Respiratory diseases - Postgraduate Medical Journalbe a boon in the detection ofrespiratory viruses, which, thus far, have been difficult to identify by rapid methods. Respiratory

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

Reviews in Medicine

Respiratory diseases

D. Geraint James

Visiting Professor ofMedicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK

Introduction

Most of the references at the end of this reviewshould be year-marked 1991 or 1992, with a fewearlier ones if they are relevant to the discussion.Asthma is excluded because its worldwide impor-tance merits a review of its own, and who better todo so than Professor Peter Barnes (see August 1992issue of Postgrad Med J).This review embraces techniques, Wegener's

granulomatosis, occupational lung disease, infec-tions, various pulmonary syndromes, neoplasia,granulomatous disorders and therapeutics. Thisyear, therapeutics highlights the newest immuno-modulators which are in use or about to becomeavailable. They provide an exciting glimpse ofwhatlies ahead.

Techniques

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) has provided ahelpful new window to the lungs. Changes in thecellular and humoral constituents of BAL fluid(BALF) have broadened our understanding ofrespiratory and multisystem disorders (Table I). Itmay be helpful in the differential diagnosis ofsarcoidosis and fibrosing alveolitis for CD4 helpercells are prominent in BALF of active sarcoidosiswhereas neutrophils are prominent in that offibrosing alveolitis (Table II).The BAL window permits new glimpses or even

wider perspectives of asbestosis, cobalt lung,AIDS, pulmonary alveolar proteinosis (milkyBALF), eosinophilic pneumonia, transplants(lung, liver and bone marrow), Crohn's disease,collagen vascular disease and Langerhan's his-tiocytosis.l

Thoracoscopy

Thoracoscopy was widely used in the 1940s in theera of artificial pneumothorax collapse therapy fortuberculosis. It enabled adhesions to be severedand improve collapse of the tuberculous lung.Antituberculous chemotherapy made collapse ther-apy obsolete, but, unfortunately, this also led tothe disuse of thoracoscopy. A recent plan fromMontreal2 should help to revive its use in theevaluation of patients with pleural disease, whichremains undiagnosed after the usual initial inves-tigations. Thoracoscopy done under local anaes-thesia is a rapid, safe and well-tolerated procedurewith an excellent diagnostic yield. Biopsy speci-mens of parietal pleura, obtained under directvision, were studied by routine histology, myco-bacterial culture, immunochemistry and electron

Table I A preponderance of certain cells in bron-choalveolar fluid may be a helpful diagnostic pointer

Cell Disorder

T4 helper SarcoidosisBeryllium disease

T8 suppressor Extrinsic allergic alveolitis(Hypersensitivity pneumonitis)Talc

Neutrophil SmokerFibrosing alveolitisAIDSMineral dustCollagen disease

Eosinophil DrugsEosinophilic pneumoniaBronchial asthma

Mast cell SarcoidosisAsthma

Multinucleate giant CobaltPlasma Multiple myelomatosisReed - Sternberg Hodgkin'sAnaplastic Lymphangitic carcinomaOKT6 staining Langerhans' histiocytosis

Correspondence: D.G. James, M.A., M.D., F.R.C.P.

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RESPIRATORY DISEASES 161

Table II Bronchoalveolar lavage is helpful in thedifferential diagnosis of sarcoidosis and fibrosing

alveolitis

Feature Sarcoidosis Fibrosing alveolitis

Dyspnoea Mild SevereClubbing No YesAdded sounds Insignificant Numerous end-

inspiratoryChest X-ray Generalized Lower zoneHilar adenopathy Present AbsentHoneycombing Infrequent CommonCAT scan

Distribution Central PeripheralChanges Linear Cystic

SACE Increased NormalBAL T4 cells Neutrophils

increasedGallium scan Positive +Response to steroids Good Fair

CT = computed tomography; SACE = serum angioten-sin converting enzyme; BAL = bronchoalveolar lavage.

microscopy. This technique led to the diagnosis ofmesothelioma and various metastatic carcinomas,asbestosis, tuberculosis, rheumatoid arthritis, sys-temic lupus, chylothorax and haemothorax.

This is the decade of endoscopic cholecystec-tomy and keyhole surgery. Could this old andwell-established technique give rise to endoscopicresection of parts of the lung? It is certainly beingused for carbon dioxide laser treatment of bullousemphysema in California.3 Patients had advancedemphysema with severe pulmonary dysfunctionand were too high a risk for conventional surgicalbullectomy. In this study, there was significantobjective improvement, which has persisted. Long-term follow-up will determine its precise value inthis severely handicapped group of patients.

Rapid diagnosis

The demand for rapid viral diagnosis has increasedin recent years particularly since antiviral chemo-therapy has made important advances. The detec-tion of pathogen-specific DNA after amplificationwith the polymerase chain reaction will revolu-tionize the whole science ofmicrobiology. This willbe a boon in the detection of respiratory viruses,which, thus far, have been difficult to identify byrapid methods. Respiratory syncytial virus causeswinter childhood bronchiolitis, and detection ofantigen by either immunofluorescence or enzymeimmunoassay is reliable.4 Polyclonal antisera(Wellcome) against influenza viruses, parainflu-enza and adenovirus group antigens are suitablefor immunofluorescence testing. Another ingen-

ious technique is fluorescent focus assay, whichentails centrifugation of the respiratory specimenon a monolayer of tissue culture cells, incubationovernight, and then staining the cells withimmunofluorescent antisera. This Australianreview4 provides an exciting perspective ofwhat wemay learn to expect during the remainder of thisdecade. Read it now before it will be overtaken bycontinuing rapid advances 'in the field' and awayfrom the reference laboratory.A joint Anglo-Chinese study has facilitated the

diagnosis of nasopharyngeal carcinoma by meansof recombinant Epstein-Barr virus (EBV) pro-teins.' Nasopharyngeal carcinoma, a tumour ofepithelial origin, is common in the Chinese with anincidence of 1 5- 30 per 100,000 per year. In Chinesepopulations it is the commonest tumour amongmen and the second most common among women.The immune response of patients with naso-pharyngeal carcinoma to EBV antigens is diagnos-tic of the tumour. The EBV thymidine kinase wasfound to be the most sensitive predictor ofnasopharyngeal carcinoma when used in a recom-binant expression system. All serum samplesanalysed showed IgG and IgA antibodies tothymidine kinase whereas samples from infectiousmononucleosis are negative. This technique issuitable for use in large-scale screening program-mes for the early diagnosis of nasopharyngealcarcinoma.The use of a rapid method of diagnosing toxo-

plasmosis by the polymerase chain reaction is apointer to the future for all microbiology speci-mens, and this DNA probe is now established as aspecific and highly sensitive means of detectingtoxoplasmosis in a variety of specimens includingserum, cerebrospinal fluid (CSF), bronchoalveolarfluid and biopsy material.6

Likewise with Pneumocystis carinii pneumonia,which can be diagnosed rapidly by DNAamplification ofsputum and bronchoalveolar fluid.It is a highly sensitive and invaluable new techni-que.7Even more important is the early diagnosis of

tuberculosis by DNA amplification. It is moresensitive than bacteriological culture, and it isparticularly recommended for the early diagnosisof tuberculous meningitis, tuberculous pleurisyand tuberculosis in human immunodeficiency virus(HIV)-positive patients.8

A new bronchoscopic sign

Pulmonary veno-occlusive disease (pulmonary vas-cular occlusive disease) is a rare disorder of un-known aetiology affecting children and youngadults, who present with dyspnoea, signs of pul-monary hypertension, cyanosis, fine crepitations,and the chest X-ray must show bilateral patchy



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consolidation. In a recent case report, fibreopticbronchoscopy showed a most unusual and pre-viously unrecognized appearance.9 The tracheaand main bronchi were normal but the lobar andsegmental bronchi showed intense hyperaemiawith vascular engorgement in the form of brightred longitudinal streaks. The sharp demarcationbetween normal main bronchi and the very redlobar and segmental bronchi is due to the venousdrainage of the bronchial tree. The trachea andmain bronchi drain into the bronchial veins, whichwere presumably normal. The more peripheralbronchi drain into the pulmonary veins, whichwere congested by the occlusive process.

Langerhans'pulmonary dendritic cells

Paul Langerhans (1847-1888) was born andstudied medicine in Berlin and became professor ofpathology in Freiburg. He is remembered by theislets of Langerhans and posthumously by Langer-hans' pulmonary dendritic cells. They are found inthe peribronchial connective tissue and in thealveolar parenchyma. As in the skin, they arederived from less sophisticated indeterminate den-dritic cells. It would be interesting to know whatmediators convert these dendritic cells into sophis-ticated Langerhans' macrophages, which are fre-quently seen in zones of alveolar hyperplasia andalveolar metaplasia induced by tobacco or otherinflammatory insults. The French'" remind us thatLangerhans' pulmonary macrophages are wellworth studying for they have a potent capacity forpresenting antigen to lymphocytes, and thereby asignificant role in the pulmonary immune responseand in the pathogenesis of histiocytosis X, nowrenamed Langerhans' granulomatosis or Langer-hans' cell histiocytosis, and in pulmonary lym-phomas. Langerhans' X or HX cells have a cleavednucleus with a finely dispersed chromatin patternwithin an eosinophilic cytoplasm. Electron micros-copy reveals pentalaminar structures within thiscytoplasm.

These cells are described under the headingTechniques because their prominence and impor-tance are being increasingly recognized and theywill repay further study to analyse their role insystemic diseases.

Mediastinal sonography

Wernecke, a Munster radiologist, pioneered sup-rasternal and parasternal mediastinal sonography,and has now applied this technique to guidance ofpercutaneous mediastinal tumour biopsy."The essential criterion for selection of patients is

the availability of an avascular approach to themediastinal tumours, so sonographic guidance ismainly suitable for the biopsy of anterior medias-

tinal and supra-aortic tumours. Accidental punc-ture of the mediastinal vessels, which is not uncom-mon under fluoroscopic guidance, can be largelyavoided with exact computed tomography guidedplanning of the biopsy route. In addition, the exactlocation of the needle tip in the target lesion can bereviewed before biopsy. The specimens obtainedwere lymphoma, bronchial carcinoma, metastases,carcinoid, thyroid cyst and haematoma. Its value isto distinguish a primary mediastinal tumourrequiring surgery from systemic lymphatic malig-nancy. This technique is simple, rapid and accur-ate, and provides yet another window to the lungs.

Intravascular ultrasound

Transthoracic and transoesophageal echocardio-graphy can reveal evidence ofpulmonary embolismbut only to the mainstem and central parts of theleft and right pulmonary arteries. Intravascularultrasound probes the periphery of the pulmonaryvascular bed.'2 A catheter is introduced via aguidewire into the main trunk of the pulmonaryartery and advanced into the left and right pul-monary trunk. It could be advanced into vesselssmaller than 1 cm in diameter. The catheter isconnected to an ultrasound device and the sono-grams are stored on videotape. It should be possi-ble to use an indwelling catheter to monitorthrombolytic therapy in pulmonary embolism.

Apoprotein-A concentration in sputum

Pulmonary alveolar proteinosis (PAP) is a disordercharacterized by accumulation of surfactant mat-erials in alveoli. It may be recognized by broncho-alveolar lavage for the wash is milky due tointra-alveolar accumulation of periodic acid-Schiffpositive proteinaceous material. The predominantphospholipid-associated glycoprotein in pulmon-ary surfactant is surfactant aprotein A (SP-A). Thismay be measured in sputum using monoclonalantibodies to SP-A.Sputum concentrations of SP-A were found in

this Japanese study to be 400 times higher in PAPthan in controls."3 This simple non-invasive tech-nique must be an attractive alternative to anyinvasive procedure.

Wegener's granulomatosis (WG)

In last year's review, we reported that FriedrichWegener lived in happy retirement in Lubeck,Germany. This year it is sad to report his death on 9July 1990, aged 83 years.'4 He lived to see tworemarkable advances in the disorder which bearshis name. He lived to see the introduction ofa mosthelpful diagnostic blood test; anti-neutrophil cyto-



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plasmic antibodies (ANCA) are identified in serumof patients with Wegener's granulomatosis byimmunofluorescence microscopy using alcohol-fixed normal human neutrophils. He also derivedconsiderable joy from the second advance, namelytreatment of the disease. When he first describedthe disorder in 1936 it carried a 100% mortality. Inthe succeeding 50 years, he witnessed the introduc-tion of corticosteroids, cyclophosphamide andantibiotics, all of which have combined to reducethe mortality to a more manageable 5%. He wasthrilled to feel that earlier diagnosis by a non-invasive procedure led to earlier effective treatmentand a substantial improvement in prognosis.The National Institutes of Health, Bethesda,

have recently analysed the pulmonary pathologicalfeatures in 87 open lung biopsies from 67 patientswith WG, and illustrated the wide variation andbroad spectrum of pathological changes ob-served.'5 The three useful diagnostic criteria wereparenchymal necrosis, vasculitis, and granulo-matous inflammation accompanied by aninflammatory infiltrate of plasma cells, neut-rophils, lymphocytes, histiocytes and eosinophils.Parenchymal necrosis comprised neutrophilicmicroabscesses or areas of geographic necrosissurrounded by palisading histiocytes and giantcells. Granulomas were poorly formed with scat-tered giant cells. Vasculitis was almost alwayspresent in arteries and veins; commonly necrotizingand granulomatous with cicatricial changes and,infrequently, fibrinoid necrosis. Minor changeswere alveolar haemorrhage, bronchiolitisobliterans with organizing pneumonia (BOOP)and nodular interstitial fibrosis.

Despite a diagnostic blood test and histologicalfeatures of a granulomatous vasculitis there con-tinue to be diagnostic difficulties. This is evident bya recent case report of a patient with a T celllymphoma of the lung mimicking WG.16 Thebronchial biopsy was compatible withWG, ANCAwas positive, and the initial response to cyclophos-phamide and prednisolone was most encouraging.However, 5 months after presentation a repeatbronchial biopsy revealed lymphoma and under-lined the dictum 'all that glisters is not Wegener'sgranulomatosis'.

Occupational lung disease

Asbestos

After deposition of asbestos, the initial lesion is anaccumulation of alveolar macrophages in thealveolar ducts and peribronchial region adjacent tothe terminal respiratory bronchiole. This is thick-ened by interstitial macrophages and later byfibroblasts; and type 1 alveolar cells are injured by

this process and by mediators released by macro-phages as they phagocytose free asbestos fibres.These chemical mediators include fibronectin,platelet-derived growth factor, alveolar macro-phage-derived growth factor and insulin-likegrowth factor. What starts insidiously and progres-ses inexorably ends lethally with the developmentof interstitial and pleural fibrosis, mesothelioma,lung cancer and gastrointestinal malignancy. Thesecostly diseases are well-reviewed in an authoritativerecent state of the art.'7 The processes ofinflammation, fibrosis and carcinogenesis appearto be closely interwined; proto-oncogenes areupregulated in activated alveolar macrophagesfrom fibrotic lungs. Furthermore asbestos cantransfect DNA into cells. Cigarette smokingprepares a highly metaplastic bronchial epitheliumand so provides co-carcinogenicity.

Circumscribed pleural plaques and diffuse pleur-al thickening, collectively termed pleural fibrosis, isthe most common radiographic manifestation ofasbestos exposure. Its development is dependent onthe cumulative dose of asbestos exposure and theelapsed time since the first exposure. Autopsystudies and computed tomographic (CT) scanssuggest that the standard chest radiograph onlyidentifies about 50-80% of the pleural plaquesthat are actually present.'8 This is disclosed by arecent survey at the London Chest Hospital, inwhich CT scanning was compared with chestradiography in 20 patients with asbestos-inducedpleural disease.'9 CT scan always reveals involve-ment in the paravertebral area. CT demonstrateddiscrete plaques in 95% of patients but these wereonly identified in 59% of patients by chest radio-graphy. Diffuse pleural thickening was evident onthe CT scan in all patients and in 70% on theradiograph. CT and chest radiograph scores in-versely correlated with all lung function measure-ments except KCO. Increasingly extensive pleuraldisease is associated with increasingly severe im-pairment of lung function. The superiority of CTmay be important for those claiming state compen-sation for asbestos-induced disease.

Clay dyepneumoconiosis

This benign pneumoconiosis among rush matworkers is only seen in Japan. The rush mat (tatamiand fancy mat) is treated with a clay dye whichcontains quartz, chlorite, kaolin and sericite, with ahigh free silica content. The rush is dipped into a40% colloidal soluton ofclay dye, which imparts tothe mat a silver-green hue and also a certain degreeof elasticity essential for matting purposes.20 In thecourse of 10 years, the chest X-ray reveals smallround opacities less than 1.5 mm in diameter,distributed throughout the lungs. The histopath-ology is of small pneumoconiotic weakly fibrotic



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nodules composed of macrophages phagocytosingor attached to dust particles around peripheralperivascular and alveolar regions. The diseaseprocess shows fine dust foci but only a weaktendency to progress to fibrosis, possibly becausethe clay coats free silica thereby reducing fibrogenicpotential.

Hut lung

Occupational lung disease is more common in menbut clay dye pneumoconiosis is frequent in Japan-ese women workers, and hut lung is a domesticallyacquired pneumoconiosis in women from the Tran-skei district of South Africa.2' Its alternative nameis Transkei silicosis. It is due to silica particlesinhaled when they are hand-grinding maize be-tween rocks in poorly ventilated huts. The maizekernels are ground between an oblong top rock,which is handled, and a large base rock on theground. Twenty-five women were studied by CapeTown workers, who report that most women weresymptom-free but radiological findings rangedfrom a military pattern to extensive fibrosisresembling progressive massive fibrosis. Autopsieson two patients who died from respiratory failureconfirmed features of silicoanthracosis. This dom-estically acquired pneumoconiosis is not only dueto maize grinding but also due to smoky wood-fuelled stoves in poorly ventilated huts; hence themore appropriate term 'hut lung'.

SWORD

This stands for Surveillance of Work-related andOccupational Respiratory Disease.22 Members ofthe British Thoracic Society set up a reportingscheme for this endeavour in which yellow cardsare returned concerning any patients with possibleoccupational lung disease. The SWORD schemewill provide an important base of information,from which we may track trends and monitor theefficacy of preventive measures in respiratorydisease.

Papworth Hospital, Cambridge

The Tim Higgenbottam-John Wallwork teammaintain standards of excellence in their pioneer-ing human lung transplantation programme,which is still in its infancy compared with otherforms of organ transplantation. Improved surgicaltechnique, preservation of donor organs, andcyclosporin have been important advances, butthese advances have been offset by acute pul-monary infections, fatal obliterative bronchiolitis,and chronic rejection. Chronic rejection is themajor cause of death of long-term survivors of

heart-lung transplantation. In a Papworth seriesof 61 patients who had received heart-lung trans-plants, 7 patients developed chronic rejection, 4died with extensive obliterative bronchiolitis, 12have shown lung fibrosis, and opportunistic lunginfections resulted in pneumonia on 19 occasions.23Herpes simplex virus infection is sufficiently fre-quent to warrant prophylactic acyclovir for the first2 months after surgery and at times of augmented

24immunosuppression .2Early detection and prompt treatment of acute

rejection is an essential step in the prevention of thecrippling obliterative bronchiolitis ofchronic rejec-tion. Close monitoring of lung function withregular routine and diagnostic transbronchial lungbiopsy enables accurate diagnosis ofacute rejectionand may have lessened the incidence of chronic

25rejection.Papworth has a wider range of interests than just

the transplant programme for they have alsoinvestigated impairment of endothelium-derivedrelaxing factor (EDRF) in the pulmonary circula-tion in chronic hypoxic lung disease. Endothelium-dependent pulmonary artery relaxation in vitro isimpaired in arteries from patients with end-stagechronic obstructive lung disease compared withcontrol pulmonary arteries from patients undergo-ing lobectomy for lung carcinoma. The responsesof all vascular rings to the endothelium-dependentvasodilators, acetylcholine and adenosine diphos-phate, were studied immediately after lung ex-cision. The impairment may contribute to thedevelopment of pulmonary hypertension in chron-ic hypoxic lung disease.26

Endothelin-l, a potent endothelium-derivedvasoconstrictor peptide, has been studied in Que-bec, and, in particular, its role in pulmonaryhypertension, by measuring its concentration inarterial and venous plasma.27 Patients with pul-monary hypertension were found to have substan-tial alterations in plasma immunoreactive endo-thelin- 1, reflecting changes in net release orclearance by the lung. In patients with primarypulmonary hypertension, the high levels in arterialcompared with venous plasma suggest pulmonaryproduction of endothelin- 1 which may contributeto pulmonary vascular resistance.

Tuberculosis

Can we eradicate tuberculosis?

In April 1989, Dr Louis Sullivan, US Secretary ofHealth and Human Services announced his en-dorsement of the goal of eliminating tuberculosisfrom the United States by the year 2010. Thislaudable ambition has led to an Advisory Commit-tee for the Elimination ofTuberculosis and its joint



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curriculum with the American Thoracic Societyand the Centers for Disease Control, Atlanta; allgreatly respected bodies. The most recent docu-ment developed by these groups is an excellent'Core Curriculum on Tuberculosis', obtainablefrom Technical Information Services, Center forPrevention Services, Atlanta, Georgia.28 It encom-passes epidemiology, transmission and path-ogenesis of tuberculosis, diagnosis, preventivetherapy and treatment. An estimated 10 ,millionpersons in the USA are infected and about 90% ofnew cases arise from this already infected pool. In1986, after three decades of steadily decreasingtuberculosis morbidity, there was a turnaroundincrease in annual tuberculosis morbidity largelydue to patients with acquired immunodeficiencysyndrome (AIDS), but also due to medicallyunderserved low-income populations and Afro-Asian and Latin American migrants. Other high-risk groups who particularly need to be screenedare alcoholics, intravenous drug users, residents oflong-term care facilities (including prisons) andsome health care workers. Much of this is alreadywell accepted but it needs to be restated as tuber-culosis soars in New York.29 Its prevalence in thiscity in 1990 was 46 cases per 100,000, which is fivetimes the national average. Moreover a case-control survey has shown nosocomial spread ofdrug-resistant tuberculosis in some of the city'shospitals. This may lead to the resurrection oftuberculosis sanatoriums in one of the most sophis-ticated cities in the most productive country in theworld. There is similar frightening emergence ofdrug-resistant tuberculosis in drug addicts inItaly.30 The global toll of tuberculosis is worldwide,a fact emphasized by recent figures of the ChiefMedical Officer, Tuberculosis Unit, World HealthOrganisation.3" In 1990, there were 8 million newcases of tuberculosis in developing and indus-trialized countries; 95% in the former and 5% inthe latter. The worldwide pool of infected personsis 1,722 million, nearly one-half living in South-East Asia and the Western Pacific. Africa has anincidence of272 cases per 100,000. The incidence oftuberculosis in Hong Kong is 124 per 100,000 perannum, which is considerably more than in thewhite population in the UK. This has led to awarning that clinicians must be alerted to thepossibility of tuberculosis, particularly its extra-thoracic form, in migrants from Hong Kong whenthe lease back occurs in 1997.32The Medical Research Council in conjunction

with the Hong Kong Chest Service and the Sing-apore Tuberculosis Service have recently updatedtheir results of the chemotherapy of tuberculosis.The conduct of these continuing trials are elegant,and their design continues to command worldrespect. They are recommended reading in theirentirety.33 34

Mycobacterium avium- intracellulare (MAI)

Organisms of this complex comprise two closelyrelated species, M. avium and M. intracellulare.They have little virulence in the normal host, andchest physicians used to recognize them as anuncommon cause of pneumonia in patients withchronic lung disease. Those were the days beforeAIDS. They are now of considerable clinicalimportance in the AIDS population. By 31 De-cember 1990, there were 12,202 cases of dissem-inated non-tuberculous mycobacterial infectionamong the 161,073 patients with AIDS reported tothe Atlanta Centers for Disease Control.3s M.avium complex, and also cytomegalovirus infec-tion, become apparent when cell-mediated immun-ity is considerably depressed with CD4+ countsreduced to 100 or less cells/mm3. Clinical presenta-tions include fever, night sweats, weight loss (allsuggesting toxicity by tumour necrosis factor),pneumonia and endobronchial lesions as well asseveral extrathoracic lesions. Antimycobacterialagents include amikocin, ethambutol, streptomy-cin, ciprofloxacin and clofazimine. Horsburgh'sauthoritative review should be consulted for de-tailed management of this fatal disorder.35

Fungal infection

The Journal of Antimicrobial Chemotherapy hasproduced an excellent supplement on develop-ments in the management of fungal infection.36 Itcontains succinct accounts of invasive pulmonaryaspergillosis, rhinocerebral mucormycosis, pul-monary cryptococcosis, new approaches to sero-diagnosis, and the advent of fluconazole anditraconazole. The recognition of polyvalent andmonoclonal antibodies to the major fungal patho-gens has led to the marketing of diagnostic kits forthe detection of circulating antigens in body fluids.Monoclonal antibodies to cell wall and cytoplas-mic components of Cryptococcus neoformans andHistoplasma capsulatum have been described. La-tex particle agglutination and double antibodyliposomal-based formats are being marketed forsystemic candidosis and invasive aspergillosis.Chromosomal DNA probes may lead to the detec-tion of fungal elements in clinical specimens. Thissupplement is worth consulting in its entirety.

Invasive candidiasis is a major nosocomial infec-tion that is difficult to diagnose. It has now beenfound that the presence of candida enolase in theblood is a novel marker for invasive candidiasis. Itappears to be a useful indication of deep infectionin patients with cancer and neutropenia; it com-plements the diagnostic usefulness of blood cul-tures.37 The British Society for AntimicrobialChemotherapy Working Party have set out the



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indications for, and interpretation of, the tests thatcan be done with the major antifungal drugs inclinical use at present.38 They pay particular atten-tion to flucytosine, ketoconazole, fluconazole anditraconazole. They set out sensitivity tests, assaysof serum concentration, and regimens for adminis-tration of flucytosine in renal impairment, linkingthe dose with creatinine clearance. This is the typeof article that will help the chest physician when heis faced with a respiratory mycosis.

BOOP

The name has stuck in the international literatureso we must learn to recognize it for it is steroidsensitive, treatable and reversible. It stands forbronchiolitis obliterans organizing pneumonia(BOOP), which envelops two or perhaps even moreconditions, but particularly cryptogenic organizingpneumonia and obliterative bronchiolitis.394' TheFrench4' recognize BOOP as a clinico-pathologicalentity with a well-recognized morphogenesis.Diffuse alveolar injury leads to basement mem-brane denudation and intra-alveolar exudate offibrinogen, immunoglobulins, coagulation factorsand fibronectin. Interstitial fibroblasts migrate intoalveoli through denuded gaps in the epithelialbasement membrane. The final step is the secretionof collagens I, III, V and fibronectin by fibroblastsforming a loose connective tissue fibrosis, which issurprisingly reversible. The diagnosis is confirmedby lung biopsy and it is usually steroid-responsive.It may be associated with primary biliary cirrhosis,the CREST syndrome and digital vasculitis and itmay well overlap with various connective tissuedisorders. Within the orbit of these overlap syn-dromes is the association of cryptogenic organiz-ing pneumonitis with rheumatoid arthritis.42 TheFrench43 have undertaken a wide survey of pleuro-pulmonary disease in rheumatoid arthritis, em-ploying lung function tests, bronchoalveolarlavage and high resolution computed tomography.In this series nearly 50% of patients with rheum-atoid arthritis had pleuropulmonary manifesta-tions. This was particularly evident in men withsubcutaneous nodules and positive rheumatoidfactor. Bronchiolitis obliterans induced by penicil-lamine was the most severe iatrogenic feature, butthey also observed hypersensitivity pneumonitisrelated to low dose methotrexate.

If you, dear readers, have reached thus far onBOOP, then you should take two further interest-ing academic steps. First, enjoy the Case Recordsof the Massachusetts General Hospital concerninga 68 year old man admitted with respiratorysymptoms and an abnormal chest X-ray. Don'tcheat by looking for the diagnosis at the end of thearticle. Just work out, step by step, your British

management of this American patient." When youhave done so you are nearly home and that meansreading Geddes' splendid editorial summarizing allviews on BOOP and COP.45 It brings it all intoperspective for another year or so. The fact that thesame pattern of events occurs as a result ofinfections, drugs and connective tissue disorderssuggests that it is not a single clinicopathologicalentity but rather one way in which the lung mountsan inflammatory response to a range of differentinsults. The term BOOP is probably best restrictedto those cases of unknown cause.45

What shaU we call this syndrome?

The title of the article is too cumbersome foreveryday use but the chest physician should beaware of it in women aged 45 years or sowith pulmonary fibrosis and various multisystemsigns.' These include Raynaud's phenomenon,polyarthralgia, polymyositis, sclerodactyly, ker-atoconjunctivitis sicca, dysphagia, facial telangiec-tasis, hepatitis, subcutaneous calcinosis, tendonitisand clubbing. The majority of patients have agreatly elevated sedimentation rate, raised serumimmunoglobulins, and a third have a positiverheumatoid factor. The common laboratory find-ing in this series was the presence ofautoantibodiesagainst aminoacyl-tRNA synthetase; either histi-dyl-tRNA synthetase (anti-Jo 1) or alanyl-TRNA(anti-PL12) or threonyl-tRNA (anti-PL7) syn-thetase. The most important clinical determinantof outcome in this group of patients was theseverity of the interstitial pulmonary disease. Fivepatients had transbronchial lung biopsies whichshowed features of interstitial lung fibrosis, twopatients had chronic inflammatory cell infiltratesand one patient had evidence of active alveolitiswith infiltrations of polymorphonuclear cells. Nobiopsy showed evidence of vasculitis. Varioustreatments included prednisolone, azathioprine,cyclophosphamide, methotrexate, cyclosporin andtotal body irradiation.

Neoplasia

Non-small cell lung cancer (NSCLC)

A whole volume of the US Current Problems inCancer is devoted to non-small cell lung cancer,comprising squamous, large cell and adenocar-cinoma, and forming 75% of lung cancer in theUnited States.47 Genetic mutalions in dominantoncogenes such as K-ras, loss ofgenetic material onchromosomes 3p, llp and 17p, and deletions ormutations in tumour suppressor genes such as rband p53 have been documented in these tumour cell



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lines. NSCLC arises in a setting of bronchialmetaplasia and dysplasia due to cigarette smokingand other pollutants. The prognosis is based onextent of tumour dissemination, ambulatory stateand weight loss. Stages I and II NSCLC areconfined within the pleural reflection, Stage III hasextended through the pleura or metastasized toipsilateral or subcarinal lymph nodes and StUIge IVis characterized by distant metastases. Stages I andII are managed by surgical resection with approx-imate 5-year survival of45% and 25% respectively;Stage III by a combination of resection andradiotherapy with a 5-year survival of 15%. StageIV NSLC has a 5-year survival of less than 1%despite chemotherapy.Growth hormone is a secretory product of some

primary bronchial neoplasms and has been asso-ciated occasionally with the development ofhypertrophic pulmonary osteoarthropathy andacromegaly. It may also be associated with fingerclubbing.'8 Increased plasma growth hormoneslevels correlated with clubbing; following chemo-therapy in one patient hormone levels fell tonormal and clubbing completely resolved. Furtherstudies are needed to decipher whether the hor-mone is secreted by the tumour cells or thesurrounding lung or from the pituitary after itsstimulation by growth hormone releasing hor-mone.

There is renewed interest in the expression ofABO blood-group antigens in relation to thedevelopment of lung cancer. Expression of blood-group antigen A in tumour cells is an importantfavourable prognostic factor in patients withNSCLC.4' The authors of this report suggest thatthis factor should be taken into account whenstratifying patients in future clinical trials toevaluate the efficacy of post-operative adjuvantchemotherapy. Patients who are negative forblood-group antigen A seem to merit aggressivetherapeutic approaches in view of their poorerprognosis; perhaps chemotherapy and irradiationas an alternative to immediate surgery.The Belgians have applied meta-analysis on

studies of chemotherapy of NSCLC, involving atotal of 6,247 patients. Polychemotherapy had asignificantly better response rate than mono-therapy, and the best results were associated withcisplatin, vindesine, vinblastine, mitomycin C andifosfamide.5 These differences were most obviousin those with limited rather than disseminateddisease.Workers at Yale University have tried to over-

come the bleak outcome of Stage Illa NSCLC bypre-operative (neoadjuvant) chemotherapy in or-der to decrease tumour bulk so that inoperablepatients become surgical candidates.5'

Lymphoma

A joint Anglo-American study of AIDS-relatednon-Hodgkin lymphoma analysed cases reportedto the Centers for Disease Control, Atlanta, up to30 June 1989. During this period 97,258 AIDScases were reported, of whom 2,824 (2.9%) hadnon-Hodgkin lymphoma: a condition that wasabout 60 times more common in AIDS patientsthan in the general US population.52 It was twice ascommon in whites as in blacks and in men as inwomen. It was most common in patients withhaemophilia or clotting disorders and least com-mon in those born in the Caribbean or Africa whohad acquired HIV by heterosexual contact. Infec-tious agents, particularly Epstein-Barr virus, areassociated with lymphoma in these immunosup-pressed patients. The most difficult question is whyBurkitt's lymphoma is commonly associated withHIV infection but not with other types ofimmuno-suppression.The European Lymphoma Co-operative Group

have studied 772 patients with early-stage Hodg-kin's disease, and assessed the value of an elevated(>30 mm/h) Westergren erythrocyte sedimenta-tion rate (ESR) for predicting early relapse andsurvival after therapy in patients with clinical StageI or II Hodgkin's disease. An unexplained elevatedESR after therapy, especially modern radiother-apy, strongly suggests the presence of aggressiveand resistant Hodgkin's disease. An elevated ESRis predictive ofearly relapse and poor prognosis; itspresence justifies early aggressive therapy.53Another test which provides useful prognostic

information in low-grade lymphoma is the serumP-2 microglobulin (P-2M) level. It has been eval-uated in 80 previously untreated Stage I to IVpatients in Houston.54 P-2M is a low molecularweight polypeptide, the light-chain molecule of themajor histocompatibility complex class 1 antigens.It is found on the membrane surface of almost allnucleated cells, and its membrane turnover is theprincipal source of P-2M in the blood and bodyfluids. The complete remission rate for patientswith P-2M level of 3 mg/l or greater was 36%compared with 71% for those with a level of lessthan 3 mg/I. The mechanism is possibly thattumour cells release P-2M through membraneturnover. A similar helpful prognostic value isnoted in myeloma, in which patients with thehighest values have the shortest survival.

Sarcoidosis

Last year's review of respiratory diseases did notinclude sarcoidosis. As a result of this omission, wereceived several letters enquiring whether we hadlost our taste and zest for this obsession of ours.



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168 D.G. JAMES

Not so. This year has much more to include for inSeptember 1991 was held the XII World Congresson Sarcoidosis in Kyoto, Japan, organized underthe auspices of the World Association of Sar-coidosis and Other Granulomatous Disorders(WASOG). The Proceedings of this Congress willappear as a special supplement of the journal,Sarcoidosis.55 Indeed, as you read this article so willthe supplement be available to update you on whatsarcoidologists from 23 countries think aboutsarcoidosis and other granulomatous disorderssuch as Wegener's granulomatosis, summertimehypersensitivity pneumonitis, eosinophilic granu-loma and occupational granulomatoses.

Sarcoidosis is published in Milan, Italy, in Eng-lish every March and September. Each issue con-tains about 86 pages of articles on all aspects ofsarcoidosis and other disorders which mimic it. It isalso a thesaurus or treasure trove of informationconcerning conferences, events and news aroundthe world.An ambitious enterprise of the Kyoto conference

was an epidemiological survey of sarcoidosis in 16cities around the world. It analysed 2,702 new casesseen during 1981-1985, with women comprising62% ofthe total. The age at presentation was in the20-50 year range in 78% ofthis series. Histologicalconfirmation of the diagnosis is now frequentlyobtained by fibreoptic bronchoscopy and trans-bronchial biopsy. Open lung biopsy, scalene nodeand mediastinal lymph node biopsy are no longerpopular. All patients in this series had intrathoracicsarcoidosis. The tempo of the disease varies withthe community in which it is studied. The blackpopulation in the US and the West Indians inLondon often have severe, extensive and cripplingdisease whereas it is mild and with a high spon-taneous rate of resolution in the Irish. Just asLondon sees much sarcoidosis among its migrantsfrom the West Indies so does Paris see it in itsmigrants from Martinique, and New York City inits Puerto Rican-born population. Is this due togenetic predisposition or environmental factorsconfronting susceptible individuals migrating froma rural to an urban community? Is the breedingground for sarcoidosis in their native homeland orwithin the sophisticated new world in which theyadapt themselves? It may be a bit of both worlds.

The road from granuloma to fibrosis

Antigenic invasion by micro-organisms or chemi-cals or cancer is met by a granulomatousinflammatory response involving close interplaybetween activated macrophages bearing increasedexpression of major histocompatibility (MHC)Class II molecules and CD4 + lymphocytes. TheseCD4 cells help to initiate a cascade of chemotactic

factors including interleukins 1 and 2 (IL- 1 andIL-2), macrophage-activating and macrophage-inhibiting factors and gamma interferon. Themajority of T-cells bear the T-cell receptor (TCR)ap complex but a very small subpopulation bear adistinct TCR composed of gamma and deltasubunits in lymphoid organs and skin. This smallsubpopulation of TCR '6 lymphocytes is prom-inent in leprosy, leishmaniasis and sarcoidosis, allchronic granulomatous disorders which seem torespond to mycobacterial stimulation.56What of the lymphokines involved in this

granulomatous response? Pulmonary alveolarmacrophages harvested in bronchoalveolar fluid ofsarcoidosis patients release tumour necrosis factorin vitro in response to Escherichia coli endotoxinlipopolysaccharide and spontaneously.56'57 Thosewho have lived through the long history of claimsfor mycobacteria or their mucopolysaccharides asthe causes of sarcoidosis will now recall, amongstothers, the pine pollen theory of sarcoidosis. Pinepollen was acid-fast staining and resembled thewax fraction ofthe tubercle bacilli. Have we arrivedback in square one of the aetiology of sarcoidosis?58The sarcoid granuloma also produces angio-

tensin-converting enzyme, calcitriol, metallopep-tidase and lysozyme, and the road to fibrosis ishastened by collagenase, type III procollagen N-terminal peptide, hyaluronic acid and fibronectin.The chest physician's road to fibrbsis would be

incomplete nowadays without hoardings extollingthe importance of molecular biology and macro-phage-derived growth and progression factors. Donot progress along this road without first consul-ting an excellent topical review by Shaw."9 It issophisticated and academic but he also has aChurchillian quality to make it readable andenjoyable. He suggests that the macrophage is theconductor of fibrotic events and plays a role viaplatelet-derived growth factor (PDGF) as gate-keeper in regulating the transition from inflamma-tion to fibrosis, aided and abetted by gamma-interferon (IFN-') from neighbouring lym-phocytes. He suggests that in sarcoidosis there maybe a conflict between the profibrotic influence ofIFN-y on macrophage PDGF gene activation, andthe antifibrotic effects of combinations of IFN-',tumour necrosis factor and interleukin I on thefibroblast.

Immunomodulation

Immunotherapy has become a major branch oftherapeutics, but, like Janus, it is two-headed.Immunomodulators may overcome adverse im-mune reactions, but they also depress immunityand lower resistance against infection. These arethe twin dilemmas confronting every transplant



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team, and of particular importance to the chestphysician. Corticosteroids, azathioprine, cyclo-phosphamide and chlorambucil are already wellrecognized and used worldwide. They are nowbeingjoined or supplanted by cyclosporin, FK 506,interferons, immunoglobulins and RSCD4 (TableIII). The chest physician must keep abreast of theirexpanding use since he is called upon to deal withthe immunocompromised patient with recurrentinfections.

Cyclosporin

Cyclosporin (BP) or ciclosporin (WHO), derivedfrom a Norwegian fungus, is an undecapeptidewith a cyclic sequence of 11 amino acids. It isavailable as an oral solution, as capsules, and as anintravenous infusion. It acts by inhibiting inter-leukin 2 (IL-2), produced by certain cytotoxicT-helper cells, which recognize and kill targetantigens, including foreign transplants. Cyclo-sporin is now enjoying an expanded role in themanagement ofmany autoimmune disorders, skindiseases and in ophthalmology (Figure 1). It wouldbe used more frequently but for its nephrotoxicityand other unpleasant side effects. It is being used inSouth Africa with some success as a corticosteroid-potentiating agent in cryptogenic fibrosing alveo-litis and progressive symptomatic interstitial lungdisease of unknown aetiology.1

FK 506

Since cyclosporin is toxic, there is a continuingsearch for alternatives. FK 506, a Japanese dis-covery, is a macrolide produced by Streptomycestsukubaensio, and in some respects is similar toerythromycin. It is much more powerful thancyclosporin in inhibiting IL-2 synthesis and theexpression of IL-2 receptors, even though it ischemically unrelated. In Pittsburgh, liver trans-plant patients, whose plight was desperate becausetheir liver grafts were being rejected despite con-ventional immunosuppression, are leading normallives on FK 506 alone.61 They are well withoutcorticosteroids and azathioprine. It is now under-going intensive clinical trials in Britain. It may besight-saving in Behcet's disease (Ohno, personalcommunication).

Interferons

Human interferons are a family of proteins whichactivate intracellular oligo-adenylate synthetase tointerfere with and inhibit viral RNA. This inter-ference led to their name interferon. They have awide range of antiviral and antitumour effects.Interferon is prepared by recombinant technology,and is available as a megaunit dosage for sub-cutaneous, intramuscular, intravenous, intrathecal

and intralesional use. Trials are under way to assessits role in viral infections, malignancy and autoim-mune disorders, in conjunction with other treat-ments. For patients with chronic granulomatousdisease, interferon gamma therapy is an effectiveand well-tolerated treatment that reduces the fre-quency of serious infections.62

Immunoglobulins

Intravenous immunoglobulin preparations arenow much improved compared with the outdatedintramuscular preparations. It can be administeredin a larger dose, minimizing the anaphylacticreactions of the old intramuscular versions. It isprepared from pooled human plasma and providespassive immune prophylaxis against hepatitis A,measles, rubella in pregnancy, congenital hypo-gammaglobulinaemia and idiopathic thrombocy-topenic purpura.When considering intravenous immunoglobulin

replacement therapy it is important to distinguishand consider particularly those patients who mayhave near-normal immunoglobulin levels but havemarked impairment in their ability to producespecific antibodies after immunisation with poly-saccharide and protein antigens. These are the trulydeficient persons who need replacement immuno-globlin.63,' The National Institute of Child Healthhas conducted a multicentre randomised double-blind placebo (albumin)-controlled trial in 372HIV-infected children and shown that intravenousimmunoglobulin in a dose of400 mg/kg per monthwas effective in significantly increasing the time freeof serious bacterial infections for those childrenwith CD4+ lymphocyte counts <0.2 x 109 perlitre.65The use of intravenous immunoglobulin after

bone marrow transplantation reduced the inci-dence and severity ofinterstitial pneumonia relatedto cytomegalovirus, sepsis and graft-versus-hostdisease.63 It is of value in chronic lymphocyticleukaemia but its cost may be prohibitive.66

Intravenous immunoglobulin has been effectivein immunoregulatory disorders, such as immunethrombocytopenic purpura, immune neutropeniaand the Kawasaki syndrome.'M It blocks the uptakeof antibody-coated cells in the spleen, inhibitsantibody synthesis, and inhibits inflammation. Itmay have a future potential use in polymyositis,Guillain-Barre syndrome, myasthenia gravis andsteroid-dependent asthma.64

Intravenous immunoglobulin is recommendedfor systemic vasculitis.67 Following treatment therewas a fall in circulating anti-neutrophil cytoplasmantibodies (ANCA) and in C-reactive proteinchanges and clearing of radiological charges with-out adverse effects. It was infused at 0.4 g/kg perday for 5 days.



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170 D.G. JAMES

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OPHTHALMOLOGYUveitisBehcet's diseaseAutoimmune retinitisDysthyroid eye diseaseCorneal graftsScleritis

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colitis - DERMATOLOGYPsoriasisLichen planusAtopic eczemaPemphigusPemphigoidAlopecia areataPyoderma gangrenosumDermatomyositis

Figure 1 The expanding uses of cyclosporin.

Others

Table III also draws attention to other immuno-modulators which are on the horizon and appearpromising; next year they may become widely usedif the cost is not prohibitive.' They include recom-binant soluble CD4 polypeptide and IMREG-l forAIDS;69 CD4 monoclonal antibody for psoriasis;70monoclonal antibody (HA-lA; centoxin) forGram-negative septicaemia and septic shock;7' andrecombinant granulocyte-colony stimulating fac-tor (rG-CSF) for neutropenia and infection inpatients treated with cytotoxic chemotherapy fornon-myeloid malignancy and for reduction of feverand neutropenia induced by chemotherapy inpatients with small-cell lung cancer.72

Other treatments

Surfactant therapy

Neonatologists continue to find surfactant helpful,and it is now seen to be a significant advantage toadminister the initial dose as prophylactic ratherthan as rescue therapy in very premature infants.73It is administered into the trachea to preventrespiratory distress syndrome (RDS or hyalinemembrane disease). The first such drug to belicensed in Britain is Colfosceril palmitate (Exo-surf, Wellcome). Treatment has halved the overall

mortality from RDS in premature infants duringthe first week of life, and complications such aspneumothorax are fewer. One vial of Exosurf costs£314 and up to four may be needed to treat onebaby. 74'75

Device-related infection and disinfection

Ten bronchoscopes that had been used on patientswith AIDS were examined for microbial con-tamination by irrigating the suction biopsy channelwith viral transport medium. Samples, tested bypolymerase chain reaction, revealed HIV and also,occasionally, Pneumocystis carinii and commensalbacteria and hepatitis B virus once. Cleaning indetergent and 2 min disinfection in 2% alkalineglutaraldehyde proved effective. HIV is more resis-tant to glutaraldehyde in the presence ofprotein sodetergent precleaning is essential after every bron-choscopy procedure and should not be delayeduntil after disinfection.76The principal life-threatening complication in

patients who have vascular catheters is septi-caemia. To assess the best means of cutaneousdisinfection before insertion of an intravascularcatheter, a prospective study of three antisepticswas undertaken.77 The use of2% chlorhexidine wasfound to be superior to 10% povidone-iodine or70% alcohol before catheter insertion and duringfollow-up care.



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172 D.G. JAMES

References

Techniques1. James, D.G., Rizzato, G. & Sharma, O.P. Bronchopul-

monary lavage (BAL), a window of the lungs. Sarcoidosis1992, 9 (in press).

2. Menzies, R. & Charbonneau, M,. Thoracoscopy for thediagnosis ofpleural disease. Ann Int Med 1991,114:271-276.

3. Wakabayashi, A., Brenner, M., Kayalah, R. et al. Thoracos-copic carbon dioxide laser treatment of bullous emphysema.Lancet 1991, 337: 881-884.

4. Chuen Lee, P. & Hallsworth, P. Rapid viral diagnosis inperspective. Br Med J 1990, 300: 1413- 1418.

5. Littler, E., Baylis, S.A., Zeng, Y., Conway, M.J., Mackett, M.& Arrand, J.R. Diagnosis of nasopharyngeal carcinoma bymeans of recombinant Epstein-Barr virus proteins. Lancet1991, 337: 685-689.

6. Ambroise-Thomas, P. & Cristina, N. Results and prospectsofnew DNA probes and polymerase chain reaction (PCR) intoxoplasmosis. Bull Acad Natle Med 1991, 175: 39-49.

7. Wakefield, A.E., Guiver, L., Miller, R.F. & Hopkin, J.M.DNA amplification on induced sputum samples for diagnosisof Pneumocystis carinii pneumonia. Lancet 1991, 337:1378-1379.

8. Brisson-Noel, A., Aznar, C., Chureau, C. et al. Diagnosis oftuberculosis by DNA amplification in clinical practiceevaluation. Lancet 1991, 338: 364-366.

9. Matthews, A.W. & Buchanan, R. A case of pulmonaryveno-occlusive disease and a new bronchoscopic sign. RespirMed 1990, 84: 503- 505.

10. Soler, P., Tazi, A., Basset, F.F. & Hance, A.J. Les cellulesdendritiques pulmonaires. Rev Mal Respir 1991, 8: 191-196.

11. Wernecke, K. Percutaneous biopsy of mediastinal tumoursunder sonographic guidance. Thorax 1991, 46: 157-159.

12. Gorge, G., Erbel, R., Schuster, S., Ge, J. & Meyer, J.Intravascular ultrasound in diagnosis of acute pulmonaryembolism. Lancet 1991, 337: 623-624.

13. Masuda, T., Shimura, S., Sasaki, H. & Takishima, T. Surfac-tant aproptein-A concentration in sputum for diagnosis ofpulmonary alveolar proteinosis. Lancet 1991, 337: 580-582.

Wegener's Granulomatosis14. James, D.G. In memoriam: Dr Friedrich Wegener

(1907-1990). Sarcoidosis 1991, 8: 80-81.15. Travis, W.D., Hoffman, G.S., Leavitt, R.Y., Pass, H.I. &

Fauci, A.S. Surgical pathology of the lung in Wegener'sgranulomatosis. Review of 87 open lung biopsies from 67patients. Am J Surg Pathol 1991, 15: 315-333.

16. Small, J.H., Round, A., Simpson, R.H.W. & Ferguson, A.D.Wegener's granulomatosis simulated by a T cell lymphoma ofthe lung. Thorax 1991, 46: 465-466.

Occupational lung disease17. Rom, W.N., Travis, W.D. & Brady, A.R. Cellular and

molecular basis of the asbestos-related diseases. Am RevRespir Dis 1991, 143: 408-422.

18. Schwartz, D.A. New developments in asbestos-inducedpleural disease. Chest 1991, 99: 191-198.

19. Al Jarad, N., Poulakis, N., Pearson, M.C., Rubens, M.B. &Rudd, R.M. Assessment of asbestos-induced pleural diseaseby computed tomography-correlation with chest radiographand lung function. Respir Med 1991, 85: 203-208.

20. Hosoda, Y., Ueda, A. & Fujii, M.D. Clay dye pneumo-coniosis among rush mat workers. Sem Respir Med 1991, 12:55-57.

21. Grobbelaar, J.P. & Bateman, E.D. Hut lung: a domesticallyacquired pneumoconiosis ofmixed aetiology in rural women.Thorax 1991, 46: 334-340.

22. Seaton, A. Surveillance of work related and occupationalrespiratory disease-SWORD. Thorax 1991, 46: 548.

Papworth Hospital23. Scott, J.P., Higenbottam, T.W., Wallwork, J. et al. Natural

history of chronic rejection in heart-lung transplant recip-ients. J Heart Transplant 1990, 9: 510-515.

24. Smyth, R.L., Higenbottam, T.W., Wallwork, J. et al. Herpessimplex virus infection in heart-lung transplant recipients.Transplantation 1990, 49: 735-739.

25. Scott, J.P., Higenbottam, T.W., Clelland, C.A., Smyth, R.L.,Stewart, S. & Wallwork, J. The natural history of chronicrejection in heart-lung transplant recipients: a clinical,pathological, and physiological review of 29 long-termsurvivors. Transplant Proc 1990, 22: 1474-1476.

26. Dinh-Xuan, A.T., Higenbottam, T.W., Wallwork, J. et al.Impairment of endothelium-dependent pulmonary-arteryrelaxation in chronic obstructive lung disease. N Engl J Med1991, 324: 1539-1547.

27. Stewart, D.J., Levy, R.D., Cernacek, P. & Langleben, D.Increased plasma endothelin-l in pulmonary hypertension:Marker or mediator of disease? Ann Intern Med 1991, 114:464-469.

Tuberculosis28. US Department of Health and Human Services. Core Cur-

riculum on Tuberculosis. Centers for Disease Control, At-lanta, Georgia, 1991, pp. 1-40.

29. Charatan, F. Tuberculosis soars in New York. Br MedJ 1991,303: 209.

30. Monno, L., Angarano, G., Carbonara, S. et al. Emergence ofdrug-resistant Mycobacterium tuberculosis in HIV-infectedpatients. Lancet 1991, 337: 852.

31. Kochi, A. The global tuberculosis situation and the newcontrol strategy of the World Health Organisation. Tubercle1991, 72: 1-6.

32. Nisar, M., Williams, C.S.D. & Davies, P.D.O. Experience oftuberculosis in immigrants from Hong Kong-implicationsfor the imminent lease back ofHong Kong. Respir Med 1991,85: 219-222.

33. Hong Kong Chest Service/British Medical Research Council.Controlled trial of 2, 4 and 6 months of pyrazinamide in6-month three-times-weekly regimens for smear-positive pul-monary tuberculosis, including an assessment of a combinedpreparation ofisoniazid, rifampin and pyrazinamide. Am RevRespir Dis 1991, 143: 700-705.

34. Singapore Tuberculosis Service/British Medical ResearchCouncil. Assessment of a daily combined preparation ofisoniazid, rifampin and pyrazinamide in a controlled trial ofthree 6-month regimens for smear-positive pulmonary tuber-culosis. Am Rev Respir Dis 1991, 143: 707-712.

35. Horsburgh, C.R. Mycobacterium avium complex infection inthe acquired immunodeficiency syndrome. N Engl J Med1991, 324: 1332-1338.

Fungal infections36. Spellar, D.C.E. & Warnock, D.W. Developments in the

management of fungal infection. J Antimicrob Chemother1991, 28 (Suppl A): 1- 103.

37. Walsh, T.J., Hathorn, J.W., Sobel, J.D. et al. Detection ofcirculating candida enolase by immunoassay in patients withcancer and invasive candidiasis. N Engl J Med 1991, 324:1026-1031.

38. British Society for Antimicrobial Chemotherapy WorkingParty. Laboratory monitoring of antifungal chemotherapy.Lancet 1991, 337: 1577-1580.

BOOP39. Bellomo, R., Finlay, M., McLaughlin, P. & Tai, E. Clinical

spectrum of cryptogenic organising pneumonia. Thorax1991, 45: 554-558.

40. Woodhead, M.A. & Dubois, R.M. Bronchiolitis obliterans,cryptogenic organising pneumonitis and BOOP. Respir Med1991, 85: 177-178.



j.bmj.com

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j.68.797.160 on 1 March 1992. D

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41. Cordier, J.F., Loire, R. & Peyrol, S. Bronchiolitis obliteransorganising pneumonia (BOOP). Rev Mal Respir 1991, 8:139- 152.

42. Rees, J.H., Woodhead, M.A., Sheppard, M.N. & DuBois,R.M. Rheumatoid arthritis and cryptogenic organisingpneumonitis. Respir Med 1991, 85: 243-246.

43. Perez, T., Dansin, E., Wallaert, B. & Tonnel, A.B. Manifesta-tions pleuro-pulmonaires de la polyarthrite rhumatoide. RevMal Respir 1991, 8: 169-189.

44. Case Records of the Massachusetts General Hospital. Case17-1991. N Engi J Med 1991, 324: 1195-1205.

45. Geddes, D.M. BOOP and COP. Thorax 1991, 46: 545-547.

New syndrome46. Marguerie, G., Bunn, C.C., Beynon, H.L.C. et al. Poly-

myositis, pulmonary fibrosis and autoantibodies to amino-acyl-tRNA synthetase enzymes. Q J Med 1990, NS 77: 282:1019- 1038.

Neoplasia47. Idhe, D.C. & Minna, J.D. Non small cell lung cancer Part 1:

Biology, diagnosis and staging. Current Problems in Cancer.Mosby Year Book 1991, XV: 63-104.

48. Gosney, M.A., Gosney, J.R. & Lye, M. Plasma growthhormone and digital clubbing in carcinoma of the bronchus.Thorax 1990, 45: 545-547.

49. Lee, J.S., Ro, J.Y., Sahin, A.A. et al. Expression of blood-group antigen A - a favourable prognostic factor in non-small cell lung cancer. N Engl J Med 1991, 324: 1084- 1090.

50. Donnadieu, N., Paesmans, M. & Sculier, J.P. Chimiotherapiedes cancers bronchiques non a petites cellules. Meta-analysede la litterature en fonction de l'extension de la maladie. RevMal Respir 1991, 8: 197-204.

51. Murren, J.R., Buzaid, A.C. & Hait, W.A. Critical analysis ofneoadjuvant therapy for Stage Illa non-small cell lungcancer. Am Rev Respir Dis 1991, 143: 889-894.

52. Beral, V., Peterman, T., Berkelman, R. & Jaffe, H. AIDS-associated non-Hodgkin lymphoma. Lancet 1991, 337:805-809.

53. Henry-Amar, M., Friedman, S., Hayat, M. et al. Erythrocytesedimentation rate predicts early relapse and survival inearly-stage Hodgkin disease. Ann Intern Med 1991, 114:361-365.

54. Litam, P., Swan, F., Cabanillas, F. et al. Prognostic value ofserum P-2 microglobulin in low-grade lymphoma. Ann InternMed 1991, 114: 855-860.

Sarcoidosis55. Proceedings of the Twelfth World Congress on Sarcoidosis,

Kyoto, Japan. Sarcoidosis 1992 (Suppl).56. Miyachi, A., Noda, M., Ina, Y. et al. Tumour necrosis factor

in granulomatous lung disease. Sarcoidosis 1989, 6: 80.57. Foley, N.M., Millar, A.B., Meager, A., Johnson, N.M. &

Rook, G.A.W. Tumour necrosis factor production byalveolar macrophages in pulmonary sarcoidosis and tuber-culosis. Sarcoidosis 1992 (in press).

58. James, D.G. What makes granulomas tick? Thorax 1991, 46:734-736.

59. Shaw, R.J. The role of lung macrophages at the interfacebetween chronic inflammation and fibrosis. Respir Med 1991,85: 267-273.

Immunomodulators60. Moolman, J.A., Bardin, P.G., Rossouw, D.J. & Joubert, J.W.

Cyclosporin as a treatment for interstitial lung disease ofunknown aetiology. Thorax 1991, 46: 592- 595.

61. Starzl, T.E., Todo, S., Fung, J. et al. FK506 for liver, kidneysand pancreas transplantation. Lancet 1989, Hi: 1000-1004.

62. International Chronic Granulomatous Disease Co-operativeStudy Group. A controlled trial of interferon gamma toprevent infection in chronic granulomatous disease. N EnglJMed 1991, 324: 509-516.

63. Buckley, R.H. & Schiff, R.I. The use of immune globulin inimmunodeficiency diseases. N Engl J Med 1991, 325:110-117.

64. Stiehm, E.R. New uses for intravenous immune globulin. NEngl J Med 1991, 325: 123-125.

65. The National Institute ofChild Health and Human Develop-ment Intravenous Immunoglobulin Study Group. Intra-venous immune globulin for the prevention of bacterialinfections in children with symptomatic human immuno-deficiency virus infection. N Engl J Med 1991, 325: 73-80.

66. Weeks, J.C., Tierney, M.R. & Weinstein, M.C. Costseffectiveness of prophylactic intravenous immune globulin inchronic lymphocytic leukaemia. N Engi J Med 1991, 325:81-86.

67. Jayne, D.R.W., Davies, M.J., Fox, C.J.V., Black, C.M. &Lockwood, C.M. Treatment of systemic vasculitis withpooled intravenous immunoglobulin. Lancet 1991, 337:1137-1139.

68. Taylor, D. Centoxin-birth of a budgetbuster. Br MedJ 1991,302: 1229.

69. Gottlieb, M.S., Zackin, R.A., Fiala, M. et al. Response totreatment with the leukocyte-derived immunomodulatorIMREG-1 in immunocompromised patients with AIDS-related complex. Ann Intern Med 1991, 115: 84-91.

70. Prinz, J., Braun-Falco, O., Daddona, P. et al. Chimaeric CD4monoclonal antibody in treatment of generalised pustularpsoriasis. Lancet 1991, 338: 320-321.

71. Ziegler, E.J., Fisher, C.J., Sprung, C.L. et al. Treatment ofgram-negative bacteremia and septic shock with HA-IAhuman monoclonal antibody against endotoxin. A rando-mized, double-blind, placebo-controlled trial. N Engl J Med1991, 324: 429-436.

72. Crawford, J., Ozer, H., Stoller, R. et al. Reduction bygranulocyte colony-stimulating factor of fever and neutro-penia induced by chemotherapy in patients with small-celllung cancer. N Engi J Med 1991, 325: 164-170.

Other treatments73. Kendig, J.W., Notter, R.H., Cox, C. et al. A comparison of

surfactant as immediate prophylaxis and as rescue therapy innewborns of less than 30 weeks gestation. N EnglJMed 1991,324: 865-871.

74. Avery, M.E. & Merritt, T.A. Surfactant-replacement ther-apy. N Engl J Med 1991, 324: 910-911.

75. Anonymous. Colfosceril palmitate (Exosurfl-artificial sur-factant for immature lungs. Drug Therapeut Bull 1991, 29:46.

Device-related infection and disinfection76. Hanson, P.J.V., Gor, D., Clarke, J.R. et al. Recovery of the

human immunodeficiency virus from fibreoptic bronchos-copes. Thorax 1991, 46: 410-412.

77. Maki, D.G., Ringer, M. & Alvarado, C.J. Prospectiverandomised trial of povidone-iodine, alcohol, and chlorhex-idine for prevention of infection associated with centralvenous and arterial catheters. Lancet 1991, 338: 339-343.



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