Postgrad Med J (1992) 68, 160- 173 ) The Fellowship of Postgraduate Medicine, 1992

Reviews in Medicine

Respiratory diseases
D. Geraint James
Visiting Professor of Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK

Introduction
Most of the references at the end of this review Thoracoscopy
should be year-marked 1991 or 1992, with a few
earlier ones if they are relevant to the discussion. Thoracoscopy was widely used in the 1940s in the
Asthma is excluded because its worldwide impor- era of artificial pneumothorax collapse therapy for
tance merits a review of its own, and who better to tuberculosis. It enabled adhesions to be severed
do so than Professor Peter Barnes (see August 1992 and improve collapse of the tuberculous lung.
issue of Postgrad Med J). Antituberculous chemotherapy made collapse ther-
This review embraces techniques, Wegener's apy obsolete, but, unfortunately, this also led to
granulomatosis, occupational lung disease, infec- the disuse of thoracoscopy. A recent plan from
tions, various pulmonary syndromes, neoplasia, Montreal2 should help to revive its use in the
granulomatous disorders and therapeutics. This evaluation of patients with pleural disease, which
year, therapeutics highlights the newest immuno- remains undiagnosed after the usual initial inves-
modulators which are in use or about to become tigations. Thoracoscopy done under local anaes-
available. They provide an exciting glimpse of what thesia is a rapid, safe and well-tolerated procedure
lies ahead. with an excellent diagnostic yield. Biopsy speci-
mens of parietal pleura, obtained under direct
vision, were studied by routine histology, myco-
Techniques bacterial culture, immunochemistry and electron
Bronchoalveolar lavage
Table I A preponderance of certain cells in bron-
Bronchoalveolar lavage (BAL) has provided a choalveolar fluid may be a helpful diagnostic pointer
helpful new window to the lungs. Changes in the
cellular and humoral constituents of BAL fluid Cell Disorder
(BALF) have broadened our understanding of
respiratory and multisystem disorders (Table I). It T4 helper Sarcoidosis
may be helpful in the differential diagnosis of Beryllium disease
sarcoidosis and fibrosing alveolitis for CD4 helper T8 suppressor Extrinsic allergic alveolitis
cells are prominent in BALF of active sarcoidosis (Hypersensitivity pneumonitis)
whereas neutrophils are prominent in that of Talc
Neutrophil Smoker
fibrosing alveolitis (Table II). Fibrosing alveolitis
The BAL window permits new glimpses or even AIDS
wider perspectives of asbestosis, cobalt lung, Mineral dust
AIDS, pulmonary alveolar proteinosis (milky Collagen disease
BALF), eosinophilic pneumonia, transplants Eosinophil Drugs
(lung, liver and bone marrow), Crohn's disease, Eosinophilic pneumonia
collagen vascular disease and Langerhan's his- Bronchial asthma
tiocytosis.l Mast cell Sarcoidosis
Asthma
Multinucleate giant Cobalt
Plasma Multiple myelomatosis
Reed - Sternberg Hodgkin's
Anaplastic Lymphangitic carcinoma
OKT6 staining Langerhans' histiocytosis
Correspondence: D.G. James, M.A., M.D., F.R.C.P.
RESPIRATORY DISEASES 161

Table II Bronchoalveolar lavage is helpful in the ious technique is fluorescent focus assay, which
differential diagnosis of sarcoidosis and fibrosing entails centrifugation of the respiratory specimen
alveolitis on a monolayer of tissue culture cells, incubation
Feature Sarcoidosis Fibrosing alveolitis
overnight, and then staining the cells with
immunofluorescent antisera. This Australian
Dyspnoea Mild Severe review4 provides an exciting perspective of what we
Clubbing No Yes may learn to expect during the remainder of this
Added sounds Insignificant Numerous end- decade. Read it now before it will be overtaken by
inspiratory continuing rapid advances 'in the field' and away
Chest X-ray Generalized Lower zone from the reference laboratory.
Hilar adenopathy Present Absent A joint Anglo-Chinese study has facilitated the
Honeycombing Infrequent Common diagnosis of nasopharyngeal carcinoma by means
CAT scan of recombinant Epstein-Barr virus (EBV) pro-
Distribution Central Peripheral teins.' Nasopharyngeal carcinoma, a tumour of
Changes Linear Cystic
SACE Increased Normal epithelial origin, is common in the Chinese with an
BAL T4 cells Neutrophils incidence of 1 5 - 30 per 100,000 per year. In Chinese
increased populations it is the commonest tumour among
Gallium scan Positive + men and the second most common among women.
Response to steroids Good Fair The immune response of patients with naso-
pharyngeal carcinoma to EBV antigens is diagnos-
CT = computed tomography; SACE = serum angioten- tic of the tumour. The EBV thymidine kinase was
sin converting enzyme; BAL = bronchoalveolar lavage. found to be the most sensitive predictor of
nasopharyngeal carcinoma when used in a recom-
binant expression system. All serum samples
analysed showed IgG and IgA antibodies to
microscopy. This technique led to the diagnosis of thymidine kinase whereas samples from infectious
mesothelioma and various metastatic carcinomas, mononucleosis are negative. This technique is
asbestosis, tuberculosis, rheumatoid arthritis, sys- suitable for use in large-scale screening program-
temic lupus, chylothorax and haemothorax. mes for the early diagnosis of nasopharyngeal
This is the decade of endoscopic cholecystec- carcinoma.
tomy and keyhole surgery. Could this old and The use of a rapid method of diagnosing toxo-
well-established technique give rise to endoscopic plasmosis by the polymerase chain reaction is a
resection of parts of the lung? It is certainly being pointer to the future for all microbiology speci-
used for carbon dioxide laser treatment of bullous mens, and this DNA probe is now established as a
emphysema in California.3 Patients had advanced specific and highly sensitive means of detecting
emphysema with severe pulmonary dysfunction toxoplasmosis in a variety of specimens including
and were too high a risk for conventional surgical serum, cerebrospinal fluid (CSF), bronchoalveolar
bullectomy. In this study, there was significant fluid and biopsy material.6
objective improvement, which has persisted. Long- Likewise with Pneumocystis carinii pneumonia,
term follow-up will determine its precise value in which can be diagnosed rapidly by DNA
this severely handicapped group of patients. amplification of sputum and bronchoalveolar fluid.
It is a highly sensitive and invaluable new techni-
Rapid diagnosis que.7
Even more important is the early diagnosis of
The demand for rapid viral diagnosis has increased tuberculosis by DNA amplification. It is more
in recent years particularly since antiviral chemo- sensitive than bacteriological culture, and it is
therapy has made important advances. The detec- particularly recommended for the early diagnosis
tion of pathogen-specific DNA after amplification of tuberculous meningitis, tuberculous pleurisy
with the polymerase chain reaction will revolu- and tuberculosis in human immunodeficiency virus
tionize the whole science of microbiology. This will (HIV)-positive patients.8
be a boon in the detection of respiratory viruses,
which, thus far, have been difficult to identify by A new bronchoscopic sign
rapid methods. Respiratory syncytial virus causes
winter childhood bronchiolitis, and detection of Pulmonary veno-occlusive disease (pulmonary vas-
antigen by either immunofluorescence or enzyme cular occlusive disease) is a rare disorder of un-
immunoassay is reliable.4 Polyclonal antisera known aetiology affecting children and young
(Wellcome) against influenza viruses, parainflu- adults, who present with dyspnoea, signs of pul-
enza and adenovirus group antigens are suitable monary hypertension, cyanosis, fine crepitations,
for immunofluorescence testing. Another ingen- and the chest X-ray must show bilateral patchy
162 D.G. JAMES

consolidation. In a recent case report, fibreoptic tinal and supra-aortic tumours. Accidental punc-
bronchoscopy showed a most unusual and pre- ture of the mediastinal vessels, which is not uncom-
viously unrecognized appearance.9 The trachea mon under fluoroscopic guidance, can be largely
and main bronchi were normal but the lobar and avoided with exact computed tomography guided
segmental bronchi showed intense hyperaemia planning of the biopsy route. In addition, the exact
with vascular engorgement in the form of bright location of the needle tip in the target lesion can be
red longitudinal streaks. The sharp demarcation reviewed before biopsy. The specimens obtained
between normal main bronchi and the very red were lymphoma, bronchial carcinoma, metastases,
lobar and segmental bronchi is due to the venous carcinoid, thyroid cyst and haematoma. Its value is
drainage of the bronchial tree. The trachea and to distinguish a primary mediastinal tumour
main bronchi drain into the bronchial veins, which requiring surgery from systemic lymphatic malig-
were presumably normal. The more peripheral nancy. This technique is simple, rapid and accur-
bronchi drain into the pulmonary veins, which ate, and provides yet another window to the lungs.
were congested by the occlusive process.
Intravascular ultrasound
Langerhans'pulmonary dendritic cells
Transthoracic and transoesophageal echocardio-
Paul Langerhans (1847-1888) was born and graphy can reveal evidence ofpulmonary embolism
studied medicine in Berlin and became professor of but only to the mainstem and central parts of the
pathology in Freiburg. He is remembered by the left and right pulmonary arteries. Intravascular
islets of Langerhans and posthumously by Langer- ultrasound probes the periphery of the pulmonary
hans' pulmonary dendritic cells. They are found in vascular bed.'2 A catheter is introduced via a
the peribronchial connective tissue and in the guidewire into the main trunk of the pulmonary
alveolar parenchyma. As in the skin, they are artery and advanced into the left and right pul-
derived from less sophisticated indeterminate den- monary trunk. It could be advanced into vessels
dritic cells. It would be interesting to know what smaller than 1 cm in diameter. The catheter is
mediators convert these dendritic cells into sophis- connected to an ultrasound device and the sono-
ticated Langerhans' macrophages, which are fre- grams are stored on videotape. It should be possi-
quently seen in zones of alveolar hyperplasia and ble to use an indwelling catheter to monitor
alveolar metaplasia induced by tobacco or other thrombolytic therapy in pulmonary embolism.
inflammatory insults. The French'" remind us that
Langerhans' pulmonary macrophages are well Apoprotein-A concentration in sputum
worth studying for they have a potent capacity for
presenting antigen to lymphocytes, and thereby a Pulmonary alveolar proteinosis (PAP) is a disorder
significant role in the pulmonary immune response characterized by accumulation of surfactant mat-
and in the pathogenesis of histiocytosis X, now erials in alveoli. It may be recognized by broncho-
renamed Langerhans' granulomatosis or Langer- alveolar lavage for the wash is milky due to
hans' cell histiocytosis, and in pulmonary lym- intra-alveolar accumulation of periodic acid-Schiff
phomas. Langerhans' X or HX cells have a cleaved positive proteinaceous material. The predominant
nucleus with a finely dispersed chromatin pattern phospholipid-associated glycoprotein in pulmon-
within an eosinophilic cytoplasm. Electron micros- ary surfactant is surfactant aprotein A (SP-A). This
copy reveals pentalaminar structures within this may be measured in sputum using monoclonal
cytoplasm. antibodies to SP-A.
These cells are described under the heading Sputum concentrations of SP-A were found in
Techniques because their prominence and impor- this Japanese study to be 400 times higher in PAP
tance are being increasingly recognized and they than in controls."3 This simple non-invasive tech-
will repay further study to analyse their role in nique must be an attractive alternative to any
systemic diseases. invasive procedure.
Mediastinal sonography
Wegener's granulomatosis (WG)
Wernecke, a Munster radiologist, pioneered sup-
rasternal and parasternal mediastinal sonography, In last year's review, we reported that Friedrich
and has now applied this technique to guidance of Wegener lived in happy retirement in Lubeck,
percutaneous mediastinal tumour biopsy." Germany. This year it is sad to report his death on 9
The essential criterion for selection of patients is July 1990, aged 83 years.'4 He lived to see two
the availability of an avascular approach to the remarkable advances in the disorder which bears
mediastinal tumours, so sonographic guidance is his name. He lived to see the introduction of a most
mainly suitable for the biopsy of anterior medias- helpful diagnostic blood test; anti-neutrophil cyto-
RESPIRATORY DISEASES 163

plasmic antibodies (ANCA) are identified in serum this process and by mediators released by macro-
of patients with Wegener's granulomatosis by phages as they phagocytose free asbestos fibres.
immunofluorescence microscopy using alcohol- These chemical mediators include fibronectin,
fixed normal human neutrophils. He also derived platelet-derived growth factor, alveolar macro-
considerable joy from the second advance, namely phage-derived growth factor and insulin-like
treatment of the disease. When he first described growth factor. What starts insidiously and progres-
the disorder in 1936 it carried a 100% mortality. In ses inexorably ends lethally with the development
the succeeding 50 years, he witnessed the introduc- of interstitial and pleural fibrosis, mesothelioma,
tion of corticosteroids, cyclophosphamide and lung cancer and gastrointestinal malignancy. These
antibiotics, all of which have combined to reduce costly diseases are well-reviewed in an authoritative
the mortality to a more manageable 5%. He was recent state of the art.'7 The processes of
thrilled to feel that earlier diagnosis by a non- inflammation, fibrosis and carcinogenesis appear
invasive procedure led to earlier effective treatment to be closely interwined; proto-oncogenes are
and a substantial improvement in prognosis. upregulated in activated alveolar macrophages
The National Institutes of Health, Bethesda, from fibrotic lungs. Furthermore asbestos can
have recently analysed the pulmonary pathological transfect DNA into cells. Cigarette smoking
features in 87 open lung biopsies from 67 patients prepares a highly metaplastic bronchial epithelium
with WG, and illustrated the wide variation and and so provides co-carcinogenicity.
broad spectrum of pathological changes ob- Circumscribed pleural plaques and diffuse pleur-
served.'5 The three useful diagnostic criteria were al thickening, collectively termed pleural fibrosis, is
parenchymal necrosis, vasculitis, and granulo- the most common radiographic manifestation of
matous inflammation accompanied by an asbestos exposure. Its development is dependent on
inflammatory infiltrate of plasma cells, neut- the cumulative dose of asbestos exposure and the
rophils, lymphocytes, histiocytes and eosinophils. elapsed time since the first exposure. Autopsy
Parenchymal necrosis comprised neutrophilic studies and computed tomographic (CT) scans
microabscesses or areas of geographic necrosis suggest that the standard chest radiograph only
surrounded by palisading histiocytes and giant identifies about 50-80% of the pleural plaques
cells. Granulomas were poorly formed with scat- that are actually present.'8 This is disclosed by a
tered giant cells. Vasculitis was almost always recent survey at the London Chest Hospital, in
present in arteries and veins; commonly necrotizing which CT scanning was compared with chest
and granulomatous with cicatricial changes and, radiography in 20 patients with asbestos-induced
infrequently, fibrinoid necrosis. Minor changes pleural disease.'9 CT scan always reveals involve-
were alveolar haemorrhage, bronchiolitis ment in the paravertebral area. CT demonstrated
obliterans with organizing pneumonia (BOOP) discrete plaques in 95% of patients but these were
and nodular interstitial fibrosis. only identified in 59% of patients by chest radio-
Despite a diagnostic blood test and histological graphy. Diffuse pleural thickening was evident on
features of a granulomatous vasculitis there con- the CT scan in all patients and in 70% on the
tinue to be diagnostic difficulties. This is evident by radiograph. CT and chest radiograph scores in-
a recent case report of a patient with a T cell versely correlated with all lung function measure-
lymphoma of the lung mimicking WG.16 The ments except KCO. Increasingly extensive pleural
bronchial biopsy was compatible with WG, ANCA disease is associated with increasingly severe im-
was positive, and the initial response to cyclophos- pairment of lung function. The superiority of CT
phamide and prednisolone was most encouraging. may be important for those claiming state compen-
However, 5 months after presentation a repeat sation for asbestos-induced disease.
bronchial biopsy revealed lymphoma and under-
lined the dictum 'all that glisters is not Wegener's Clay dye pneumoconiosis
granulomatosis'.
This benign pneumoconiosis among rush mat
workers is only seen in Japan. The rush mat (tatami
Occupational lung disease and fancy mat) is treated with a clay dye which
contains quartz, chlorite, kaolin and sericite, with a
Asbestos high free silica content. The rush is dipped into a
40% colloidal soluton of clay dye, which imparts to
After deposition of asbestos, the initial lesion is an the mat a silver-green hue and also a certain degree
accumulation of alveolar macrophages in the of elasticity essential for matting purposes.20 In the
alveolar ducts and peribronchial region adjacent to course of 10 years, the chest X-ray reveals small
the terminal respiratory bronchiole. This is thick- round opacities less than 1.5 mm in diameter,
ened by interstitial macrophages and later by distributed throughout the lungs. The histopath-
fibroblasts; and type 1 alveolar cells are injured by ology is of small pneumoconiotic weakly fibrotic
164 D.G. JAMES

nodules composed of macrophages phagocytosing heart-lung transplantation. In a Papworth series

or attached to dust particles around peripheral of 61 patients who had received heart-lung trans-
perivascular and alveolar regions. The disease plants, 7 patients developed chronic rejection, 4
process shows fine dust foci but only a weak died with extensive obliterative bronchiolitis, 12
tendency to progress to fibrosis, possibly because have shown lung fibrosis, and opportunistic lung
the clay coats free silica thereby reducing fibrogenic infections resulted in pneumonia on 19 occasions.23
potential. Herpes simplex virus infection is sufficiently fre-
quent to warrant prophylactic acyclovir for the first
Hut lung 2 months after surgery and at times of augmented
immunosuppression .224
Occupational lung disease is more common in men Early detection and prompt treatment of acute
but clay dye pneumoconiosis is frequent in Japan- rejection is an essential step in the prevention of the
ese women workers, and hut lung is a domestically crippling obliterative bronchiolitis ofchronic rejec-
acquired pneumoconiosis in women from the Tran- tion. Close monitoring of lung function with
skei district of South Africa.2' Its alternative name regular routine and diagnostic transbronchial lung
is Transkei silicosis. It is due to silica particles biopsy enables accurate diagnosis of acute rejection
inhaled when they are hand-grinding maize be- and may 25have lessened the incidence of chronic
tween rocks in poorly ventilated huts. The maize rejection.
kernels are ground between an oblong top rock, Papworth has a wider range of interests than just
which is handled, and a large base rock on the the transplant programme for they have also
ground. Twenty-five women were studied by Cape investigated impairment of endothelium-derived
Town workers, who report that most women were relaxing factor (EDRF) in the pulmonary circula-
symptom-free but radiological findings ranged tion in chronic hypoxic lung disease. Endothelium-
from a military pattern to extensive fibrosis dependent pulmonary artery relaxation in vitro is
resembling progressive massive fibrosis. Autopsies impaired in arteries from patients with end-stage
on two patients who died from respiratory failure chronic obstructive lung disease compared with
confirmed features of silicoanthracosis. This dom- control pulmonary arteries from patients undergo-
estically acquired pneumoconiosis is not only due ing lobectomy for lung carcinoma. The responses
to maize grinding but also due to smoky wood- of all vascular rings to the endothelium-dependent
fuelled stoves in poorly ventilated huts; hence the vasodilators, acetylcholine and adenosine diphos-
more appropriate term 'hut lung'. phate, were studied immediately after lung ex-
cision. The impairment may contribute to the
SWORD development of pulmonary hypertension in chron-
ic hypoxic lung disease.26
This stands for Surveillance of Work-related and Endothelin-l, a potent endothelium-derived
Occupational Respiratory Disease.22 Members of vasoconstrictor peptide, has been studied in Que-
the British Thoracic Society set up a reporting bec, and, in particular, its role in pulmonary
scheme for this endeavour in which yellow cards hypertension, by measuring its concentration in
are returned concerning any patients with possible arterial and venous plasma.27 Patients with pul-
occupational lung disease. The SWORD scheme monary hypertension were found to have substan-
will provide an important base of information, tial alterations in plasma immunoreactive endo-
from which we may track trends and monitor the thelin- 1, reflecting changes in net release or
efficacy of preventive measures in respiratory clearance by the lung. In patients with primary
disease. pulmonary hypertension, the high levels in arterial
compared with venous plasma suggest pulmonary
production of endothelin- 1 which may contribute
Papworth Hospital, Cambridge to pulmonary vascular resistance.
The Tim Higgenbottam-John Wallwork team
maintain standards of excellence in their pioneer- Tuberculosis
ing human lung transplantation programme,
which is still in its infancy compared with other Can we eradicate tuberculosis?
forms of organ transplantation. Improved surgical
technique, preservation of donor organs, and In April 1989, Dr Louis Sullivan, US Secretary of
cyclosporin have been important advances, but Health and Human Services announced his en-
these advances have been offset by acute pul- dorsement of the goal of eliminating tuberculosis
monary infections, fatal obliterative bronchiolitis, from the United States by the year 2010. This
and chronic rejection. Chronic rejection is the laudable ambition has led to an Advisory Commit-
major cause of death of long-term survivors of tee for the Elimination ofTuberculosis and its joint
RESPIRATORY DISEASES 165

curriculum with the American Thoracic Society Mycobacterium avium - intracellulare (MAI)
and the Centers for Disease Control, Atlanta; all
greatly respected bodies. The most recent docu- Organisms of this complex comprise two closely
ment developed by these groups is an excellent related species, M. avium and M. intracellulare.
'Core Curriculum on Tuberculosis', obtainable They have little virulence in the normal host, and
from Technical Information Services, Center for chest physicians used to recognize them as an
Prevention Services, Atlanta, Georgia.28 It encom- uncommon cause of pneumonia in patients with
passes epidemiology, transmission and path- chronic lung disease. Those were the days before
ogenesis of tuberculosis, diagnosis, preventive AIDS. They are now of considerable clinical
therapy and treatment. An estimated 10 ,million importance in the AIDS population. By 31 De-
persons in the USA are infected and about 90% of cember 1990, there were 12,202 cases of dissem-
new cases arise from this already infected pool. In inated non-tuberculous mycobacterial infection
1986, after three decades of steadily decreasing among the 161,073 patients with AIDS reported to
tuberculosis morbidity, there was a turnaround the Atlanta Centers for Disease Control.3s M.
increase in annual tuberculosis morbidity largely avium complex, and also cytomegalovirus infec-
due to patients with acquired immunodeficiency tion, become apparent when cell-mediated immun-
syndrome (AIDS), but also due to medically ity is considerably depressed with CD4 + counts
underserved low-income populations and Afro- reduced to 100 or less cells/mm3. Clinical presenta-
Asian and Latin American migrants. Other high- tions include fever, night sweats, weight loss (all
risk groups who particularly need to be screened suggesting toxicity by tumour necrosis factor),
are alcoholics, intravenous drug users, residents of pneumonia and endobronchial lesions as well as
long-term care facilities (including prisons) and several extrathoracic lesions. Antimycobacterial
some health care workers. Much of this is already agents include amikocin, ethambutol, streptomy-
well accepted but it needs to be restated as tuber- cin, ciprofloxacin and clofazimine. Horsburgh's
culosis soars in New York.29 Its prevalence in this authoritative review should be consulted for de-
city in 1990 was 46 cases per 100,000, which is five tailed management of this fatal disorder.35
times the national average. Moreover a case-
control survey has shown nosocomial spread of
drug-resistant tuberculosis in some of the city's Fungal infection
hospitals. This may lead to the resurrection of
tuberculosis sanatoriums in one of the most sophis- The Journal of Antimicrobial Chemotherapy has
ticated cities in the most productive country in the produced an excellent supplement on develop-
world. There is similar frightening emergence of ments in the management of fungal infection.36 It
drug-resistant tuberculosis in drug addicts in contains succinct accounts of invasive pulmonary
Italy.30 The global toll of tuberculosis is worldwide, aspergillosis, rhinocerebral mucormycosis, pul-
a fact emphasized by recent figures of the Chief monary cryptococcosis, new approaches to sero-
Medical Officer, Tuberculosis Unit, World Health diagnosis, and the advent of fluconazole and
Organisation.3" In 1990, there were 8 million new itraconazole. The recognition of polyvalent and
cases of tuberculosis in developing and indus- monoclonal antibodies to the major fungal patho-
trialized countries; 95% in the former and 5% in gens has led to the marketing of diagnostic kits for
the latter. The worldwide pool of infected persons the detection of circulating antigens in body fluids.
is 1,722 million, nearly one-half living in South- Monoclonal antibodies to cell wall and cytoplas-
East Asia and the Western Pacific. Africa has an mic components of Cryptococcus neoformans and
incidence of 272 cases per 100,000. The incidence of Histoplasma capsulatum have been described. La-
tuberculosis in Hong Kong is 124 per 100,000 per tex particle agglutination and double antibody
annum, which is considerably more than in the liposomal-based formats are being marketed for
white population in the UK. This has led to a systemic candidosis and invasive aspergillosis.
warning that clinicians must be alerted to the Chromosomal DNA probes may lead to the detec-
possibility of tuberculosis, particularly its extra- tion of fungal elements in clinical specimens. This
thoracic form, in migrants from Hong Kong when supplement is worth consulting in its entirety.
the lease back occurs in 1997.32 Invasive candidiasis is a major nosocomial infec-
The Medical Research Council in conjunction tion that is difficult to diagnose. It has now been
with the Hong Kong Chest Service and the Sing- found that the presence of candida enolase in the
apore Tuberculosis Service have recently updated blood is a novel marker for invasive candidiasis. It
their results of the chemotherapy of tuberculosis. appears to be a useful indication of deep infection
The conduct of these continuing trials are elegant, in patients with cancer and neutropenia; it com-
and their design continues to command world plements the diagnostic usefulness of blood cul-
respect. They are recommended reading in their tures.37 The British Society for Antimicrobial
entirety.33 34 Chemotherapy Working Party have set out the
166 D.G. JAMES

indications for, and interpretation of, the tests that management of this American patient." When you
can be done with the major antifungal drugs in have done so you are nearly home and that means
clinical use at present.38 They pay particular atten- reading Geddes' splendid editorial summarizing all
tion to flucytosine, ketoconazole, fluconazole and views on BOOP and COP.45 It brings it all into
itraconazole. They set out sensitivity tests, assays perspective for another year or so. The fact that the
of serum concentration, and regimens for adminis- same pattern of events occurs as a result of
tration of flucytosine in renal impairment, linking infections, drugs and connective tissue disorders
the dose with creatinine clearance. This is the type suggests that it is not a single clinicopathological
of article that will help the chest physician when he entity but rather one way in which the lung mounts
is faced with a respiratory mycosis. an inflammatory response to a range of different
insults. The term BOOP is probably best restricted
to those cases of unknown cause.45
BOOP
The name has stuck in the international literature What shaU we call this syndrome?
so we must learn to recognize it for it is steroid
sensitive, treatable and reversible. It stands for The title of the article is too cumbersome for
bronchiolitis obliterans organizing pneumonia everyday use but the chest physician should be
(BOOP), which envelops two or perhaps even more aware of it in women aged 45 years or so
conditions, but particularly cryptogenic organizing with pulmonary fibrosis and various multisystem
pneumonia and obliterative bronchiolitis.394' The signs.' These include Raynaud's phenomenon,
French4' recognize BOOP as a clinico-pathological polyarthralgia, polymyositis, sclerodactyly, ker-
entity with a well-recognized morphogenesis. atoconjunctivitis sicca, dysphagia, facial telangiec-
Diffuse alveolar injury leads to basement mem- tasis, hepatitis, subcutaneous calcinosis, tendonitis
brane denudation and intra-alveolar exudate of and clubbing. The majority of patients have a
fibrinogen, immunoglobulins, coagulation factors greatly elevated sedimentation rate, raised serum
and fibronectin. Interstitial fibroblasts migrate into immunoglobulins, and a third have a positive
alveoli through denuded gaps in the epithelial rheumatoid factor. The common laboratory find-
basement membrane. The final step is the secretion ing in this series was the presence ofautoantibodies
of collagens I, III, V and fibronectin by fibroblasts against aminoacyl-tRNA synthetase; either histi-
forming a loose connective tissue fibrosis, which is dyl-tRNA synthetase (anti-Jo 1) or alanyl-TRNA
surprisingly reversible. The diagnosis is confirmed (anti-PL12) or threonyl-tRNA (anti-PL7) syn-
by lung biopsy and it is usually steroid-responsive. thetase. The most important clinical determinant
It may be associated with primary biliary cirrhosis, of outcome in this group of patients was the
the CREST syndrome and digital vasculitis and it severity of the interstitial pulmonary disease. Five
may well overlap with various connective tissue patients had transbronchial lung biopsies which
disorders. Within the orbit of these overlap syn- showed features of interstitial lung fibrosis, two
dromes is the association of cryptogenic organiz- patients had chronic inflammatory cell infiltrates
ing pneumonitis with rheumatoid arthritis.42 The and one patient had evidence of active alveolitis
French43 have undertaken a wide survey of pleuro- with infiltrations of polymorphonuclear cells. No
pulmonary disease in rheumatoid arthritis, em- biopsy showed evidence of vasculitis. Various
ploying lung function tests, bronchoalveolar treatments included prednisolone, azathioprine,
lavage and high resolution computed tomography. cyclophosphamide, methotrexate, cyclosporin and
In this series nearly 50% of patients with rheum- total body irradiation.
atoid arthritis had pleuropulmonary manifesta-
tions. This was particularly evident in men with
subcutaneous nodules and positive rheumatoid Neoplasia
factor. Bronchiolitis obliterans induced by penicil-
lamine was the most severe iatrogenic feature, but Non-small cell lung cancer (NSCLC)
they also observed hypersensitivity pneumonitis
related to low dose methotrexate. A whole volume of the US Current Problems in
If you, dear readers, have reached thus far on Cancer is devoted to non-small cell lung cancer,
BOOP, then you should take two further interest- comprising squamous, large cell and adenocar-
ing academic steps. First, enjoy the Case Records cinoma, and forming 75% of lung cancer in the
of the Massachusetts General Hospital concerning United States.47 Genetic mutalions in dominant
a 68 year old man admitted with respiratory oncogenes such as K-ras, loss of genetic material on
symptoms and an abnormal chest X-ray. Don't chromosomes 3p, llp and 17p, and deletions or
cheat by looking for the diagnosis at the end of the mutations in tumour suppressor genes such as rb
article. Just work out, step by step, your British and p53 have been documented in these tumour cell
RESPIRATORY DISEASES 167

lines. NSCLC arises in a setting of bronchial Lymphoma

metaplasia and dysplasia due to cigarette smoking
and other pollutants. The prognosis is based on A joint Anglo-American study of AIDS-related
extent of tumour dissemination, ambulatory state non-Hodgkin lymphoma analysed cases reported
and weight loss. Stages I and II NSCLC are to the Centers for Disease Control, Atlanta, up to
confined within the pleural reflection, Stage III has 30 June 1989. During this period 97,258 AIDS
extended through the pleura or metastasized to cases were reported, of whom 2,824 (2.9%) had
ipsilateral or subcarinal lymph nodes and StUIge IV non-Hodgkin lymphoma: a condition that was
is characterized by distant metastases. Stages I and about 60 times more common in AIDS patients
II are managed by surgical resection with approx- than in the general US population.52 It was twice as
imate 5-year survival of 45% and 25% respectively; common in whites as in blacks and in men as in
Stage III by a combination of resection and women. It was most common in patients with
radiotherapy with a 5-year survival of 15%. Stage haemophilia or clotting disorders and least com-
IV NSLC has a 5-year survival of less than 1% mon in those born in the Caribbean or Africa who
despite chemotherapy. had acquired HIV by heterosexual contact. Infec-
Growth hormone is a secretory product of some tious agents, particularly Epstein-Barr virus, are
primary bronchial neoplasms and has been asso- associated with lymphoma in these immunosup-
ciated occasionally with the development of pressed patients. The most difficult question is why
hypertrophic pulmonary osteoarthropathy and Burkitt's lymphoma is commonly associated with
acromegaly. It may also be associated with finger HIV infection but not with other types of immuno-
clubbing.'8 Increased plasma growth hormones suppression.
levels correlated with clubbing; following chemo- The European Lymphoma Co-operative Group
therapy in one patient hormone levels fell to have studied 772 patients with early-stage Hodg-
normal and clubbing completely resolved. Further kin's disease, and assessed the value of an elevated
studies are needed to decipher whether the hor- (>30 mm/h) Westergren erythrocyte sedimenta-
mone is secreted by the tumour cells or the tion rate (ESR) for predicting early relapse and
surrounding lung or from the pituitary after its survival after therapy in patients with clinical Stage
stimulation by growth hormone releasing hor- I or II Hodgkin's disease. An unexplained elevated
mone. ESR after therapy, especially modern radiother-
There is renewed interest in the expression of apy, strongly suggests the presence of aggressive
ABO blood-group antigens in relation to the and resistant Hodgkin's disease. An elevated ESR
development of lung cancer. Expression of blood- is predictive ofearly relapse and poor prognosis; its
group antigen A in tumour cells is an important presence justifies early aggressive therapy.53
favourable prognostic factor in patients with Another test which provides useful prognostic
NSCLC.4' The authors of this report suggest that information in low-grade lymphoma is the serum
this factor should be taken into account when P-2 microglobulin (P-2M) level. It has been eval-
stratifying patients in future clinical trials to uated in 80 previously untreated Stage I to IV
evaluate the efficacy of post-operative adjuvant patients in Houston.54 P-2M is a low molecular
chemotherapy. Patients who are negative for weight polypeptide, the light-chain molecule of the
blood-group antigen A seem to merit aggressive major histocompatibility complex class 1 antigens.
therapeutic approaches in view of their poorer It is found on the membrane surface of almost all
prognosis; perhaps chemotherapy and irradiation nucleated cells, and its membrane turnover is the
as an alternative to immediate surgery. principal source of P-2M in the blood and body
The Belgians have applied meta-analysis on fluids. The complete remission rate for patients
studies of chemotherapy of NSCLC, involving a with P-2M level of 3 mg/l or greater was 36%
total of 6,247 patients. Polychemotherapy had a compared with 71% for those with a level of less
significantly better response rate than mono- than 3 mg/I. The mechanism is possibly that
therapy, and the best results were associated with tumour cells release P-2M through membrane
cisplatin, vindesine, vinblastine, mitomycin C and turnover. A similar helpful prognostic value is
ifosfamide.5 These differences were most obvious noted in myeloma, in which patients with the
in those with limited rather than disseminated highest values have the shortest survival.
disease.
Workers at Yale University have tried to over-
come the bleak outcome of Stage Illa NSCLC by Sarcoidosis
pre-operative (neoadjuvant) chemotherapy in or-
der to decrease tumour bulk so that inoperable Last year's review of respiratory diseases did not
patients become surgical candidates.5' include sarcoidosis. As a result of this omission, we
received several letters enquiring whether we had
lost our taste and zest for this obsession of ours.
168 D.G. JAMES

Not so. This year has much more to include for in factors including interleukins 1 and 2 (IL- 1 and
September 1991 was held the XII World Congress IL-2), macrophage-activating and macrophage-
on Sarcoidosis in Kyoto, Japan, organized under inhibiting factors and gamma interferon. The
the auspices of the World Association of Sar- majority of T-cells bear the T-cell receptor (TCR)
coidosis and Other Granulomatous Disorders ap complex but a very small subpopulation bear a
(WASOG). The Proceedings of this Congress will distinct TCR composed of gamma and delta
appear as a special supplement of the journal, subunits in lymphoid organs and skin. This small
Sarcoidosis.55 Indeed, as you read this article so will subpopulation of TCR '6 lymphocytes is prom-
the supplement be available to update you on what inent in leprosy, leishmaniasis and sarcoidosis, all
sarcoidologists from 23 countries think about chronic granulomatous disorders which seem to
sarcoidosis and other granulomatous disorders respond to mycobacterial stimulation.56
such as Wegener's granulomatosis, summertime What of the lymphokines involved in this
hypersensitivity pneumonitis, eosinophilic granu- granulomatous response? Pulmonary alveolar
loma and occupational granulomatoses. macrophages harvested in bronchoalveolar fluid of
Sarcoidosis is published in Milan, Italy, in Eng- sarcoidosis patients release tumour necrosis factor
lish every March and September. Each issue con- in vitro in response to Escherichia coli endotoxin
tains about 86 pages of articles on all aspects of lipopolysaccharide and spontaneously.56'57 Those
sarcoidosis and other disorders which mimic it. It is who have lived through the long history of claims
also a thesaurus or treasure trove of information for mycobacteria or their mucopolysaccharides as
concerning conferences, events and news around the causes of sarcoidosis will now recall, amongst
the world. others, the pine pollen theory of sarcoidosis. Pine
An ambitious enterprise of the Kyoto conference pollen was acid-fast staining and resembled the
was an epidemiological survey of sarcoidosis in 16 wax fraction of the tubercle bacilli. Have we arrived
cities around the world. It analysed 2,702 new cases back in square one of the aetiology of sarcoidosis?58
seen during 1981-1985, with women comprising The sarcoid granuloma also produces angio-
62% of the total. The age at presentation was in the tensin-converting enzyme, calcitriol, metallopep-
20-50 year range in 78% ofthis series. Histological tidase and lysozyme, and the road to fibrosis is
confirmation of the diagnosis is now frequently hastened by collagenase, type III procollagen N-
obtained by fibreoptic bronchoscopy and trans- terminal peptide, hyaluronic acid and fibronectin.
bronchial biopsy. Open lung biopsy, scalene node The chest physician's road to fibrbsis would be
and mediastinal lymph node biopsy are no longer incomplete nowadays without hoardings extolling
popular. All patients in this series had intrathoracic the importance of molecular biology and macro-
sarcoidosis. The tempo of the disease varies with phage-derived growth and progression factors. Do
the community in which it is studied. The black not progress along this road without first consul-
population in the US and the West Indians in ting an excellent topical review by Shaw."9 It is
London often have severe, extensive and crippling sophisticated and academic but he also has a
disease whereas it is mild and with a high spon- Churchillian quality to make it readable and
taneous rate of resolution in the Irish. Just as enjoyable. He suggests that the macrophage is the
London sees much sarcoidosis among its migrants conductor of fibrotic events and plays a role via
from the West Indies so does Paris see it in its platelet-derived growth factor (PDGF) as gate-
migrants from Martinique, and New York City in keeper in regulating the transition from inflamma-
its Puerto Rican-born population. Is this due to tion to fibrosis, aided and abetted by gamma-
genetic predisposition or environmental factors interferon (IFN-') from neighbouring lym-
confronting susceptible individuals migrating from phocytes. He suggests that in sarcoidosis there may
a rural to an urban community? Is the breeding be a conflict between the profibrotic influence of
ground for sarcoidosis in their native homeland or IFN-y on macrophage PDGF gene activation, and
within the sophisticated new world in which they the antifibrotic effects of combinations of IFN-',
adapt themselves? It may be a bit of both worlds. tumour necrosis factor and interleukin I on the
fibroblast.
The road from granuloma to fibrosis
Immunomodulation
Antigenic invasion by micro-organisms or chemi-
cals or cancer is met by a granulomatous Immunotherapy has become a major branch of
inflammatory response involving close interplay therapeutics, but, like Janus, it is two-headed.
between activated macrophages bearing increased Immunomodulators may overcome adverse im-
expression of major histocompatibility (MHC) mune reactions, but they also depress immunity
Class II molecules and CD4 + lymphocytes. These and lower resistance against infection. These are
CD4 cells help to initiate a cascade of chemotactic the twin dilemmas confronting every transplant
RESPIRATORY DISEASES 169

team, and of particular importance to the chest and intralesional use. Trials are under way to assess
physician. Corticosteroids, azathioprine, cyclo- its role in viral infections, malignancy and autoim-
phosphamide and chlorambucil are already well mune disorders, in conjunction with other treat-
recognized and used worldwide. They are now ments. For patients with chronic granulomatous
being joined or supplanted by cyclosporin, FK 506, disease, interferon gamma therapy is an effective
interferons, immunoglobulins and RSCD4 (Table and well-tolerated treatment that reduces the fre-
III). The chest physician must keep abreast of their quency of serious infections.62
expanding use since he is called upon to deal with
the immunocompromised patient with recurrent Immunoglobulins
infections.
Intravenous immunoglobulin preparations are
Cyclosporin now much improved compared with the outdated
intramuscular preparations. It can be administered
Cyclosporin (BP) or ciclosporin (WHO), derived in a larger dose, minimizing the anaphylactic
from a Norwegian fungus, is an undecapeptide reactions of the old intramuscular versions. It is
with a cyclic sequence of 11 amino acids. It is prepared from pooled human plasma and provides
available as an oral solution, as capsules, and as an passive immune prophylaxis against hepatitis A,
intravenous infusion. It acts by inhibiting inter- measles, rubella in pregnancy, congenital hypo-
leukin 2 (IL-2), produced by certain cytotoxic gammaglobulinaemia and idiopathic thrombocy-
T-helper cells, which recognize and kill target topenic purpura.
antigens, including foreign transplants. Cyclo- When considering intravenous immunoglobulin
sporin is now enjoying an expanded role in the replacement therapy it is important to distinguish
management of many autoimmune disorders, skin and consider particularly those patients who may
diseases and in ophthalmology (Figure 1). It would have near-normal immunoglobulin levels but have
be used more frequently but for its nephrotoxicity marked impairment in their ability to produce
and other unpleasant side effects. It is being used in specific antibodies after immunisation with poly-
South Africa with some success as a corticosteroid- saccharide and protein antigens. These are the truly
potentiating agent in cryptogenic fibrosing alveo- deficient persons who need replacement immuno-
litis and progressive symptomatic interstitial lung globlin.63,' The National Institute of Child Health
disease of unknown aetiology.1 has conducted a multicentre randomised double-
blind placebo (albumin)-controlled trial in 372
FK 506 HIV-infected children and shown that intravenous
Since cyclosporin is toxic, there is a continuing immunoglobulin in a dose of 400 mg/kg per month
search for alternatives. FK 506, a Japanese dis- was effective in significantly increasing the time free
covery, is a macrolide produced by Streptomyces of serious bacterial infections for those children
tsukubaensio, and in some respects is similar to with CD4+ lymphocyte counts <0.2 x 109 per
erythromycin. It is much more powerful than litre.65
cyclosporin in inhibiting IL-2 synthesis and the The use of intravenous immunoglobulin after
expression of IL-2 receptors, even though it is bone marrow transplantation reduced the inci-
chemically unrelated. In Pittsburgh, liver trans- dence and severity ofinterstitial pneumonia related
plant patients, whose plight was desperate because to cytomegalovirus, sepsis and graft-versus-host
their liver grafts were being rejected despite con- disease.63 It is of value in chronic lymphocytic
ventional immunosuppression, are leading normal leukaemia but its cost may be prohibitive.66
lives on FK 506 alone.61 They are well without Intravenous immunoglobulin has been effective
corticosteroids and azathioprine. It is now under- in immunoregulatory disorders, such as immune
going intensive clinical trials in Britain. It may be thrombocytopenic purpura, immune neutropenia
sight-saving in Behcet's disease (Ohno, personal and the Kawasaki syndrome.'M It blocks the uptake
communication). of antibody-coated cells in the spleen, inhibits
antibody synthesis, and inhibits inflammation. It
Interferons may have a future potential use in polymyositis,
Guillain-Barre syndrome, myasthenia gravis and
Human interferons are a family of proteins which steroid-dependent asthma.64
activate intracellular oligo-adenylate synthetase to Intravenous immunoglobulin is recommended
interfere with and inhibit viral RNA. This inter- for systemic vasculitis.67 Following treatment there
ference led to their name interferon. They have a was a fall in circulating anti-neutrophil cytoplasm
wide range of antiviral and antitumour effects. antibodies (ANCA) and in C-reactive protein
Interferon is prepared by recombinant technology, changes and clearing of radiological charges with-
and is available as a megaunit dosage for sub- out adverse effects. It was infused at 0.4 g/kg per
cutaneous, intramuscular, intravenous, intrathecal day for 5 days.
170 D.G. JAMES

0-
0
C C
C4d
., .
la
4) CO
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.-
COd
e
0 CO
cd 0
U)
. >000
(A
.

E w
r4 0

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Cd
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aCOci
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r
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ol

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L. + o 0

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qo LZ
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Cd 10
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o~~~~~o CIS

to 00 00 oo
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CO34-
o~~~~~~~~~-
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= 0 E

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U U C
RESPIRATORY DISEASES 171

OPHTHALMOLOGY
Uveitis
Behcet's disease Myasthenia gravis
Autoimmune retinitis
Dysthyroid eye disease
Corneal grafts
Scleritis

iatoid

colitis - DERMATOLOGY
Psoriasis
Lichen planus
Atopic eczema
Pemphigus
Pemphigoid
Alopecia areata
Pyoderma gangrenosum
Dermatomyositis
Figure 1 The expanding uses of cyclosporin.

Others mortality from RDS in premature infants during

the first week of life, and complications such as
Table III also draws attention to other immuno- pneumothorax are fewer. One vial of Exosurf costs
modulators which are on the horizon and appear £314 and up to four may be needed to treat one
promising; next year they may become widely used baby. 74'75
if the cost is not prohibitive.' They include recom-
binant soluble CD4 polypeptide and IMREG-l for
AIDS;69 CD4 monoclonal antibody for psoriasis;70 Device-related infection and disinfection
monoclonal antibody (HA-lA; centoxin) for
Gram-negative septicaemia and septic shock;7' and Ten bronchoscopes that had been used on patients
recombinant granulocyte-colony stimulating fac- with AIDS were examined for microbial con-
tor (rG-CSF) for neutropenia and infection in tamination by irrigating the suction biopsy channel
patients treated with cytotoxic chemotherapy for with viral transport medium. Samples, tested by
non-myeloid malignancy and for reduction of fever polymerase chain reaction, revealed HIV and also,
and neutropenia induced by chemotherapy in occasionally, Pneumocystis carinii and commensal
patients with small-cell lung cancer.72 bacteria and hepatitis B virus once. Cleaning in
detergent and 2 min disinfection in 2% alkaline
glutaraldehyde proved effective. HIV is more resis-
Other treatments tant to glutaraldehyde in the presence of protein so
detergent precleaning is essential after every bron-
Surfactant therapy choscopy procedure and should not be delayed
until after disinfection.76
Neonatologists continue to find surfactant helpful, The principal life-threatening complication in
and it is now seen to be a significant advantage to patients who have vascular catheters is septi-
administer the initial dose as prophylactic rather caemia. To assess the best means of cutaneous
than as rescue therapy in very premature infants.73 disinfection before insertion of an intravascular
It is administered into the trachea to prevent catheter, a prospective study of three antiseptics
respiratory distress syndrome (RDS or hyaline was undertaken.77 The use of 2% chlorhexidine was
membrane disease). The first such drug to be found to be superior to 10% povidone-iodine or
licensed in Britain is Colfosceril palmitate (Exo- 70% alcohol before catheter insertion and during
surf, Wellcome). Treatment has halved the overall follow-up care.
172 D.G. JAMES

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