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'9) lY T~-n~ L~N CET, NU~RC_~ 2 8,1981 THE LANCET Long Term Oxygen and Advanced Chronic Bronchitis IN its advanced stages, chronic bronchitis is often complicated by hypoxic cor pulmonale, pulmonary hypertension, and secondary polycy~haemia. Several uncontrolled trials have shown that long term domiciliary oxygen therapy can help to reverse these complications, but until lately there was no controlled trial to determine whether oxygen therapy influenced survival. Two major studies have now been reported--that of the Nocturnal Oxygen Therapy Trial Group in the U.S.A.,l who compared oxygen given for 12 hours every night with continuous (24 hours daily) oxygen; and, on p. ~81ofthis issue, that of the British Medical Research Council Working Party, who compared survival in'patients given oxygen for 15 hours in every 24, with that in patients given no oxy- gen. In both trials the oxygen was administered from a variety of sources--from, compressed oxygen gas cylinders, liquid oxygen reservoirs, or oxygen concen- trators~via nasal prongs, the aim being to achieve an arterial oxygen tension in excess of 60 mm Hg; in addi- tion to tests of lung function and arterial blood gas analysis, most ofthe patients were assessed at intervals by right heart catheterisation and measurement of haematocrit or red cell mass. We should feel indebted to all the patients and investigators who took part in these careful and detailed studies. Overall, in the British trial, patients given oxygen survive.dflonger than those who did not; and in the American trial, those given oxygen for 24 hours a day survived longer than those given oxygen for 12 hours a day only. So it seems that the more continuous the therapy, the greater the benefit in terms of survival. Both groups tried to find out whether the observations made on entry to the studies might be helpful in predic- ting benefit from oxygen. In the U.K., female patients responded better to oxygen therapy than did males. A high initial arterial PCO2 and red cell mass tended to b e associated with early death; and the working party sug- gests that these earlier deaths in both treated and un- treated groups may have explained why oxygen therapy did not improve survival curves until patients had participated in the trial for more than 500 days: perhaps the illcr patients were too ill to derive benefit from long term oxygen. Surprisingly there was no reduction in pulmonary hypertension in the okygen treated patients. In the American study, the patients had a lower mean PaCOz on entry to the trial (43 701 mm Hg compared with about 50 mm Hg in the U.K. trial), and the improved survival of the 24 hours con- tinuous therapy group was apparent from the first months of the study. Patients with a raised PaCO:, or with mo~ disturbance, seemed to benefit most from the continuous oxygen therapy. Since these two important studies show that the long term relief of hypoxaemia increases the survival of some patients, should all hypoxic bronchitic patients now receive long term oxygen therapy? Before deciding whether such a radical development in the treatment of a common disease is a practical possibility, we need to know whether the quality ofsurvival is im- proved as well as the duration. This question is not, un- fortunately, answered in either trial. In the American study, several psychological assessments used to gauge quality oflife revealed no difference between the two oxygen treated groups, but of course untreated patients were not assessed. In the U.K. trial there were few ob- jective measurements to help us judge quality of life; there was no reduction in hospital admission in the oxygen treated group compared with controls, and no improvement in workxecord; but then many of the patients were elderly and disabled. Some ofthe treated patients felt better generally, but their morale and outlook may have benefited from the placebo effect of having oxygen available, and from extra home visits by the investigating teams. It is a major defect that formal exercise testing ,was not included in the assessments, ; but the study was initiated in 1973, well before such simple and repeatable tests as the 12-minute walking distance: had been developed. The'other possible approach, to compare a group receiving oxygen with one receiving air from cylinders, might have helped to measure possible effects of oxygen on the patient's wellbeing but was understandably rejected by the M.R.C. Working Party on grounds of cost. Chronic bronchitis in its later stages is often distressing and unpleasant, and prolongation of life, as with terminal cancer, is only to be sought if the quality of life can be improved; we have not yet been clearly shown that okygen can do this. Is long. term oxygen at home practical, and how expensive is it? Of the various.methods for delivering. oxygen only one.is available in the U.K. on prescrip- lion,the standard 48 cubic feet gas cylinder, which can be delivered by a retail chemist. For 15 hours of oxygen daily at 2 litres/minute, fifteen cylinders will be required weekly, costing around £3500 a year. Oxygen concentrators, which concentrate oxygen from air, are powered by electricity and cost about £ 1000 to buy and £500 a year to run, and are not l~ortable. Liquid oxygen tanks (Union Carbide Walker System) are semi- portable and 1 year's supply costs about £1000. Chronic bronchitis accounts for nearly 30 000 deaths annually in the U.K. and if long term oxygen were given to even a third of these patients for their last 2 years of life, the cost would be tens of millions of pounds annually. As with chronic renal dialysis, hard hTpozcmi¢ ~r¢m¢ ob~tP.univ~ =irw=y= d~:~.A~-* 1.*~ ?,fed 1980; ~3:391- 2. McGa'~a CR, Gu~ S¥, McH~tdy GJR. Twe|v= minute ~=lhng T!04231100

702 decisions have to be made. Unless long term oxygen can be shown to improve the quality of survival, permit continuation ofwork, or reduce hospital admissions, its use may be hard to justify, and yet doctors will be tempted to prescribe it for many of their suffering patients, in the hope of benefit. Conventional therapy may, however, otter much more--weight reduction, no smoking, and regular exercise? together with bronchodihtors, diuretics, and for the polycythaemic, isovolaemic ex- change transfusion with dextran 40.4 If hypoxaemia and cot pulmonate remain severe, long term oxygen might then be considered for a few, the young having priority over the old, the ex-smoker over the smoker, and those who can continue work over the retired. The numbers so treated should remain smalluntil we can be sure that long term oxygen improves the quality of life. But surely none but the medically myopic will leave it at that; the main thrust must surely be towards preven- tion, by continuing health education, research, and political action. ORAL ENCOUNTERS WITH ANTIGEN THe- skin and gut are both epithelial surfaces so it is interesting that antigen experienced at one or the other should elicit totally differenrimmunological responses. The dichotomy was well illustrated by Chase'ss observation that in animals whose skin was painted with dinitrochlorob enzene" (DNCB), delayed hypersensitivity devdoped while those which were first given DNCB by mouth could no longer be sensitised by skin contact• Mice injected with lymphocyte, from DNCB-fed, tolerant, animals become tolerant themselves and the cells responsible for tolerance transfer are a subset of thymus-dependent (T) suppressor lymphocyte,.6 The feeding of a range of other substances including oval. bumin, bovine serum albumin, and sheep eryt~ocytes induces hyporesponsiveness of both cell-mediated and anti- body-mediated immunity, whether they are given singly as large feeds or chronically in small amounts• Unresponsive- hess is restricted to antigens which require the participation ofT lymphocyte, in the induction of antibody responses7 and animals which are already sensifised do not generally become tolerant as a result of antigen feeding. Under certain circum- stances the induction of oral tolerance is accompanied by the appearance of suppressor B lymphocytess and suppressive serum factors) The induction of tolerance implies an initial uptake of intact antigeh by the gut, and this has been demonstrated 3. Editorial. Eau¢i~e =nd the breathless btonchili¢. Lance* 1980; ii: Sl4-15. 4. Harrison BDW, G regoty g], CIa~kTJH, S¢o~t GW. Exchange transfusion w~th Dea- itao 40 in ~ly~h~emia secood=~ ~o hy~xic lun~ disuse. Br ~ 19~]; ik S. C~sc M. I~;b,;on ofe~pcrs~nlal drag =l~ ~ prior feeding of the ~nshlslag agent. ~ E~p Bfol.~d 1946; $1: 257-~9. 6. Torsi ~. Or~ tolerate. Tremplanralion I 9~; aS: ~. Tim, RG, Chdhr JM, Or=ll~ i~uc~ tolerant: d~nhi~ =¢ 1~ ceRulat I~d- la~A dll~g d?pl lmm=~l (in press). 8. A~erson G, Zrmbah ~t, Peter= ~, May~w B, ~s W~ Pr~u~on ff 9. And¢¢ ~ ~c~c~ JF~ Vacr~a J~. Ctmhia~ CL A ~c~ f~ t~ indu~ien ~ M~ 1975; 14~ I~ THELaNCET, ,~L-~ RC~-128,19 81 directly in human infams~° and laboratory animals. It is tempting to speculate that oral tolerance might prevent the immune system f~om reacting to a large number of relatively non-pathogenic proteins. This view is not easily reconciled with the fact that the gut is a very efficient route for immunisation aga'mst pathogens such as poliovirus. The paradox that orally encountered antigen can induce pro- tecfive immunity and systemic tolerance has been further explored in mice by Challacombe and Tomasi.I 1 They found that a single feeding ofovalbumin (OVA) was sufficient both to suppress the induction of OVA responsiveness by T cells and to stimulate ~he appearance ofanti-OYA antibodies in the saliva. Similar results were obtained after the feeding ofkilled Streptococcus mmans, except that the degree of T cell suppression was rather less. Mesemeric lymph node cells from mice which had eaten OVA or'S. mutans transferred antigen-specific tolerance to syngeneic mice. In general it is the physical form of the antigen and the relative triggering of helper or s.uppressor T lymphocytes ", which determines the response to immunisation. The "characteristics of the gut response are probal~ly determined by..the presence, in Peyer's patches, of IgA-specific helper T cel~l: and IgG and IgE specific suppressors.. S~varbrick et 14 al. found that the induction of tolerance by antigen feeding was accompanied by a reduction in the amount of antigen which the orally immunised animals absorbed; there was no change in the rate ofantigen elimination from the serum. The immune exclusion which they and othersIs have found is probably due to secretory IgA rather than IgG antibodies. Some indication of the importance of secretory IgA in limiting antigen uptake comes from the finding that 50°7o of patients with selective IgA deficiency have predpitating antibodies to cow's milk proteins in their serumJ~ Circulating immune complexes, mostly involving the garnma-globn.lin which is present in cow's milk,1~ were present in all the patients with milk precipitins. Patients with selective lgA deficiency have an increased incidence of a variety of auto-immune and immune-complex associated dis- orders bur the extent to which these might be due to dietary antigen absorption is unknown. Low levels of cow's milk/IgG circulating immune complexes have been detected in healthy adults after drinking cow's milk.Is It would be interesting to know whether dietary proteins other than those commonly experienced in infancy app~r in post-prandial immune complexes. Ifnot, one might wonder whether the widespread priming of infants with cow's milk containing formulae in the weeks before their immunity matures has interfered with their subsequent ability to become tolerant. Such speculations could have important implications for infant feeding practices. 10. Ro~hberg RM. Imrn unoglobulin and =pecific ant ibody synthesis dunng the tint week~ of hfe of premature infants..~ Pedia~r 1969; 75:391-99. I I.Challacombe SJ, Tomari TB. Systemic toleran¢~ and ~.-¢retory m~muai]y after oral immuniz= non..1 E~p Nled ~ 980; 152: I ,I 59-72. 12. ~[~on CO, He& JA, St,ober W. T tea reguhtion ofmurine ]gA s~nthesLL~ F.xp Med 1979; 14~: 632-43, 13. Ngan J, Kind I~. Suppeessor T cells for IgE and lag in Peyer's patcbe~ of mice made toletam by =drnmistra6On o1" ovalbumm. ] Immu~ol 1978; 120:861-6S. 14. Swarbnek F,T,$to~=s CR, Soo~hilI JF.Al~orpfioa ofantigctuafier oral immunization and the simultaneous indua~oa ol'spedfi¢ s~temic tolerance. ~ut 1979; 121-25. 15. Walker WA, Isselbacher KJ, Bloch KJ. Intestinal up~=ke ol'macroraolecult~: effect of oral immunlzauoa. $clmce 1972/17~: 608-10. 16. Cunningham-gandles C.~ ~randels WF~ Good R~ Day NK. Milk prec~pitlrm, oreuhtiag immune complexes and lgA deficiency. PrecN~tlAmdSd U.~A 1978i ~$: ~]87-89. IT. Cuamnr, ham-Rundl~ C, B raadess W]~, Good RA~ Day .~K. Bovine amigeas and the ferm=tmn at" ¢~roalatmg immhne coraph~¢¢ in selcCuve immunoglo~l/a A defgien~..J' Cl=a I~e~t 1979;, ~: 272-79. 18. Fagan¢lll R, L~sky RJ. B~t¢~'.~, Wragk ]~. Immu~ ce~aplexes coat=bring ~eins ia muma! a~ aeo~ie salients alter ~al challenge ar~ effect ~t" T!04231101