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needed as to the critical subcellular components."These theoretical considerations have been current

for some time; what has stimulated recent interest18 is °

in-vivo findings by workers in the USA3 that, wheninjected into the testis of a mouse, thallium-201, aradionuclide widely used in investigations of the heart,produces a biological effect (killing of spermatogonialcells) greater than that expected on the basis ofconventional macroscopic dosimetry and comparisonwith external X rays. Similar effects have been seenwith iron-556 and indium-Ill. The importance ofthese results does not lie so much in their direct

extrapolation to the effects of these Auger-emittingradionuclides in the testis of man but rather in thedemonstration that Auger electrons have biologicaleffects in vivo, and that these actions cannot beaccounted for by the conventional macroscopicdosimetry of MIRD. These observations were

strikingly confirmed in vitro when thallium-201 andother Auger-emitting radionuclides were shown to killestablished Chinese hamster V79 lung fibroblasts. 4,5,19The in-vitro intracellular concentration of thalliumions may rise to 130 times their concentration in theexternal medium, possibly because of their chemicalsimilarity to potassium ions.4 Thus two factors maycontribute to the biological consequences of Auger-emitting radionuclides-namely, one due to thedistribution of the radionuclides in relation to the cell

nucleus, and the other due to the high LET nature ofsome energy depositions from Auger cascades inrelation to the critical subcellular macromolecules.In view of the enormous beneficial value of

diagnostic nuclear medicine, its potential for furtherdevelopment, and its possible extension to therapeuticuse it is clearly important to find a way of assessing therisk associated with the use of Auger-emittingradiopharmaceuticals. A meeting held lately underthe auspices of the Medical Research Council’sCommittee on the Effects of Ionizing Radiation

brought together people who use the techniques andpeople whose interest is in the fundamental

radiobiology and physics underlying nuclear medicine.It was soon apparent that we know little about thesubcellular physiology of commonly used

radiopharmaceuticals-an aspect of the subjectessential to any rational assessment of the likely extentof biological impact of the Auger decays. Although thefactors by which effective doses are under or overestimated by macroscopic dosimetry are unlikely toexceed one order of magnitude, realistic dosimetry isessential for an assessment of risk of harm againstwhich the benefits of a clinical investigation should beweighed.Similar difficulties may be encountered in assessing

the risk to human beings exposed to environmentalAuger-emitting radionuclides. Information on the

17 Goodhead DT, Charlton DE. Analysis of high-LET radiation effects in terms of localenergy deposition. (Proceedings of Ninth Symposium on Microdosimetry,Toulouse, May, 1985.) Radiat Prot Dosim (in press).

18 Gaulden ME "Biological dosimetry" of radionuclides and radiation hazards. J NuclMed 1983; 24: 160-64.

19. Kassis AI, Adelstein SJ, Haydock C, Sastry KSR. Radiotoxicity of 7 5Se and 3 5S:theory and application to a cellular model Radiat Res 1980; 84: 407-25.

cellular and subcellular physiology of an ingestedradionuclide may be a prerequisite for accurate

assessment of the possible additional hazard due to theAuger cascade electrons.

Haemorrhagic Shock andEncephalopathy

IT is now two years since workers at the Hospital forSick Children, Great Ormond Street, London,reported in The Lancet what seemed to be a newdisorder-" haemorrhagic shock and encephalo-pathy".’ Ten infants had presented with a suddenonset of shock, coma and convulsions, bleeding,disseminated intravascular coagulation, watery diar-rhoea, and impaired hepatic and renal function.

Despite intensive treatment, seven of the ten died andthe survivors were all neurologically damaged. Post-mortem studies revealed haemorrhages and petechiaein several organs, and severe cerebral oedema. A searchfor the cause revealed no specific microbial agent,toxin, or metabolic disorder, but the infants did showan unusual pattern of plasma proteins with reducedalpha-1-antitrypsin and increased trypsin. This obser-vation led to the suggestion that the pathogenesis mighthave involved massive release of proteolytic enzymesinto the circulation, overwhelming the natural proteaseinhibitors. While the disorder in these ten cases hadindividual features in common with other acute

illnesses, such as Reye’s syndrome, the staphylococcaltoxic shock syndrome, septicaemia, and heatstroke, theGreat Ormond Street workers felt that it could be

distinguished from them on clinical or laboratorygrounds.

Other cases were soon reported from the UK,2-4 theNetherlands,5 and the United States,b’ and hypothesesto explain the disorder included suggestions that it wasdue to a bacterial toxin produced by abnormal gutflora,8 that it was related to the syndrome of idiopathicacute pancreatitis in children,9’lO and that it was due toheatstroke."-’4 Five infants with an illness similar to

haemorrhagic shock and encephalopathy had beenreported in 1979 by Bacon and co-workersl5 in

1 Levin M, Kay JDS, Gould JD, et al Haemorrhagic shock and encephalopathy. A newsyndrome with a high mortality in young children. Lancet 1983, ii: 64-67.

2. Morris JA, Matthews TS Haemorrhagic shock and encephalopathy syndrome: A newsyndrome in young children. Lancet 1983; n: 278.

3. McGucken RB Haemorrhagic shock and encephalopathy syndrome. Lancet 1983; ii:1087.

4. David TJ, Mughal MZ. Haemorrhagic shock and encephalopathy syndrome:Epidemic of a new disease. J R Soc Med 1984; 77: 721-22

5 Lafeber HN, van der Voort E, De Groot R. Haemorrhagic shock and encephalopathysyndrome. Lancet 1983, n: 795.

6 Schrager GO, Shah A. Haemorrhagic shock/encephalopathy syndrome in infancy.Lancet 1983; n: 396.

7. Whittington LK, Roscelli JD, Parry WH. Haemorrhagic shock and encephalopathyFurther description of a new syndrome. J Pediatr 1985; 106: 599-602.

8. Morris JA Haemorrhagic shock and encephalopathy. Lancet 1983; ii: 686.9 Morens DM. Haemorrhagic shock, encephalopathy and the pancreas. Lancet 1983; ii:

967

10. Morens DM, Hammar SL, Heicher DA. Idiopathic acute pancreatitis in childrenassociation with a clinical picture resembling Reye’s syndrome. Am J Dis Child1974, 128: 401-04.

11. Bacon CJ. Haemorrhagic shock and encephalopathy a new syndrome in youngchildren. Lancet 1983; n: 278.

12 Beaufils F, Aujard Y Haemorrhagic shock and encephalopathy syndrome. Lancet1983, ii: 1086

13 Bacon CJ Over heating in infancy Arch Dis Child 1983; 58: 673-74.14. Bacon CJ, Bellman MH. Heatstroke as a possible cause of encephalopathy in infants. Br

Med J 1983; 287: 328.15 Bacon C, Scott D, Jones P Heatstroke in well-wrapped infants. Lancet 1979; i: 422-25

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Newcastle under the heading "heatstroke in well-

wrapped infants". A history of excessive heating,overdressing, or swaddling in bedclothes was presentin all the Newcastle cases, and hyperpyrexia wasthought to be the cause of the illness. A larger group ofinfants, also suspected of having heatstroke, had beenreported in 1978 by Aujard et al’6 under the heading"hyperthermie majeure de 1’enfant". Again over-

heating was implicated as the cause and the clinicalfeatures were similar to those of haemorrhagic shockand encephalopathy.As with any illness reported to be a new disorder,

there are several questions to be asked. Is haemorrhagicshock and encephalopathy really a new syndrome, orhas a new name simply been given to a group ofseriously ill patients previously known by some othertitle? If haemorrhagic shock and encephalopathy reallyis a new entity, why has it only lately been recognised?What are its distinguishing features? How common isit? What is its aetiology? And can anything be done toimprove the prognosis of what seems to be a usuallyfatal illness? Answers to some of these questions arebeginning to emerge.Amongst more than fifteen published articles on

haemorrhagic shock and encephalopathy, perhaps themost illuminating is the report of the NationalSurveillance Scheme for haemorrhagic shock andencephalopathy undertaken between 1982 and 1984 inthe UK.17 The Communicable Disease SurveillanceCentre (Colindale) and the British PaediatricAssociation had the good sense to organise nationalsurveillance soon after the disorder was described.Paediatricians were asked to report to the surveillance

centre any patient with acute onset of encephalopathy, shock,bleeding or disseminated intravascular coagulation,diarrhoea, falling haemoglobin, falling platelet count,acidosis, raised serum transaminases, and impaired renalfunction. Patients were excluded if they had raised plasmaammonia concentrations or histological evidence of Reye’ssyndrome, or evidence of an identifiable bacterial or viralinfection. Because haemorrhagic shock and encephalopathywas an apparently new condition, and the range of clinicalfeatures was unknown, these criteria were intended to act asdiagnostic pointers rather than a rigid case definition and itwas not specified how many of the criteria should be satisfied.By November, 1984, forty-four cases had been reported in theUK, ranging in age from 3 weeks to 15 years (87% under 1year). 62% were boys. There was no clear geographical ortemporal clustering of cases, and patients presented in allseasons of the year. Most were White but other racial groupswere affected. Typically, the child had been completely welland developing normally, but four had pre-existingneurological abnormalities. Furthermore, there seemed to bean increased incidence of unexplained deaths in infancy in thefamilies. 57% of patients had had a prodromalillness-generally a mild nonspecific illness with diarrhoea,vomiting, pyrexia, or symptoms of upper-respiratory-tractinfection. The presentation of the illness was abrupt andremarkably similar in all cases. Convulsions, coma, shock,

16. Aujard Y, Beaufils F, Bourillon A, Huault G. Hyperthermie majeure de l’enfant. ArchFr Pédiatr 1978; 35: 477-85

17 Joint British Paediatric Association and Communicable Diseases Surveillance CentreSurveillance Scheme for Haemorrhagic Shock Encephalopathy Syndrome.Surveillance Report for 1982-4. Br Med J 1985; 290: 1578-79.

and bleeding or evidence of disseminated intravascular

coagulation were present in almost every case on-admission.Watery diarrhoea, which often became bloody, occurred soonafter the onset. 88% of cases had at least eight of the elevendiagnostic features and 60% had all the listed features. Theleast consistent features were impaired renal function (whichwas not observed in four cases) and a normal plasma ammonia(mildly raised in six cases). Where the ammonia is raised,distinction from Reye’s syndrome may be difficult.The outcome of cases in the CDSC study was very similar

to that in the Great Ormond Street series. 60% of the patientsdied and 80% of the survivors were reported to be severelyneurologically damaged. However, there are reports ofmilder cases with a better outcome.7 The post-mortemfindings showed a fairly consistent picture. Petechial

haemorrhages were seen in many organs. 1, 17 The intestinescontained haemorrhagic fluid, and an inflammatory infiltratewas commonly seen in the small-bowel lamina propria. Inseveral cases there were enlarged intestinal lymph nodes butthere was no evidence of pancreatitis. Patchy centrilobularhepatic necrosis was common. Intravascular thrombi wereseen in the blood vessels of many organs. The brain was

usually soft and oedematous. While none of these features isunique to haemorrhagic shock and encephalopathy, takentogether they represent an unusual and characteristic picture.What can be said about pathogenesis? Great efforts

have been made to identify an aetiological agent, but noconsistent viral or bacterial pathogen has beenidentified: the organisms isolated were a cross-sectionof the normal flora found in children of a similar age.Screening for industrial toxins and heavy metals wasalso negative. In view of the possible role of overheatingand overwrapping in the pathogenesis of haemorrhagicshock and encephalopathy, the CDSC conducted astudy of the environmental temperatures, heating,dressing, and bedding of affected infants at the onset ofthe illness No convincing evidence of excessiveenvironmental temperature or overwrapping was

found, although there was some similarity in the

clothing of affected patients. A case-control study wasjudged necessary to settle the questions on the role ofabnormal dressing and hyperpyrexia.We can conclude that haemorrhagic shock and

encephalopathy is a distinctive clinical entity that isnow being recognised with increasing frequency andmay well be more common (in the UK, at least) thanReye’s syndrome or the staphylococcal toxic shocksyndrome. There is no hard evidence to support thehypothesis that overheating and overwrapping is thecause," but there is an undoubted similarity betweenhaemorrhagic shock and encephalopathy and somecases previously reported as having heatstroke.’s,’6 Thefailure to identify a bacterial or viral cause may indicatethat haemorrhagic shock and encephalopathy is anunusual response to various different insults.However, we need only recall the difficulties in

identifying the cause of such infective illnesses as

legionnaires’ disease, non-A, non-B hepatitis, andLyme arthritis to appreciate the need for an open mindon the question of a microbiological cause. From thepractical point of view, no specific treatment can beoffered, so we must rely on vigorous resuscitation andsupport. The evidence of deficient protease inhibitors

536

and high levels of circulating proteolytic enzymessuggests that treatment with fresh frozen plasma orconcentrated protease inhibitors may be beneficial, butthere are no studies of the efficacy of such measures. Inview of the high mortality and residual neurologicaldamage in survivors, a major clinical task is the care andsupport of families who have suffered the sudden lossor damage of a previously well child. Guilt, fear, andanxiety about the cause of the illness and about theadequacy of medical care affects not only the bereavedfamilies but also the medical personnel.

INTERLEUKIN-1 IN DEFENCE OF THE HOST

INFECTIOUS, inflammatory, and immunological stimuli ofvarious kinds can induce in the host a remarkably consistentseries of reactions collectively termed the acute phaseresponse. The components of this response are stimulated bymonokines-hormone-like mediators produced bymacrophages and the cells of the reticuloendothelial system.These monokines have hitherto been known as "endogenouspyrogen" (now no longer thought to be produced bypolymorphonuclear cells), which acts via prostaglandin E2 toreset the hypothalamic thermoregulatory centre; 1 "leucocyteendogenous mediator", which stimulates neutrophil releasefrom the bone marrow, changes in plasma cations, andhepatic protein production;2 and "lymphocyte activatingfactor", a substance essential for T lymphocyte proliferationand hence B cell function.3 There is good reason to believethat these substances are closely related (if not identical)molecules, and they are now collectively termed interleukin-1 I(I I_ 1).4The acute phase response is characterised also by a

substantial negative nitrogen balance, only part of which isdue to the increased caloric demands of fever. Of much

greater importance is an accelerated catabolism of muscleprotein’ and, although this is accompanied by the myalgiaand reduced physical performance associated with so manyacute infections,6 it still serves a useful purpose. Theaminoacids thus mobilised contribute not only to theincreased energy requirements, via gluconeogenesis, but alsoto the synthesis of proteins in proliferating immunologicalcells and acute phase reactants released from the liver. Theprotein catabolism can be studied in vitro by measurement ofaminoacid release from isolated rat muscle strips and has nowbeen shown to be induced by a small glycopeptide found inthe plasma of subjects with sepsis.’ Furthermore these effectscan be reproduced with purified 11-1, suggesting that 11-1 isthe mediator found in the plasma. It seems that Il- acts on themuscle to stimulate the synthesis of prostaglandin E2 which is

1 Bernheim HA, Block LH, Atkins E. Fever: pathogenesis, pathophysiology, andpurpose. Ann Intern Med 1979, 91: 261-70.

2. Kampschmidt RF Leukocytic endogenous mediator/endogenous pyrogen. In:Powanda MC, Canonico PG, eds. The physiologic and metabolic responses of thehost Amsterdam Elsevier/North Holland, 1981 55-74.

3. Wood DD. Purification and properties of human B cell-activating factor I.

Comparison of the plaque-stimulating activity with thymocyte-stimulating activity.J Immunol 1979; 123: 2395-99.

4. Dinarello CA Interleukin-1. Rev Infect Dis 1984, 6: 51-95.5. Beisel WR. Metabolic response to infection. Annu Rev Med 1975; 26: 9-20.6 Friman G Effects of acute infectious diseases on isometric muscle strength. Scand J

Clin Lab Invest 1977; 37: 303-08.7. Clowes GHA Jr, George BC, Villee CA Jr, Saravis CA. Muscle proteolysis induced by a

circulating peptide in patients with sepsis or trauma. N Engl J Med 1983; 308:545-52

8. Baracos V, Rodemann HP, Dinarello CA, Goldberg AL. Stimulation of muscle proteindegradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). Amechanism for the increased degradation of muscle proteins during fever N Engl JMed 1983; 308: 553-58

itself responsible for releasing muscle-cell lysosomalproteases. This activity of Il- can be blocked by incubationof the muscle strips with indomethacin, providing oneexplanation for the efficacy of antipyretics in relieving themyalgia associated with infection.This makes the results reported by a group of American and

Swedish workers rather surprising.9 These researchers usedsandfly fever virus to produce a transient febrile illness involunteers. Although myalgia and a deterioration in physicalperformance were prominent in most of those infected, nochanges could be detected in the levels of lysosomal enzymesin muscle biopsy specimens taken during the febrile period.There was also no correlation between the degree of fever andmyalgia. Previously Elstrom et allo had found enzymechanges in human beings with more sustained fevers, and thenegative results in the later study may merely reflect thedifficulty of measuring small changes in enzyme levels inbiopsy specimens. Perhaps now that Il-l levels can bemeasured in the serum of patients" the relation betweenfever, physical performance, myalgia, and Il- can be studiedfurther.The effects of Il- on neutrophil numbers and lymphocyte

proliferation are of obvious benefit in the defence against theinciting disease. The changes in serum cations are also

advantageous. A reduction in serum iron concentrations actsas a major host defence mechanism by suppressing thegrowth of microorganisms and indeed certain tumour cells,12and similarly a fall in the serum zinc reduces the availability ofan essential microbial nutrient. 13Many of the effects of Il- are therefore well coordinated to

mobilise and enhance host defences. But what of the rise in

body temperature? Is this energy-costly process of any benefitto the host? The temperature sensitivity of some organisms 14and tumour cellsls is, of course, well known but we mustremember that raised temperatures in vitro do not mimic

fever, where the presence and effects of Il- must be taken intoaccount.

Fascinating experiments with lizards showed that, wheninfected with subcutaneous bacteria, these animals

preferentially raised their body temperatures by moving towarmer surroundings16 and that the increased survivalassociated with this behaviour was due to an enhanced

inflammatory response to the infection." Benefits of feverhave also been reported in infected mammals: artificial

cooling or the use of antipyretics produced an increase in viralreplication in the nasal secretions of ferrets infected withinfluenza virus 18 and a decreased survival in rabbits withgram-negative infections.19 In vitro, a rise in incubation

9. Friman G, Wright JE, Ilback NG, et al Does fever or myalgia indicate reduced physicalperformance capacity in viral infections? Acta Med Scand 1985, 217: 353-61

10. Åström E, Friman G, Pilstrom L. Effects of viral and mycoplasma infections onultrastructure and enzyme activities in human skeletal muscle Acta Pathol MicrobiolScand(A) 1975; 84: 113-22.

11. Bendtzen K, Baek L, Berild D, et al. Demonstration of circulating leukocytic pyrogen/interleukin-1 during fever N Engl J Med 1984; 310: 596.

12 Bullen JJ. The significance of iron in infection Rev Infect Dis 1981; 3: 1127-38.13 Sugarman B Zinc and infection. Rev Infect Dis 1983; 5: 137-4714 Mackowiak PA. Direct effects of hyperthermia on pathogenic microorganisms.

teleologic implications with regard to fever Rev Infect Dis 1981; 3: 508-20.15 Wallach DFW. Basic mechanisms in tumor thermotherapy J Molec Med 1977, 2:

381-403

16 Kluger MJ, Ringler DH, Anver MP Fever and survival Science 1975, 188: 166-6817 Bernheim HA, Bodel PT, Askenase PW, Atkins E. Effects of fever on host defense

mechanisms after infection in the lizard Dipsosaurus dorsalis. Br J Exp Pathol 1978,59: 76-84.

18 Husseini RH, Sweet C, Collie MH, Smith H Elevation of nasal viral levels bysuppression of fever in ferrets infected with influenza viruses of differing virulenceJ Infect Dis 1982; 145: 520-24

19 Hoffman-Goetz L, Kluger MJ Protein deprivation: its effects on fever and plasma ironduring bacterial infection in rabbits. J Physiol (Lond) 1979, 295: 419-30