitutional disturbance       ing CNPA requires clarification, they seemed
                               with fever and weight loss is accompanied by           to result in considerable benefit for three of the
                               radiological signs of upper lobe infiltration,          patients in this series. Furthermore, in contrast
                               cavitation, and lung destruction. It is striking       to the poor outcome described in previous
                               that three of our patients only began to improve       reports of aspergillosis complicating atypical
                               after addition of corticosteroids, although there      mycobacterial lung disease, all of our patients
                               was no evidence of allergic bronchopulmonary           are alive at the time of writing.
                               aspergillosis (ABPA). We postulate that the
                               better response compared with the (scant)               1 Falkinham J. Epidemiology of infection by non-tuberculous
                               literature was because of this. In the light of this       mycobacteria. Clin Microbiol Rev 1996;9:177–215.
                               we suggest that a local hypersensitivity reaction       2 Jenkins PA. The epidemiology of opportunistic mycobacte-
                                                                                          rial infection in Wales, 1952–1978. Rev Infect Dis
                               (type III) contributes to tissue destruction.              1981;3:1021–3.
                               Histological studies provide some support for           3 Yates MD, Grange JM, Collins CH. The nature of
                                                                                          mycobacterial disease in southeast England, 1977–84. J
                               this.13 Constitutional symptoms of fever and               Epidemiol Community Health 1986;40:295–300.
                               sputum production in patients with ABPA and             4 American Thoracic Society. Diagnosis and treatment of dis-
                                                                                          ease caused by non-tuberculous mycobacteria. Am J Respir
                               aspergilloma have been attributed to a type III            Crit Care Med 1997;156 : S1–25.
                               hypersensitivity reaction in the lung surround-         5 France AJ, Mcleod DT, Calder MA, et al. Mycobacterium
                                                                                          malmoense infections in Scotland: an increasing problem.
                               ing     the     fungus,    which     is    present         Thorax 1987;42:592–5.
                               intrabronchially.14 15                                  6 Bollert FGE, Sime PJ, MacNee W, et al. Pulmonary
                                                                                          Mycobacterium malmoense and Aspergillus infection: a fatal
                                  The optimal treatment for CNPA is unclear.              combination. Thorax 1994;49:521–2.
                               Itraconazole (with starting doses of 200 mg             7 Debieuvre D, Dubiez JC, Dalphin JC, et al. Infection
                                                                                          pulmonaire à Mycobacterium malmoense compliquée d’un
                               twice daily) has been used with clinical                   aspergillome. Med Mal Infect 1993;23:374–6.
                               benefit.12 16–18 The bioavailability of itracona-        8 Johnston IDA. Mycobacterium xenopi infection and aspergil-
                                                                                          loma. Tubercle 1988;69:139–44.
                               zole solution is much better than that of               9 Maliwan N, Zvetina JR. Pulmonary mycetoma following
                               capsules, which is important for patients with             Mycobacterium kansasii infection. Arch Intern Med 1985;
                                                                                          145:2180–3.
                               damaged gut or those receiving enzyme induc-           10 Binder RE, Faling JF, Pugatch RD, et al. Chronic necrotiz-
                               ers. The pharmacological interaction between               ing pulmonary aspergillosis: a discrete clinical entity. Medi-
                                                                                          cine 1982;61:109–24.
                               rifampicin/rifabutin and itraconazole is com-          11 Gefter WB, Weinrad TR, Epstein DM, et al. Semi-invasive
                               plex. Itraconazole inhibits liver enzymes result-          pulmonary aspergillosis. Radiology 1981;140:313–21.
                                                                                      12 Saraceno JL, Phelps DT, Futerfas R, et al. Chronic necrotiz-
                               ing in increased levels of rifabutin which are             ing pulmonary aspergillosis: approach to management.
                               associated with uveitis (as in case 2).19 Ri-              Chest 1997;112: 541–8.
                                                                                      13 Yousem SA. The histological spectrum of chronic necrotiz-
                               fampicin, a liver enzyme inducer, has been                 ing forms of pulmonary aspergillosis. Human Pathol 1997;
                               shown to lower itraconazole levels. The eVect              28:650–6.
                                                                                      14 Scadding JG. The bronchi in allergic aspergillosis. Scand J
                               of rifabutin, which has diVerent enzyme induc-             Respir Dis 1967;48: 372–7.
                               ing properties,20 on itraconazole levels is less       15 Hilvering C, Stevens EAM, Orie NGM. Fever in aspergillus
                                                                                          mycetoma. Thorax 1970;25:19–24.
                               clear but the available evidence suggests that         16 Viviani MA, Tortorano AM, Pagano A, et al. European
                               they will be reduced.21 Adequate levels were               experience with itraconazole in systemic mycoses. J Am
                                                                                          Acad Dermatol 1990;23:587–93 .
                               achieved with capsules in our patients apart           17 Caras WE, Pluss JL. Chronic necrotizing pulmonary
                               from patient 2 who is being changed to the                 aspergillosis: pathologic outcome after itraconazole
                                                                                          therapy. Mayo Clin Proc 1996;71:25–30.
                               suspension.                                            18 Caras WE. Chronic necrotizing pulmonary aspergillosis:
                                  Our patients have received treatment with               approach to management. Chest 1998;113:852–3.
                                                                                      19 Lefort A, Launay O, Carbon C. Uveitis associated with
                               itraconazole for periods ranging from seven                rifabutin prophylaxis and itraconazole therapy. Ann Intern
                               months (patient 4) to 20 months (patient 1)                Med 1996;125:939–40.
                                                                                      20 Strolin Benedetti M. Inducing properties of rifabutin, and
                               and treatment is still ongoing in patients 2 and           eVects on the pharmacokinetics and metabolism of
                               3 (both >12 months). Despite this, patient 2               concomitant drugs. Pharmacol Res 1995;32:177–87.
                                                                                      21 Smith JA, Hardin TC, Patterson TF, et al. Rifabutin
                               has remained sputum positive for Aspergillus.              decreases itraconazole plasma levels in patients with HIV
                               He also had partial responses to intravenous               infection. 2nd National Conference on Human Retroviruses and
                                                                                          Related Infections, Washington, 29 January–2 February 1995,
                               amphotericin B during two periods of exacer-               abstract 126.
                               bation of symptoms. The variable response to           22 Daly RC, Pairolero JM, Trasket VF, et al. Pulmonary
                                                                                          aspergilloma. Results of surgical treatment. J Thorac
                               treatment may be partly a result of the degree             Cardiovasc Surg 1986;92:981–8.
                               of lung destruction and extent of disease at the       23 McWhinney PH, Kibbler CC, Hamon MD, et al. Progress
                                                                                          in the diagnosis and management of aspergillosis in the
                               time of presentation. Patient 2 had the most               bone marrow transplantation: 13 years experience. Clin
                               extensive radiological changes at the start of             Infect Dis 1993;17:397–404.
                                                                                      24 Giron J, Poey C, Fadjet P, et al. CT-guided percutaneous
                               treatment. Intravenous amphotericin B has a                treatment of inoperable pulmonary aspergillomas: a study
                               place in the management of patients who are                of 40 cases. Eur J Radiol 1998;28:235–42.




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