- Email: [email protected]
ATYPICAL CLOSTRIDIUM DIFFICILE COLITIS IN NEUTROPENIC PATIENTS
162 CALCIUM CHANNEL BLOCKERS IN MIGRAINE
SIR,-While your June 12 editorial on the treatment of migraine on platelet factors as the cause of migraine, none of the therapies mentioned directly addressed the altered vasoactivity of
focused
the cerebral circulation. Most migraines include a prodromal phase of cerebrovascular vasoconstriction. Intracarotid xenon injection techniques have demonstrated decreased regional cerebral blood flow during the prodrome, with resultant cerebral ischaemia.l,2 The ischaemia probably accounts for the neurological accompaniments in
migraines. Calcium channel blockers act on vascular smooth muscle to prevent contraction. They serve to decrease vasospasm and reduce ischaemia in the heart,3brain,4and retina.5 If the initial phase of migraine is due to vasoconstriction and if calcium channel blockers inhibit this vasoconstriction these agents should be effective in
migraine prophylaxis. Flunarizine, a calcium channel blocker now available in Europe, is effective in the prophylaxis of migraine.Our experience with an individual who had not responded to previous treatments, including propranolol, tricyclics, lithium, and biofeedback, showed that oral verapamil can be effective in migraine prophylaxis. We have since undertaken a randomised, double-blind, placebo controlled study to assess the efficacy of verapamil in migraine prophylaxis in the large
migraine population. While it is still too early to state the proper role of calcium channel blockers in the treatment of migraine, they may offer hope for patients in whom standard migraine prophylaxis has failed. Internal Medicine, U.S.A.F. Medical Center, Wright-Patterson AFB, Ohio 45433, U.S.A.
it has the weakest association with tardive dyskinesia. 10 Dopamine receptor binding studies suggest paucity of extrapyramidal sideeffects is due to thioridazine’s site specific blockade of limbic dopamine receptors. II Furthermore, it appears that extrapyramidal side-effects are correlated with blood levels of thioridazine sidechain sulphone. 12 Any contribution made by thioridazine to the clinical picture described by Murdoch and Williamson may be due to idiosyncratic metabolism of thioridazine. V.A. Downtown Medical Center,
Medical College of Georgia, Augusta, Georgia 30910, U.S.A.
RICHARD L. BORISON
Department of Human Biology and Health, University of Surrey, Guildford, Surrey
ANTHONY J. BLOWERS
SIR,-The report by Dr Murdoch and Professor Williamson and subsequent correspondence has reminded me of a Malaysian student who came to see me several months ago. He was very worried at the prospect of flying to Spain for a holiday, claiming that flying had a peculiar effect on him. Not long after take-off on two previous flights he had experienced muscle spasms around his neck and shoulders which pulled his face and head into bizarre positions, to his alarm and to the consternation of fellow travellers. These spasms would continue for much of the flight and even persist for an hour or two after landing. On closer questioning I discovered that he had been taking prochlorperazine for travel sickness. Health Centre, 20 Cleveland Square, Middlesbrough, Cleveland TS 12NX
Department of
GLEN D. SOLOMON
NOT PARKINSON’S DISEASE
SlR,—Dr Murdoch and Professor Williamson (May 29, p. 1212) presented four cases of apparent drug-induced parkinsonism in elderly patients on low doses of phenothiazines, thioridazine in three cases. This side-effect was still evident even after the drug had been discontinued for over a month. Although we agree that parkinsonism may be a frequent concomitant of neuroleptic use in the elderly, in the four cases presented there is very little to substantiate the contribution of neuroleptics to the clinically observed neurological disabilities. Were the patients taking other drugs? Elderly patients are often on antihypertensive therapy and some antihypertensive drugs are notorious for their ability to produce parkinsonism. As long as 6 weeks after discontinuation of thioridazine parkinsonism was still manifest. Drugs are almost totally eliminated after ten half-lives, so elimination of thioridazine would be complete by 160 h. Without thioridazine blood levels, it is highly speculative to attribute parkinsonism to it as long as a month after drug withdrawal. In large multicentre controlled studies thioridazine had the lowest frequency of extrapyramidal side-effects;in some cases the incidence was no greater than that for placebo.In well controlled studies in geriatric patients thioridazine produced less parkinsonism than did other neuroleptics,8,9 and we have found that
H.J. WATERS
ATYPICAL CLOSTRIDIUM DIFFICILE COLITIS IN NEUTROPENIC PATIENTS
SIR,-Experience in an outbreak of thirteen cases of Clostridium difficile colitis in the Cambridge leukaemia unit over the past three years has shown that an atypical, previously unrecognised clinical picture is not uncommon in neutropenic patients. Some of these patients lack the characteristic colonic pseudomembranes, they often have no diarrhoea, and ascites, severe jaundice, and acute abdominal symptoms develop early in their illness. Changes in the colon may be difficult to recognise at post mortem because of autolysis. A recent case, operated on for presumed peritonitis, having been diagnosed clinically on the basis of ascites, jaundice, and an acute abdomen, has provided us with unusual material for histology. A 17-year-old boy in his first relapse of acute lymphoblastic leukaemia became feverish while neutropenic after remission induction therapy and was treated with two 5 day courses of parenteral antibiotics, including cephalosporins and systemic vancomycin. On the fifth day of the second course he complained of colicky central abdominal pain and over the next 8 h tenderness and guarding in the right iliac fossa developed, with abdominal distension, scanty bowel sounds, and icterus. He had vomited several times but did not have diarrhoea. A diagnosis of pseudomembranous colitis was suspected by one of us (D. S.) who had seen similar cases during an outbreak at another leukaemia unit. Despite severe neutropenia and thrombocytopenia an emergency laparotomy was done. The ascending colon was much thickened and oedematous and a right hemicolectomy was done. Bowel contents taken for C. difficile toxin estimation and culture and subsequently found to be positive. Postoperatively the patient again became febrile and the jaundice deepened rapidly. Total bilirubin 276 mol/1 (normal 2-14); alanine transferase 58 U/1 (normal 7-40), were
1.
Skinhoj E. Hemodynamic studies within the brain during migraine. Arch Neurol 1973;
29: 95-98. 2. Edmeads J. Cerebral blood flow in migraine. Headache 1977; 17: 148-52. 3. Karlsberg R, Welcome: The calcium channel blockers. Chest 1981; 80: 657-59. 4. Louis P. A double-blind placebo-controlled prophylactic study of flunarizine in migraine. Headache 1981; 21: 235-39. 5. Nihard P. Effect of calcium-entry-blockers on arterioles, capillaries, and venules ofthe retina. Angiology 1982; 33: 37-45. 6. Galbrecht CR, Klett CJ. Predicting response to phenothiazine: the right drug for the right patient. J Nerv Ment Dis 1968; 147: 173-83. 7. Schiele BC, Vestre ND, Stein KE. A comparison of thioridazine, trifluoperazine, chlorpromazine, and placebo: a double-blind controlled study on the treatment of chronic, hospitalized, schizophrenic patients. J Clin Exp Psychopathol 1961; 22: 151-62. 8. Branchey MH, Lee JH, Amin R, et al. High- and low-potency neuroleptics in elderly psychiatric patients. JAMA 1978; 239: 1860-62.
9.
Cowley LM, Glen RS. Double-blind study of thioridazine and haloperidol in geriatric patients with a psychosis associated with organic brain syndrome. J Clin Psychiatry
1979; 40: 411-19. AJ. Epidemiology of tardive dyskinesia in the elderly. Neuropharmacology 1981; 20: 1339-40. 11. Borison RL, Fields JZ, Diamond BI. Site specific blockade of dopamine receptors by neuroleptic agents in human brain Neuropharmacology 1981; 20: 1321-22. 12. Axelsson R. On the serum concentrations and antipsychotic effects of thiondazine, thioridazine side-chain sulfoxide and thioridazine side-chain sulfone, in chronic psychotic patients. Curr Ther Res 1977; 21: 587-605. 10. Blowers
163
phosphatase 100 Uti (normal 30-135). Parenteral ampicillin, metronidazole, and gentamicin were given and oral vancomycin was started as soon as the patient could take oral fluids. His condition improved and stools became C. difficile culture and toxin negative but he had a relapse of his C. difficile colitis 31f2 weeks later, having had no antibiotics for the preceding 2 weeks. alkaline
The mucosal surface of the resected colon was oedematous with focal haemorrhages but no mucosal ulcers or exudate. Mesenteric vessels were patent. On microscopy the caecal epithelium and lamina propria were viable with patchy necrosis of the muscularis mucosae, striking necrosis, and oedema of the submucosa and focal necrosis of the muscularis propria especially its inner layer. The serosa was oedematous and covered with a fine layer of fibrin. Thrombi were present only in small vessels of the necrotic area. In view of the finding of C. difficile toxin multiple sections of the specimen were taken. These revealed a single focus of mucosal necrosis 2 mm across. Gram-positive rods were seen in large numbers beneath this. There was no pseudomembrane and virtually no cellular .reaction. Other sections showed occasional grampositive rods in the oedematous submucosa suggesting a spreading infection. We have seen four similar presentations without pseudomembranes in the past 2 years and only one of these cases had diarrhoea. C. difficile and its toxin were detected in the bowel contents of all four. Only two of these patients were not receiving intravenous vancomycin or metronidazole and both yielded C. difficile from large volume (45 ml) blood cultures. In many leukaemia units patients receive intensive, and in many cases prophylactic, antibiotic therapy, and we suspect that this unusual presentation is being missed and that the illness may be incorrectly attributed to cytotoxic therapy alone or to demonstrable bacteraemia with commoner faecal organisms. We believe the unusual clinical and pathological features represent a progressive invasive infection from a small area of mucosal necrosis produced by toxigenic C. difficile in patients who are unable to localise the organism because of their associated neutropenia. ANITA RAMPLING RODERIC E. WARREN P. J. BERRY DAVID SWIRSKY C. E. HOGGARTH P. C. BEVAN
Addenbrooke’s Hospital,
Cambridge CB2 2QW
RELAPSING HEPATITIS ASSOCIATED WITH HEPATITIS A VIRUS
SIR,-Does acute hepatitis A ever relapse? Studies of recurrent episodes of viral hepatitis in drug addicts failed to implicate either
hepatitis A virus (HAV) or hepatitis B virus (HBV) in more than one episode of hepatitis in any individual.A recent study of acute viral hepatitis included six patients who were said to have relapsed.2 Two had evidence of infection with HAV, three with HBV, and one with a non-A, non-B agent. However, the exact nature of these relapses was not clear. To our knowledge, no other report of relapsing acute hepatitis A has appeared since the introduction of specific serological tests put the diagnosis of HAV infection on a firm
Last year
we
encountered five young
patients (three
in
Birmingham and two in Sheffield) who presented with typical acute viral hepatitis. HAV infection was confirmed by the detection of anti-HAV IgM in the blood by radioimmunoassay; all five patients were negative for hepatitis B surface antigen (HBsAg) by passive haemagglutination.3All five patients made a rapid clinical recovery and liver function tests improved strikingly in four (table). However, between 7 and 10 weeks after the onset of the initial illness all five patients again became jaundiced and were admitted to hospital. Their blood remained positive for anti-HAV IgM and negative for HBsAg. Cytomegalovirus antibody titres were negative in the four patients tested. Serum transaminase levels were very high, as in the first episode (table). Serum IgG levels were raised in four patients and antinuclear factor in the fifth. A liver biopsy was done on patient 3 at the time of her relapse and showed histological features typical of acute viral hepatitis. All patients recovered spontaneously and were discharged from hospital within 2 weeks of admission. 6 months after discharge all were well and had normal liver function tests, although serum IgG levels remained high in three patients and smooth muscle antibodies were still detectable in two. At this stage we can only speculate as to the cause of these relapses. There are several possibilities. Firstly, HAV may not have been eliminated during the first episode of hepatitis and was thus able to produce a second clinical infection. Secondly, HAV may have triggered an autoimmune response, leading to liver damage. Low titres of smooth muscle antibodies are, however, a common finding in acute viral hepatitis,4 whilst the presence of unusually high levels of serum IgG may simply reflect the chronicity of the illness. Thirdly, the second episode of hepatitis could have been caused by an unrelated non-A, non-B agent. This seems unlikely: no patient had had a recent blood transfusion or was a drug addict or homosexual. The interval between the onset of the two episodes was 7-10 weeks. This supports a fourth, intriguing possibility suggested by the work of Dr Raimondo and his colleagues (Jan. 30, p. 249). They offer evidence that two discrete episodes of hepatitis can result from the sequential expression of two agents-namely, HBV and the socalled delta agent. Delta is believed to be a virus that is invariably associated with HBV and unable to replicate without it. Such viral "complementation" is not rare, occurring both within and between many virus groups.5 Thus, despite the major differences between HBV and HAV it is nevertheless possible that the two episodes of hepatitis in our patients resulted from the expression first of HAV and then of another associated virus. Having encountered five such cases in six months we suspect that relapsing hepatitis associated with HAV is more common then is realised. We thank the their assistance.
Regional
Virus
Laboratory,
East
Birmingham Hospital, for
Department of Medical Microbiology, Medical School,
University of Birmingham, Birmingham B15 2TJ Lodge Moor Hospital, Sheffield Department of Communicable and Tropical Diseases, East Birmingham Hospital
L. D. GRUER M. W. MCKENDRICK
N. J. BEECHING A. M. GEDDES
footing. GL, Skidmore SJ, McKendrick MW, Geddes AM. Sporadic non A non B hepatitis in Birmingham. J Infect 1981; 3: 45-49. Ajdukiewicz AB, Dudley FJ, Fox RA, Doniach D, Sherlock S. Immunological studies in an epidemic of infective short incubation hepatitis. Lancet 1972; i: 803-06. Fenner F, McAuslan BR, Mims CA, Sambrook J, White DO. The biology of animal viruses. New York and London: Academic Press, 1974: 302-09
3. Busher 1 Norkrans G, Frösner G, Hermodsson
4.
2
5.
S, Iwarson S. Multiple hepatitis attacks in drug addicts. JAMA 1980; 243: 1056-58. Weir WRC, Mellor JA, Smith H, Tyrrell DAJ. Significance of hepatitis enzyme levels at discharge in acute viral hepatitis.J Infect 1981, 3: 309-15. DETAILS OF
5 PATIENTS WITH RELAPSING HEPATITIS ASSOCIATED WITH HAV
SIR,-While your June 12 editorial on the treatment of migraine on platelet factors as the cause of migraine, none of the therapies mentioned directly addressed the altered vasoactivity of
focused
the cerebral circulation. Most migraines include a prodromal phase of cerebrovascular vasoconstriction. Intracarotid xenon injection techniques have demonstrated decreased regional cerebral blood flow during the prodrome, with resultant cerebral ischaemia.l,2 The ischaemia probably accounts for the neurological accompaniments in
migraines. Calcium channel blockers act on vascular smooth muscle to prevent contraction. They serve to decrease vasospasm and reduce ischaemia in the heart,3brain,4and retina.5 If the initial phase of migraine is due to vasoconstriction and if calcium channel blockers inhibit this vasoconstriction these agents should be effective in
migraine prophylaxis. Flunarizine, a calcium channel blocker now available in Europe, is effective in the prophylaxis of migraine.Our experience with an individual who had not responded to previous treatments, including propranolol, tricyclics, lithium, and biofeedback, showed that oral verapamil can be effective in migraine prophylaxis. We have since undertaken a randomised, double-blind, placebo controlled study to assess the efficacy of verapamil in migraine prophylaxis in the large
migraine population. While it is still too early to state the proper role of calcium channel blockers in the treatment of migraine, they may offer hope for patients in whom standard migraine prophylaxis has failed. Internal Medicine, U.S.A.F. Medical Center, Wright-Patterson AFB, Ohio 45433, U.S.A.
it has the weakest association with tardive dyskinesia. 10 Dopamine receptor binding studies suggest paucity of extrapyramidal sideeffects is due to thioridazine’s site specific blockade of limbic dopamine receptors. II Furthermore, it appears that extrapyramidal side-effects are correlated with blood levels of thioridazine sidechain sulphone. 12 Any contribution made by thioridazine to the clinical picture described by Murdoch and Williamson may be due to idiosyncratic metabolism of thioridazine. V.A. Downtown Medical Center,
Medical College of Georgia, Augusta, Georgia 30910, U.S.A.
RICHARD L. BORISON
Department of Human Biology and Health, University of Surrey, Guildford, Surrey
ANTHONY J. BLOWERS
SIR,-The report by Dr Murdoch and Professor Williamson and subsequent correspondence has reminded me of a Malaysian student who came to see me several months ago. He was very worried at the prospect of flying to Spain for a holiday, claiming that flying had a peculiar effect on him. Not long after take-off on two previous flights he had experienced muscle spasms around his neck and shoulders which pulled his face and head into bizarre positions, to his alarm and to the consternation of fellow travellers. These spasms would continue for much of the flight and even persist for an hour or two after landing. On closer questioning I discovered that he had been taking prochlorperazine for travel sickness. Health Centre, 20 Cleveland Square, Middlesbrough, Cleveland TS 12NX
Department of
GLEN D. SOLOMON
NOT PARKINSON’S DISEASE
SlR,—Dr Murdoch and Professor Williamson (May 29, p. 1212) presented four cases of apparent drug-induced parkinsonism in elderly patients on low doses of phenothiazines, thioridazine in three cases. This side-effect was still evident even after the drug had been discontinued for over a month. Although we agree that parkinsonism may be a frequent concomitant of neuroleptic use in the elderly, in the four cases presented there is very little to substantiate the contribution of neuroleptics to the clinically observed neurological disabilities. Were the patients taking other drugs? Elderly patients are often on antihypertensive therapy and some antihypertensive drugs are notorious for their ability to produce parkinsonism. As long as 6 weeks after discontinuation of thioridazine parkinsonism was still manifest. Drugs are almost totally eliminated after ten half-lives, so elimination of thioridazine would be complete by 160 h. Without thioridazine blood levels, it is highly speculative to attribute parkinsonism to it as long as a month after drug withdrawal. In large multicentre controlled studies thioridazine had the lowest frequency of extrapyramidal side-effects;in some cases the incidence was no greater than that for placebo.In well controlled studies in geriatric patients thioridazine produced less parkinsonism than did other neuroleptics,8,9 and we have found that
H.J. WATERS
ATYPICAL CLOSTRIDIUM DIFFICILE COLITIS IN NEUTROPENIC PATIENTS
SIR,-Experience in an outbreak of thirteen cases of Clostridium difficile colitis in the Cambridge leukaemia unit over the past three years has shown that an atypical, previously unrecognised clinical picture is not uncommon in neutropenic patients. Some of these patients lack the characteristic colonic pseudomembranes, they often have no diarrhoea, and ascites, severe jaundice, and acute abdominal symptoms develop early in their illness. Changes in the colon may be difficult to recognise at post mortem because of autolysis. A recent case, operated on for presumed peritonitis, having been diagnosed clinically on the basis of ascites, jaundice, and an acute abdomen, has provided us with unusual material for histology. A 17-year-old boy in his first relapse of acute lymphoblastic leukaemia became feverish while neutropenic after remission induction therapy and was treated with two 5 day courses of parenteral antibiotics, including cephalosporins and systemic vancomycin. On the fifth day of the second course he complained of colicky central abdominal pain and over the next 8 h tenderness and guarding in the right iliac fossa developed, with abdominal distension, scanty bowel sounds, and icterus. He had vomited several times but did not have diarrhoea. A diagnosis of pseudomembranous colitis was suspected by one of us (D. S.) who had seen similar cases during an outbreak at another leukaemia unit. Despite severe neutropenia and thrombocytopenia an emergency laparotomy was done. The ascending colon was much thickened and oedematous and a right hemicolectomy was done. Bowel contents taken for C. difficile toxin estimation and culture and subsequently found to be positive. Postoperatively the patient again became febrile and the jaundice deepened rapidly. Total bilirubin 276 mol/1 (normal 2-14); alanine transferase 58 U/1 (normal 7-40), were
1.
Skinhoj E. Hemodynamic studies within the brain during migraine. Arch Neurol 1973;
29: 95-98. 2. Edmeads J. Cerebral blood flow in migraine. Headache 1977; 17: 148-52. 3. Karlsberg R, Welcome: The calcium channel blockers. Chest 1981; 80: 657-59. 4. Louis P. A double-blind placebo-controlled prophylactic study of flunarizine in migraine. Headache 1981; 21: 235-39. 5. Nihard P. Effect of calcium-entry-blockers on arterioles, capillaries, and venules ofthe retina. Angiology 1982; 33: 37-45. 6. Galbrecht CR, Klett CJ. Predicting response to phenothiazine: the right drug for the right patient. J Nerv Ment Dis 1968; 147: 173-83. 7. Schiele BC, Vestre ND, Stein KE. A comparison of thioridazine, trifluoperazine, chlorpromazine, and placebo: a double-blind controlled study on the treatment of chronic, hospitalized, schizophrenic patients. J Clin Exp Psychopathol 1961; 22: 151-62. 8. Branchey MH, Lee JH, Amin R, et al. High- and low-potency neuroleptics in elderly psychiatric patients. JAMA 1978; 239: 1860-62.
9.
Cowley LM, Glen RS. Double-blind study of thioridazine and haloperidol in geriatric patients with a psychosis associated with organic brain syndrome. J Clin Psychiatry
1979; 40: 411-19. AJ. Epidemiology of tardive dyskinesia in the elderly. Neuropharmacology 1981; 20: 1339-40. 11. Borison RL, Fields JZ, Diamond BI. Site specific blockade of dopamine receptors by neuroleptic agents in human brain Neuropharmacology 1981; 20: 1321-22. 12. Axelsson R. On the serum concentrations and antipsychotic effects of thiondazine, thioridazine side-chain sulfoxide and thioridazine side-chain sulfone, in chronic psychotic patients. Curr Ther Res 1977; 21: 587-605. 10. Blowers
163
phosphatase 100 Uti (normal 30-135). Parenteral ampicillin, metronidazole, and gentamicin were given and oral vancomycin was started as soon as the patient could take oral fluids. His condition improved and stools became C. difficile culture and toxin negative but he had a relapse of his C. difficile colitis 31f2 weeks later, having had no antibiotics for the preceding 2 weeks. alkaline
The mucosal surface of the resected colon was oedematous with focal haemorrhages but no mucosal ulcers or exudate. Mesenteric vessels were patent. On microscopy the caecal epithelium and lamina propria were viable with patchy necrosis of the muscularis mucosae, striking necrosis, and oedema of the submucosa and focal necrosis of the muscularis propria especially its inner layer. The serosa was oedematous and covered with a fine layer of fibrin. Thrombi were present only in small vessels of the necrotic area. In view of the finding of C. difficile toxin multiple sections of the specimen were taken. These revealed a single focus of mucosal necrosis 2 mm across. Gram-positive rods were seen in large numbers beneath this. There was no pseudomembrane and virtually no cellular .reaction. Other sections showed occasional grampositive rods in the oedematous submucosa suggesting a spreading infection. We have seen four similar presentations without pseudomembranes in the past 2 years and only one of these cases had diarrhoea. C. difficile and its toxin were detected in the bowel contents of all four. Only two of these patients were not receiving intravenous vancomycin or metronidazole and both yielded C. difficile from large volume (45 ml) blood cultures. In many leukaemia units patients receive intensive, and in many cases prophylactic, antibiotic therapy, and we suspect that this unusual presentation is being missed and that the illness may be incorrectly attributed to cytotoxic therapy alone or to demonstrable bacteraemia with commoner faecal organisms. We believe the unusual clinical and pathological features represent a progressive invasive infection from a small area of mucosal necrosis produced by toxigenic C. difficile in patients who are unable to localise the organism because of their associated neutropenia. ANITA RAMPLING RODERIC E. WARREN P. J. BERRY DAVID SWIRSKY C. E. HOGGARTH P. C. BEVAN
Addenbrooke’s Hospital,
Cambridge CB2 2QW
RELAPSING HEPATITIS ASSOCIATED WITH HEPATITIS A VIRUS
SIR,-Does acute hepatitis A ever relapse? Studies of recurrent episodes of viral hepatitis in drug addicts failed to implicate either
hepatitis A virus (HAV) or hepatitis B virus (HBV) in more than one episode of hepatitis in any individual.A recent study of acute viral hepatitis included six patients who were said to have relapsed.2 Two had evidence of infection with HAV, three with HBV, and one with a non-A, non-B agent. However, the exact nature of these relapses was not clear. To our knowledge, no other report of relapsing acute hepatitis A has appeared since the introduction of specific serological tests put the diagnosis of HAV infection on a firm
Last year
we
encountered five young
patients (three
in
Birmingham and two in Sheffield) who presented with typical acute viral hepatitis. HAV infection was confirmed by the detection of anti-HAV IgM in the blood by radioimmunoassay; all five patients were negative for hepatitis B surface antigen (HBsAg) by passive haemagglutination.3All five patients made a rapid clinical recovery and liver function tests improved strikingly in four (table). However, between 7 and 10 weeks after the onset of the initial illness all five patients again became jaundiced and were admitted to hospital. Their blood remained positive for anti-HAV IgM and negative for HBsAg. Cytomegalovirus antibody titres were negative in the four patients tested. Serum transaminase levels were very high, as in the first episode (table). Serum IgG levels were raised in four patients and antinuclear factor in the fifth. A liver biopsy was done on patient 3 at the time of her relapse and showed histological features typical of acute viral hepatitis. All patients recovered spontaneously and were discharged from hospital within 2 weeks of admission. 6 months after discharge all were well and had normal liver function tests, although serum IgG levels remained high in three patients and smooth muscle antibodies were still detectable in two. At this stage we can only speculate as to the cause of these relapses. There are several possibilities. Firstly, HAV may not have been eliminated during the first episode of hepatitis and was thus able to produce a second clinical infection. Secondly, HAV may have triggered an autoimmune response, leading to liver damage. Low titres of smooth muscle antibodies are, however, a common finding in acute viral hepatitis,4 whilst the presence of unusually high levels of serum IgG may simply reflect the chronicity of the illness. Thirdly, the second episode of hepatitis could have been caused by an unrelated non-A, non-B agent. This seems unlikely: no patient had had a recent blood transfusion or was a drug addict or homosexual. The interval between the onset of the two episodes was 7-10 weeks. This supports a fourth, intriguing possibility suggested by the work of Dr Raimondo and his colleagues (Jan. 30, p. 249). They offer evidence that two discrete episodes of hepatitis can result from the sequential expression of two agents-namely, HBV and the socalled delta agent. Delta is believed to be a virus that is invariably associated with HBV and unable to replicate without it. Such viral "complementation" is not rare, occurring both within and between many virus groups.5 Thus, despite the major differences between HBV and HAV it is nevertheless possible that the two episodes of hepatitis in our patients resulted from the expression first of HAV and then of another associated virus. Having encountered five such cases in six months we suspect that relapsing hepatitis associated with HAV is more common then is realised. We thank the their assistance.
Regional
Virus
Laboratory,
East
Birmingham Hospital, for
Department of Medical Microbiology, Medical School,
University of Birmingham, Birmingham B15 2TJ Lodge Moor Hospital, Sheffield Department of Communicable and Tropical Diseases, East Birmingham Hospital
L. D. GRUER M. W. MCKENDRICK
N. J. BEECHING A. M. GEDDES
footing. GL, Skidmore SJ, McKendrick MW, Geddes AM. Sporadic non A non B hepatitis in Birmingham. J Infect 1981; 3: 45-49. Ajdukiewicz AB, Dudley FJ, Fox RA, Doniach D, Sherlock S. Immunological studies in an epidemic of infective short incubation hepatitis. Lancet 1972; i: 803-06. Fenner F, McAuslan BR, Mims CA, Sambrook J, White DO. The biology of animal viruses. New York and London: Academic Press, 1974: 302-09
3. Busher 1 Norkrans G, Frösner G, Hermodsson
4.
2
5.
S, Iwarson S. Multiple hepatitis attacks in drug addicts. JAMA 1980; 243: 1056-58. Weir WRC, Mellor JA, Smith H, Tyrrell DAJ. Significance of hepatitis enzyme levels at discharge in acute viral hepatitis.J Infect 1981, 3: 309-15. DETAILS OF
5 PATIENTS WITH RELAPSING HEPATITIS ASSOCIATED WITH HAV