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profession ing. a

whose members

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Letters

At the 1978 Federal Assembly on May 29, the A.M.A. by resolution committed its 15 000 members to the concept of peer review, despite the uneasiness of some and the open opposition of others, including the General Practitioners Society. The passing of this resolution entailed explaining to doctors exactly what was to be meant in the Australian context by peer review. It was made quite clear that it would not mean "a review of the work of doctors by their peers or fellow doctors"; the need for such possible action, it was claimed, was already adequately catered for by ethical committees, committees of inquiry, disciplinary tribunals, and many other systems within and without hospitals. What was meant was that programmes and services in hospitals would be evaluated in terms of predetermined professional standards and operated on that basis. The evaluation would be made initially within a hospital by all the peers involved in a particular procedure, who, having made their "clinical audit," would in effect have to police it and ensure that their colleagues conformed within reason to the prescribed pattern. Well-kept records would of course be mandatory, enabling the "audit" to be reviewed as required. This type of procedure is said to be the only known method of evaluating the quality of hospital services, the appropriateness of admission to hospital, and the length of hospital stay. The A.M.A. was opposed to nationwide bureaucratic administration of peer-review systems, as in the "professional services review organisation" (P.S.R.O.) of the U.S. (the value of which is yet to be proven), and to the idea of Australian State Health Authority involvement, which would inevitably also lead to Government control. It was, however, in sympathy with the Canadian practice which had linked systems of medical-care evaluation to the requirements of hospital accreditation.

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As long ago as the late ’50s an attempt had been made in New South Wales by Dr T. Y. Nelson and Dr E. F. Thomson to introduce to Australia this North American concept of hospital accreditation. Despite many frustrations, the Australian Council on Hospital Standards finally emerged, representative of all medical professional bodies, and as a voluntary and powerful organisation. Hospitals can now apply to the council for the status of accreditation if they have conformed to the standards demanded in the publication The Accreditation

Guide for Australian Hospitals. Other public-spirited members of the medical profession who are concerned about efficiency and costs have already suc-

cessfully introduced peer-review systems for their own hospital specialties, and in one large teaching hospital all medical trainees are required to learn the costs of the equipment used, and of each test carried out, as well as the reasons and justifi-

to

the Editor

LEGIONNAIRES’ DISEASE: RADIOLOGICAL RESOLUTION AND BRONCHOSCOPY

SIR,-Bronchoscopy is often asked for in a patient with delayed radiological resolution after pneumonia. In a previously fit patient with non-cavitating pneumonia radiological changes persist at 4 weeks in only 13% of cases, at eight weeks in less than 3%.’ In legionnaires’ disease, however, resolution is much slower, irrespective of the clinical severity. In thirteen survivors from legionnaires’ disease (L.D.) admitted to this hospital since 1977, radiological changes were seen at 4 weeks in 100% and at 8 weeks in 85%. In July three patients referred to us for bronchoscopy because of delayed resolution of pneumonia were found to have .D., as was a fourth bronchoscoped in February. All have returned to normal health. Case 1.-A 57-year-old man was admitted in 1977 with leftlower-lobe pneumonia, and discharged after 10 days. 3 months later persisting radiological changes were noted. Bronchoscopy was normal. The diagnosis of L.D. was then considered, and confirmed by an immunofluorescent antibody titre (LF.A.T.) of 1 :512 (previously less than 1 :32). Case 2.-A 60-year-old man was admitted in June with lobar pneumonia, confusion, lymphopenia, hyponatrxmia, and hypoalbuminxmia, a combination which suggested L.D.23 Erythromycin was given intravenously, with rapid clinical improvement. I.F.A.T. was only 1:32, and in view of persisting pyrexia and consolidation, bronchoscopy was requested. This was performed four weeks after admission, and was normal. A serum sample taken the next day now had I.F.A.T. 1:1024. Case 3.-A 57-year-old man was transferred from another hospital for bronchoscopy because of slow clinical and radiological resolution of lobar pneumonia. L.D. was considered, and confirmed by LF.A.T. rising to 1:512. The bronchoscopy cancelled. Case 4.-Bronchoscopy was requested in a 68-year-old woman with persisting left-lower-lobe consolidation. 3 months earlier she had had pneumonia while staying in the same Benidorm (Spain) hotel that has been implicated in other cases of L.D. in 19734 and 1977,5 and was admitted to hospital there for 2 weeks. I.F.A.T. was 1:256, so bronchoscopy was not done. Delayed resolution of acute pneumonia in a previously fit patient is a problem familiar to all physicians. We suggest that in such a case legionnaires’ disease should be considered before bronchoscopy is performed. A. C. MILLER Department of Thoracic Medicine, S. B. PEARSON City Hospital, W. H. RODERICK SMITH Nottingham NG5 1PB was

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cations for the tests. The hospital industry of Australia now costs about$2.5 billion per annum, and it is estimated that if 10% of its public hospital beds were closed (many of which are not used and/or are in the wrong districts) a saving of$260 million would result. The bed ratio is high-6.8per 1000 population in N.S.W. Further, if for each patient the period in hospital was reduced by one day, the savings would run into millions of dollars. It seems reasonable, in view of the relative costs, to suggest that paramedical home care might be substituted for many patients in the later stages of a spell in hospital.

The new Guide to Clinical Review, published jointly by the Australian Council on Hospital Standards, the Australian Hospital Association, and the A.M.A., explains to doctors how criteria auditing is achieved and gives examples. It also quotes John Ruskin: "Quality is never an accident. It is always the result of intelligent effort. There must be a will to produce superior work"-to which might be added, at a reasonable cost.

SICKLE-CELL DISEASE: TWO NEW THERAPEUTIC STRATEGIES

SIR,-At the XVIIth Congress of the International Society of Hasmatology, held in Paris in July, M. Perutz noted that since 1970 more than sixty chemotherapeutic agents for sicklecell disease cued to molecular aspects of sickle haemoglobin have been proposed. At the same congress R. L. Nagel classified such agents as non-covalent, covalent, modifiers of high oxygen affinity (i.e., inducing left-shifted oxygen-dissociation curves, L.S.O.D.C., or membrane modifiers. Beutler has 1.

2. 3. 4. 5.

Israel, H. L., Weiss, W., Eisenberg, G. M., Strandness, D. E., Flippin, H. F.Med. Clins N.Am. 1956, 40, 1291. Miller, A. C., Pearson, S. B. Thorax, (in the press). Jenkins, P. F., Miller, A. C., Osman, J., Pearson, S. B., Rowley, J. M. Br. J. Dis. Chest, (in the press). Lawson, J. H., Grist, N. R., Reid, D., Wilson, T. S. Lancet, 1977, ii, 1083. Kerr, D. N. S., Brewis, R. A. L., Macrae, A. D. Br. med. J. 1978, ii, 538.

571 the rationale for inducing an L.s.o.D.c. in the of sickle-cell disease.’ The notion that a right-shifted oxygen dissociation curve (R.S.O.D.C.) may be beneficial has been overlooked. Indeed, a rightward shift might be expected to induce or exacerbate a sickle-cell crisis. This therapeutic paradox can be resolved, however. Perutz2 has explained that HbS sickles or polymerises only in the T or "deoxy" molecular conformation and that an R.S.O.D.C. alters the conformational equilibrium R—T, to favour the T form susceptible to sickling. To a significant degree, but not exclusively, sickling is mediated by hydrophobic interactions.3 If a chemotherapeutic agent produces an R.S.O.D.C. and in addition has an electric dipole moment (E.D.M.) greater than that of water but is not so polar that it may fail to penetrate the erythrocyte membrane (e.g., an E.D.M. value between 4 and 6), such a molecule would perturb the hydrophobic interactions essential to the sickling event and so reverse sickling. The HbS tetramers so dispersed, though still in the vulnerable T conformation, would be no more susceptible to sickling than if those identical Hb molecules were in the non-sickling R conformation. Such an agent, after reversing sickling because of its E.D.M., may gradually form in vivo an adduct with Hb, producing an R.S.O.D.C. This rightward shift would be no longer hazardous in the presence of adequate concentrations of the therapeutic agent since subsequent sickling would then be blocked. Adduct formers with an L.S.O.D.C. only block sickling; they do not reverse sickling and do not correct, and may mildly exacerbate, the low tissue Po2 in SS disease. In contrast, an adduct former producing an R.S.O.D.C. with an appropriate E.D.M. will block sickling, reverse sickling, and ameliorate, or possibly even correct, the tissue oxygen deficit. Thus, those therapeutic agents with appropriate E.D.M.s and producing an R.S.O.D.C. will be effective both in the treatment of acute sickle-cell crisis and prophylactically; while those producing an L.s.o.D.c. will be useful only prophylactically and will be totally ineffective in acute sickle-cell crisis. The R.S.O.D.C. in a SS crisis may indeed be of great therapeutic benefit under the conditions specified. Working from an entirely different molecular rationale, Beutler et awl.,’* aware that pyridoxal phosphate produced an R.S.O.D.C., attempted unsuccessfully to use pyridoxine in SS disease. However, their findings do not, we feel, nullify our

cogently argued treatment

,

hypothesis. A second

therapeutic strategy for SS disease arises from investigations, stimulated by reports in The Lancet and elsewhere by Targino de Araujo, de Melo, and colleagues, that piracetam was clinically effective in the treatment of SS crisis.56 At the Paris meeting (abstracts pp. 461, 978) we reported on the molecular mechanism of piracetam in this clinical context: this agent reverses sickling of SS hsemolysates by perturbation of hydrophobic interactions, has an E.D.M. between 4 and 6, reduces the viscosity of SS blood, does not shift the oxygen-dissociation curve, and inhibits platelet aggregation. Unpublished data indicate that piracetam also increases erythrocyte membrane elasticity (deformability), in part by dephosphorylation of the membrane proteins. So piracetam appears to have a number of highly desirable molecular actions which tend to support clinical claims of efficacy. Implicit in these findings is that two independently targeted therapeutic agents may be used at once to achieve distinct therapeutic benefits. One agent could be directed to the erythrocyte membrane to enhance membrane deformability; the other agent could be directed simultaneously to disperse the SS polymers within the erythrocyte. An additive effect may be anticipated; lower concentra1. 2. 3.

tions of both targeted agents seem plausible if the drugs are used together rather than singly. These two therapeutic strategies, with a molecular basis, offer new prospects for the discovery of effective therapeutic agents for sickle-cell disease. Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan 48201, U.S.A. National Institutes of Health, Bethesda, Maryland

ROBERT M. NALBANDIAN RAYMOND L. HENRY

MAKIO MURAYAMA

HÆMOGLOBINOPATHIES AND G.-6-P.D. DEFICIENCY IN LAOS

SIR,-South-East Asia probably has the world’shighest incidence of

hsemoglobinopathies, but only Thailand has been thoroughly surveyed for haemoglobin (Hb) and glucose-6-phosphate dehydrogenase (G.-6-P.D.) abnormalities. 12 In contrast, for geographical and political reasons, there is a total lack of data for Laos, a rural country located between Thailand and Vietnam. Screening for these genetic defects in such a country is warranted because of the relative homogeneity of its population (made up of the Lao ethnic group), the social life with high village endogamy, and the high incidence of malaria. One of us (D.S.) has been in charge of the department of medicine at the University Hospital of Vientiane. After four years, the genetic survey which had been undertaken was suddenly interrupted without any hope of early resumption. We report here our first results. 910 samples were investigated-295 normal controls, 468 hospital patients taken at random and their families, and 147 cord-blood samples. Screening for Hb and G.-6-P.D. abnorma-, lities was done together with clinical and haematological routine examinations. A strikingly high incidence of haematological genetic defects was found. ’

Hemoglobinopathies found in about 35% of the subjects investigated, irrespective of age and health. The abnormal component amounted to 30-40% in the heterozygotes, this proportion being decreased in cases of iron deficiency or associated a-thalassxmia. In 1 case HbE was associated with Hb Hope, a rare mutant (a136 [H14] Gly-4Asp) which had previously been HbE

was

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found in Black populations only. a-thalasssemia was very frequent, Hb Barts, in proportions than traces, being found in 43% of the 147 cord-blood samples. Hb Constant Spring, an ineffectively synthesised elongated a-chain mutantwas found in 9% of these samples. Both frequencies are the highest ever recorded. In the adults a similar figure (about 40%) for a-thalasstmia was found by summing HbH diseases, Hb Constant Spring, and silent a-thalasssemia traits ot-thalasseemia 1 or 2 (indicated by genetic data and low percentage of HbE in the A/E heterozygotes). In Laos seems to be the prime cause of clinically severe