Thorax 2000;55:717–719 717
Non-tuberculous mycobacterial lung infection
complicated by chronic necrotising pulmonary
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-
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
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
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-
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-
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
firstname.lastname@example.org 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
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.
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
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;
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-
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.