BRITISH MEDICAL JOURNAL
1405
18 NOVEMBER 1978
MEDICAL PRACTICE
Clinicopathological Conference Two
cases
of drug-induced disease
DEMONSTRATION AT THE ROYAL COLLEGE OF PHYSICIANS OF LONDON British
Medical_Journal, 1978, 2,
1405-1410
The quarterly clinicopathological conference held at the Royal College of Physicians of London on 27 April 1978 was introduced by Professor W I Cranston (1) who presented the first case. Case 1-Clinical summary PROFESSOR CRANSTON: The patient was a 27-year-old girl who worked for one of the nursing organisations. That fact significantly and wrongly coloured our attitude to the problem. She had had whooping cough in childhood and had developed bronchiectasis for which the lingula and left lower lobe had been removed in 1973. Since then she had had tetracycline during the winter months. Her father had died two months before the onset of her illness. On 23 November 1975 she was flying back from visiting- her mother in Ireland and suddenly became very thirsty. She drank about six bottles of Coca-Cola during the flight, and this severe polydipsia persisted with polyuria up to 12 times a day and twice at. night until her admission two weeks later. She had had influenza vaccine, two weeks before the onset but no other medication, and she had also then had a mild chest infection with some greenish sputum. Her general practitioner wrote that she was a level-headed young woman who was happy with her job and home. She was admitted on 2 December, when she had some crepitations in the lower left chest and an old lobectomy scar. She was producing seven or eight litres of urine a day with no chemical abnormality. The serum calcium and potassium concentrations were normal, as were the results of the liver function and glucose tolerance tests. The plasma urea concentration varied between 2-4 and 6-0 ,umol/l and the plasma creatinine concentration between 60 and 140 ,mol/l. We were left with a presumptive diagnosis of either diabetes insipidus or over-drinking.
After 13 hours of dehydration the urine osmolality was between 209 and 450 mmol (mosmol)/kg and the plasma osmolality between 304 and- 306 mmol/kg. Her weight loss was only 1-6 kg (starting weight 59 kg), although she said she had passed some unmeasured urine during the night. We, thought that she -was cheating us and was overdrinking. Another water deprivation test did, however, produce a maximum urine osmolality of 564 mmol/kg, which is certainly less than a person of this age should achieve. After vasopressin she achieved a urine osmolality of 562 mmol/kg and was able, after ammonium chloride loading, to acidify her urine to pH 4 9. After further discussion the penny dropped, and she was restored to normality. I am afraid that there is no disease, but I will now ask Dr Ledingham to give his views on the problem.
Diagnosis DR J G G LEDINGHAM (2): Thank you. In the absence of disease there is always room for argument. The problem then is why the sudden onset of thirst and polyuria in this girl. She was admitted nine days after her first symptom with 24-hour urine volumes of seven to eight litres. This does not really help us in deciding between Professor Cranston's possible diagnoses. Such urine volumes are compatible with various forms of nephrogenic diabetes insipidus, pituitary diabetes insipidus, or compulsive polydipsia. Perhaps I should begin with the history. Our patient had bronchiectasis and had undergone lobectomy, which suggests that the bronchiectasis was severe and of long standing. One might therefore consider, however reluctantly, that renal tubular amyloidosis was playing some part.- Another point in the history is that she was given tetracyclines in the winter, but we do not know if this was taken continually or only when her sputum was infected. This is a potentially important question. PROFESSOR CRANSTON: Continually for about six months each year.
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LEDINGHAM: I shall come back to these points, but the suggests. that in the first instance the doctors were considering compulsive drinking. The patient's father died recently; we do not know too much about her occupation; and her doctor's letter indicates uncertainty as to whether or not psychological factors were likely to be of importance in her case. In discussing the different'ial diagnosis in more detail I shall take the group of conditions associated with nephrogenic diabetes insipidus first, because the results of the water deprivation test are very much against there being a pituitary lesion. The investigations appear to rule out an acquired Fanconi syndrome, Sjogren's syndrome, and liver cirrhosis. Her renal function is too good for such disorders as nephrolithiasis, polycystic disease, or interstitial nephritis. Amyloidosis has been reported to cause nephrogenic diabetes insipidus,' 2 but this is rare. She did not have hypercalcaemia or hypokalaemia. Another form of nephrogenic diabetes insipidus is that associated with protein starvation, which results in a low urea concentration in the renal medulla. Medullary hyperosmolarity is lost with resultant reduction of maximal urinary concentration similar to that reported in this case. But we are not given any hint that our patient has anorexia nervosa nor any other form of protein malnutrition. Chronic sodium depletion may also lead to a form of nephrogenic diabetes insipidus in which we expect that the small amounts of sodium chloride eaten are reabsorbed avidly by the proximal renal tubules before delivery to the ascending limb of Henle's loop, where the chloride is actively reabsorbed and the work is done to make the medullary tissues hypertonic. In the absence of medullary hypertonicity, urine cannot be concentrated normally, even if antidiuretic hormone (ADH) is secreted and its action on the adenyl cyclase system of the collecting ducts is intact. Chronic water overload also causes a form of nephrogenic diabetes insipidus and is certainly a possible diagnosis on the information given. People who habitually drink seven or eight litres a day do have difficulty in concentrating their urine, probably because of washout of solute in the renal medulla. In summary thus far then, the fact that the patient could not concentrate her urine well and that there was no improvement DR
story
after'vasopressin'is compatible with chronic protein starvation, sodium depletion, or habitual water overload. To rule out these possibilities complete investigation requires, observation of the effects of several days of high protein feeding and adequate salt intake and water restriction. I take it that these tests were not considered'"tecessary ? PROFESSOR CRANSTON:
They
were not.
In considering- further the possibility of compulsive over-drinking it would be interesting to find out whether the plasma osmolarity fluctuated from day to day. In psychogenic polydipsia one would expect the plasma to be rather hypotonic with a lowish plasma sodium concentration, which is variable from day to day. In contrast, in pituitary or nephrogenic diabetes insipidus plasma osmolarity would be on the high side because here the hypertonicity is itself the stimulus' to drink. I am not sure if the plasma osmolarity of 304-306 mmol/kg was just when she was being deprived of water or was the figure at which she normally ran ? PROFESSOR CRANSTON: She ran at about 300 mmol/kg. DR LEDINGHAM: 'This is very muich- against psychogenic polydipsia, a condition in which one would expect a much lower figure; indeed such patients may continue to drink even when being given ADH, and .thereby run into trouble with hyponatraemia and water introxication. I wish to consider the drug-induced syndromes of inephrogenic diabetes insipidus later; but first what of possible central causes ? Compulsive drinking is a candidate here too, but there DR LEDINGHAM:
is nothing to suggest a hypothalamic lesion, or disease in the region of the third ventricle. Could she have pituitary diabetes insipidus? In favour of it is that the onset was particularly sudden, whereas the onset in psychogenic cases is generally rather vague. But unless you argue that the nephrogenic component shown by the concentration tests after vasopressin
18 NOVEMBER 1978
can be acquired in pituitary diabetes all the pituitary causes seem unlikely. Let us return then to nephrogenic diabetes insipidus. She might have renal amyloid-but I have traced only three case reports' 2 of renal tubular amyloid without uraemia. All patients presented with less severe polyuria than in this patient, and none were very convincing. Finally, what of drugs ? The agents that can interfere with urinary concentration are numerous-lithium carbonate, demethylchlortetracycline (Demeclocycline) (both used to treat the syndrome of inappropriate secretion of ADH), methoxyflurane anaesthesia, amphotericin B, propoxyphene, glibenclamide, and out-dated parenteral tetracycline. Methoxyfluorane anaesthesia, amphotericin B, and glybenclamide are not at all likely. I take it that she was not taking lithium carbonate. But she might have been taking demethylchlortetracycline for her bronchiectasis. This drug has had a lot of publicity recently, because at certain dose levels it is apt to produce a degree of nephrogenic diabetes insipidus.3 It has been used to treat the syndrome of inappropriate ADH secretion,4 and there is a recent report of its use in the treatment of congestive cardiac failure.5 Demethylchlortetracycline interferes with the action of ADH on the cells of the collecting duct, and the effect is dose dependent. The mechanism appears to be twofold. There is interference with the activation of adenyl cyclase in the tubular cells by circulating ADH, and the effects of cyclic 3'5' adenosine monophosphate on the renal tubular membranes are also inter-
fered with. If this patient's illness was due to demethylchlortetracycline she ought to have been taking a big dose (according to Singer's experiments3) or she may have been more susceptible because of reduced protein binding, altered hepatic handling, or renal excretion, or in association with prolonged treatment. In conclusion, the most likely diagnosis here is that the patient did have nephrogenic diabetes insipidus caused by demethylchlortetracycline given here chronically for her bronchiectasis. None of the other possibilities are very attractive. She ought to have been taking it in a dose of at least 600 mg a day for-at least a month and to have continued to take it after admission to St Thomas's Hospital; and she should have begun to improve about three weeks after it was stopped. It has a rather longer half-life than the commoner forms of tetracycline. Other less likely possibilities include renal amyloidosis, protein starvation, and compulsive polydipsia: but I will settle for demethylchlortetracycline. PROFESSOR CRANSTON: That is absolutely right. We went back and asked her what drugs she had been taking. In previous years she had been given tetracycline; this year, her treatment was changed to 600 mg/day of demethylchlortetracycline about a month before the onset of her illness. After stopping it she did get better, although it took about two months. Her most recent osmolality was 950 mmol/kg. What fooled us was the sudden onset. We have sent a yellow card to the Committee on Safety of Medicines. DR J H H MACRAE (3): Did you think of a cerebral abscess and whether she was taking frusemide or something similar, either mischievously or by dispenser's error ? PROFESSOR CRANSTON: We considered several factors of this sort but found no evidence. There were no signs of a neurological lesion. DR J HAMPSON (4): Would Dr Ledingham enlarge on the question of out-of-date tetracyclines ? DR LEDINGHAM: They have to be given parenterally and in high doses to produce a Fanconi lesion with glycosuria, phosphaturia, urate leak, and renal tubular acidosis rather than straight diabetes insipidus. That is why I did not consider them. DR J H ROSS (5): Have you any idea why it came on so dramnatically during air travel ? DR LEDINGHAM: No, I have not. I think it is quite uncharacteristic. PROFESSOR CRANSTON: I'd like to ask Dr Farebrother to present the second case.
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18 NOVEMBER 1978
Case 2-Clinical summary DR M J B FAREBROTHER (6): The second patient is a white man aged 65 who used to be employed as a butcher, more recently as a messenger, and is now retired. Until August 1977 he had smoked 20 cigarettes a day but gave up when he became ill. He had had a myocardial infarct in 1967 but no subsequent angina or shortness of breath. In August 1977 he developed a painless lump in the neck on the left side below the mandible. It was biopsied and was reported as a lymph node showing diffiuse lymphoblastic lymphoma. He was referred to the radiotherapy department, where he has been treated by Dr Thelma Bates, to whom I am grateful for permission to present the case. In mid-September he was well but was found to have slow atrial fibrillation. He had an apical pansystolic murmur radiating to the axilla. The chest was clear. There were palpable lymph nodes in the left supraclavicular fossa, and also small ones in the axillae and inguinal regions. The liver was just palpable, but the spleen could not be felt. On the chest radiograph the heart was slightly enlarged but there was no other abnormality. His lymphoma was treated with oral chlorambucil, starting with 5 mg twice a day, and the dose being reduced to 5 mg daily a fortnight later. After a month on chlorambucil he was well, and his weight was steady but the nodes were unchanged. So the chlorambucil was stopped and prednisolone (10 mg three times a day), cyclophosphamide (100 mg daily), and vincristine (1 mg intravenously weekly) were started. After another month all the nodes except one in the supraclavicular fossa had disappeared. On 1 December he was admitt-ed as an emergency complaining of breathlessness. Although he said this had come on rather quickly four days previously, he was vague, and he may have been rather short of breath for ten days or more. He was anorexic and a little nauseated. He had a cough with white sputum but no haemotysis. He had stopped his prednisolone and cyclophosphamide four days before admission. He was unwell and short of breath even sitting in bed. His temperature varied between 36 2°C and 39 00C. He had no finger clubbing, but slight central cyanosis was noted. He was still in atrial fibrillation (80/min) and had moderate ankle oedema, but the jugular venous pressure was not raised. His blood pressure was 110/70 mm Hg. His pansystolic murmur was unchanged. The trachea was central, the lungs resonant, and the breath sounds normal with no added sounds. Only the supraclavicular node was palpable; the liver and spleen were not. Blood, urine, or sputum cultures were sterile. The white cell count was only 5 9 x 109/1, but 87% were neutrophils showing toxic granulation. The chest radiograph showed diffuse fine mottling, especially in the upper zones. On admission the prednisolone was restarted (10 mg twice daily). Five days later as all the specimens had been taken for culture and he still had a high intermittent fever he was started on a cocktail of gentamicin (60 mg intramuscularly every eight hours), amoxycillin (500 mg thrice daily by mouth), and flucloxacillin (500 mg thrice daily by mouth). He also had oral candidiasis so nystatin mouth washes were prescribed. On 9 December he was more breathless than on admission and was still feverish. He now had definite finger clubbing and fine crackling end-inspiratory crepitations could be heard in his chest on both sides. His liver was palpable three finger-breadths below the right costal margin but was not tender. The chest radiograph showed reticulonodular shadowing especially in the upper zones, more on the right (fig 1). He was too breathless for spirometry, but his blood gases showed quite a low Po2 (55 mm Hg, 7?3 kPa), the Pco2 (29 mm Hg, 3 9 kPa) was also low and the pH (7 53) rather high. Many investigations for infections were negative. The positive ones were a cytomegaloVirus complement fixation titre of 1/32 on 6 December, rising, to 1/256 on 12 December; the corresponding cytomegalovirus specific IgM antibody.titres were 1/8 and 1/32. Although herpes simplex was grown from throat swabs and he had a herpetic lesion orn his lip, the antibody titres on 6 Decembe'r and 12 December were both 1/20. As his fever was unaltered by the
.;.: . .
.
.:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.
FIG I-Chest radiograph showing reticulonodular shadowing upper zones, more on right.
especially in
FIG 2-Biopsy specimen being taken from right upper lobe using a fibreoptic bronchoscope.
antibiotic cocktail it was stopped on 12 December, and the temperature became normal within 48 hours. The electrocardiogram showed old inferior myocardial infarction. Echocardiography showed deep pansystolic prolapse of the posterior mitral valve leaflet but no vegetations. He was still ill, and.four transbronchial lung biopsy specimens were taken from the right upper lobe on 16 December using a fibreoptic bronchoscope
(fig 2).
PROFESSOR CRANSTON: Thank you. I am going to ask Dr P Davies to give his views on the nature of the problem.
Diagnosis DR PETER DAVIES (7): This is the classic chest physician's dilemma of the 1970s. The patient has a disease, in this case a
1408 lymphoma, which can cause these respiratory symptoms and radiographic signs. He has a disease and is having treatment which may cause immunosuppression, so he is a candidate for all types of opportunistic infections that might produce this clinical and radiological picture. Lastly, he has been taking drugs that can produce these symptoms, signs, and shadows on the radiographs. All experience teaches that in this situation one should not stand at the end of the bed and speculate but get to work and perform a lung biopsy. The sicker the patient the more he needs a biopsy. He may need blood transfusion or platelet transfusion to make it safe but it must be done, and it was done here. His doctors chose the fibreoptic technique with fluoroscopic control. This is probably the safest technique-there is a small risk of pneumothorax and a small risk of bleeding. The difficulty is that it produces very small bits of tissue on which many things may need to be done-microbiology, histology, and electronmicroscopy. Fibreoptic biopsies produce the answer in this type of diffuse disease in about 60% of 'cases. Percutaneous needle biopsy may raise this to 65% and drill biopsy to 76% But there is much more risk of pneumothorax-about 30% in our hands. Lastly, you may perform an open lung biopsy. This is a major procedure but you do obtain a satisfactory specimen and a positive answer in 85% of cases. This man has a lymphoma with a bad prognosis-it is diffuse and poorly differentiated. As he was 65 they began gentle 'reatment, with chlorambucil. After a month they changed to cyclophosphamide, prednisolone, and vincristine, and he improved. But three weeks later he was admitted urgently with respiratory symptoms and fever. The differential diagnosis is enormous-recurrence of lymphoma, opportunistic infections, and drug reactions. Statistically the best bet is infection; about 80% of patients with lymphomas die with infection, 45% with pneumonia. Non-Hodgkin's lymphoma may invade the lung, and unlike Hodgkin's disease, without radiological evidence of mediastinal and hilar lymph nodes being affected. But lymphosarcoma does not affect the lung in more than perhaps 25% of cases. Drug-induced lung disease is rare. Firstly, we might dismiss the heart as the source of the trouble. He has the mitral valve prolapse syndrome; probably his inferior myocardial infarction 10 years before has left him with an ischaemic papillary muscle. But we should just perhaps remind ourselves that the mitral valve prolapse syndrome may be responsible for chest pain, which can suggest atypical ischaemic pain and may also be responsible for ECG changes looking like inferior myocardial infarction. However that may be, there is nothing to suggest that this man was in cardiac failure and, therefore, we cannot invoke pulmonary oedema as the explanation for widespread pulmonary shadowing, nor is there anything to suggest bacterial endocarditis to account for his fever. The first possibility we have to consider is that we are dealing with a recurrence of lymphoma. The most' importit argument against this is that the superficial lymph nodes had regressed; while it is just possible for a lymphoma to regress at one site and advance at another simultaneously it does seem highly improbable. Another small point is that he developed finger clubbing. Although clubbing has been reported with Hodgkin's disease, I have not seen a patient with non-Hodgkin's lymphoma who developed it. Next we must try to decide whether he has an infection. The lymphoproliferative diseases themselves can cause hypogammaglobulinaemia and render the patient susceptible to bacterial infection, particularly pneumonic infections, and in addition he was being treated with immunosuppressive drugs. The toxic granulation suggested bacterial infection. He was treated withgentamicin, flucloxacillin, and amoxycillin, which would cover the Gramn-negative organisms and staphylococci. Perhaps we should think of the organism that causes legionnaire's disease as it has been reported in renal transplant patients and is
susceptible to erythromycin. I don't think we need seriously consider the possibility of herpes simplex. Interestingly, in the immunosuppressed patient
BRITISH MEDICAL
JOURNAL
18 NOVEMBER 1978
serological reactions often remain while the skin reactions are often lost. On the other hand, the titres of antibodies to cytomegalovirus are definite. Although we know that 80% of normal adults have some positive reaction, the increases here are significant, particularly in IgM, which is virtually diagnostic of a recent infection. Could cytomegalovirus produce this man's symptoms and signs ? Certainly in adults pneumonia is common, but the radiological picture does not really suggest cytomegalovirus pneumonia, in which there is usually indistinct nodulation, about 2-3 mm, mostly in the periphery of the lower zones. Again we come back to the finger' clubbing, and this to me excludes the possibility of cytomegalovirus as the sole cause of this man's symptoms and signs. It may explain his enlarged liver, which is otherwise difficult to account for. Cytomegalovirus infections in immunosuppressed patients are often associated with other infections. The results of tests for were negative-candida, cryptococcus, and aspergillus. We have to think of mycobacterial or atypical mycobacterial
fungi
disease, especially with lesions in the upper lobes, but I am put off tuberculosis because he presented with breathlessness and was grossly hypoxic, which would not be produced by a granulomatous process. The clubbing is also against it. Results of the sputum tests were negative. We must consider protozoal infestations-toxoplasmosis, for which there is no evidence, and Pneumocystis carinii. In the published series pneumocystis is a common cause of diffuse pulmonary disease'in immunosuppressed patients, and cytomegalovirus often goes with it. There are factors against pneumocystis, particularly the well marked signs-crepitations and finger clubbing. In pneumocystis the radiograph may show widespread shadowing, but there are usually few physical signs. The best test is the appearances on lung biopsy but the next best, the fluorescence antibody test, gave negative results, so I rule it out. That leaves us with the possibility that, apart from the cytomegalovirus infection, he had a drug-induced pulmonary reaction. I will start by asking Dr Farebrother about this' man's oxygen treatment because oxygen is probably the commonest cause of drug-induced disease-if you regard oxygen as a drug. DR FAREBROTHER: He was given oxygen on admission on 1 December, and it was continued intermittently until he improved. It was given through an MC mask so the concentration was not controlled, probably about 40-45%. DR DAVIES: We can dismiss that. He had been taking three drugs known to cause pulmonary disease and fibrosing alveolitis -chlorambucil, cyclophosphamide, and vincristine. I think I shall blame cyclophosphamide; it was the drug he was taking when he became ill and fibrosing alveolitis has been reported more often with it than with the others, though it is also probably used more. One criticism of this suggestion is that the disease continued to develop after the drug was stopped, but there are records of disease continuing and developing for months after cyclophosphamide was stopped. Another criticism may be that it developed and even worsened while he was on steroids, but fibrosing alveolitis does not always respond to withdrawal of the offending drug and the use of steroids. I am much influenced by a patient whom I looked after last year who had de.' -natomyositis and was having 80 mg of prednisolone a day. While on this dose fibrosing alveolitis appeared and progressed for over six months and ironically only responded when he was given cyclophosphamide with virtually compfete remission. So I don't think those two objections rule out the possibility of cyclophosphamide-induced alveolitis. Of the three-lymphoma, infection, and drugs-cyclophosphamide is far the most likely to have produced these symptoms and signs. So I suggest that the lung biopsy specimen will show diffuse alveolitis with changes in the alveolar and bronchiolar walls and in the lumen of the alveoli. With luck we may also see an eosinophilic inclusion of cytomegalovirus. PROFESSOR CRANSTON: Can I ask Dr Corrin to show us the pathological findings ?
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Pathological findings DR B CORRIN (8): Some of the more important findings in this biopsy specimen are negative ones. Firstly, there is no evidence of lymphoma. Secondly, there are no viral inclusions and no evidence of pneumocystis infection. Apart from an excess of bronchiolar goblet cells the only pathological finding is patchy interstitial pulmonary fibrosis (fig 3); the process is inactive with little interstitial pneumonia and no desquamation or intra-alveolar exudates. So this is an old and non-specific finding. Various causes have to be considered.
3-Transbronchial lung biopsy specimen showing moderately interstitial puionas- fibrosi with only -mild chronic interstitial pneumonia and- no intraluminal exudates (Haematoxylin and eosin x 75). FIG
severe
clinician go and look down the microscope and discuss the findings with the pathologist? Was the general practitioner involved in this case too, because if it had been a patient in a private or cottage hospital he would have discussed with the patient the pros and cons of starting treatment when he was asymptomatic ? PROFESSOR CRANSTON: I can't myself answer that. Dr Farebrother ? DR FAREBROTHER: The treatment was in the hands of the radiotherapy department, so I don't know if they did actually go and look at the sections. But in cases of this type -there is a close liaison between them and the pathology department. I don't know if the genieral practitioner was brought in, although he originally referred him with the lump in the neck and has been involved more recently. Just a few points before I bring you up to date. Left heart failure was considered and a single parenteral dose of frusemide produced no diuresis and no change in the pulmonary shadows. The echocardiogram appeared to rule out vegetations of infective endocarditis. The tuberculosis cultures were all eventually reported to be negative. We took the lung biopsy findings to mean" that the changes were due to damage by drugs. We took the advice of the virology department and ignored the cytomegalovirus titres. We favoured chlorambucil rather than cyclophosphamide as the damaging drug and, perhaps rashly, restarted him on cyclophosphamide because the nodes were getting bigger again after three weeks off it. But we covered it with larger doses of prednisolone, -60 mg a day, until 3 January and then reduced it to 40 mg a day. Certainly there was a dramatic improvement in his bre'athing. He lost his, cyanosis, and his finger clubbing went quickly. His blood gases became remarkably better, and by early January the Po, was 87 mm Hg, Pco2 36 mm Hg. This showed that the increased ventilatory drive had been removed. He was well enough to have full pulmonary function tests (see table). The
Respiratory function tests
There is nothing to suggest that the fibrosis has resulted from chronic interstitial oedema, and no asbestos bodies are seen. Neither are there any residual granulomas suggestive of causes such as sarcoidosis, eosinophilic granuloma, or extrinsic allergic alveolitis. The pathogenesis of pulmonary'fibrosis caused by cytotoxic drugs includes necrosis of the alveolar lining and organisation of mural exudates into the interstitium. There is then regeneration of alveolar lining cells, and the alveolar walls become progressively less cellular and more fibrotic. In our biopsy specimen we had an appearance compatible with this later stage, but nevertheless quite non-specific. If we are to assume that cytotoxic drugs have been responsible for the "pulmonary fibrosis'the process has evidently been going on for longer than the three weeks since the patient ceased taking cycddposphamide, and the earlier drug,' chloranbucil, appears 'to b6the more likply candidate. The pathological -diagnosis is interstitial fibrosis of uncertain cause. PROFESSOR CRANSTON:. I'd like to ask Dr Best to comment on
the virological titres. DR
JENNIFER BEST (9): We found rising
titres of complement-
fixing antibodies to cytomegalovirus and also of cytomegalovirusspecific IgM. These suggest an active infection by cytomegalovirus. But cytomegalovirus was not isolated from eight specimens of urine or from the lung biopsy specimen. Immunosuppressed patients commonly reactivate to viruses of the herpes group, such as cytomegalovirus. In one series of patients with renal transplants3 70-900h showed evidence of reactivation of cytomegalovirus, but in all cases it was subclinical. This was possibly the case here. PROFESSOR CRANSTON:
Are there any questions ?
;'DR MACRAE: On 12 September when treatment was started you say the man was well. Was treatment started on the strength of a piece of paper emanating from the laboratory or did a
Predicted ± 2 SD
.. FEV,(l,BTPS) .. .. FVC (1, BTPS) .. .. .. FEV,/FVC % VC (1,BTPS) .. .. .. .. RV (1,BTPS) TLC (1,BTPS) . .. TLCOSB (ml/min/mm Hg)
2-61-0 2-6±1-0 68-0 ±14-4 3-6±1-16 2-2±0-78 6-0±1-82 29-0±10-2
Actual 1-7 23 73-9 2-6 3-6
After salbutamol
18'
2-8 64-3
6-2
9-6
VC = Vital capacity; 1,BTPS = Litre, body temperature, pressure (prevailing atmospheric), and saturation (water vapour); RV = Residu5l volume; TLC = Total lung capacity; TLcoSB =Transfer factor for carbon monoxide (single breath method).
ratio of the forced expiratory volume in one second to the forced vital capacity (FEVj/FVG) appeared to get worse after salbutamol, but this was because the FVC responded better than the FEV1. The 'carbon monoxide transfer factor was much reduced. We thought that he probably also had some lower zone emphysema and that 'the restrictive defect that was getting better was superimposed on it. He went home, still taking cyclophosphamide and prednisolone, but was readmitted on 8 February with a left lower lobe pneumonia and effusion. Nothing was grown from the sputum, but this appeared to be a straightforward bacterial pneumonia that responded to ampicillin and flucloxacillin. The 'cyclophosphamide was stopped for two weeks during the pneumonia but was then restarted. It was finally stopped on 14 March. The nodes remained small in early March, but he became very confused and disorientated. Psychiatric advice was that this was probably due to the prednisolone, which wks by then down to 20 mg a day. So the cyclophosphamide and the prednisolone were stopped. His mental state has improved, and his lungs have remained good but the lymphoma is again advancing. PROFESSOR CRANSTON: So the connection between the cases is
1410
that both were drug-induced. This one also has been reported to the Committee on Safety of Medicines. Thank you. This conference was recorded and edited by Dr W F Whimster.
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(6) Dr M J B Farebrother, MD, MRCP, senior lecturer, Department of Medicine, St Thomas's Hospital Medical School, London SEI 7EH. (7) Dr Peter Davies, MD, FRCP, consultant chest physician, Whittington Hospital, London N19 5J G. (8) Dr B Corrin, MD, FRCPATH, reader in pathology, St Thomas's Hospital Medical School, London SE1 7EH. (9) Dr Jennifer Best, BSC, PHD, senior lecturer, Department of Virology, St Thomas's Hospital Medical School, London SEI 7EH.
APPOINTMENTS OF SPEAKERS
(1) Professor W I Cranston, MD, FRCP, professor of medicine, St Thomas's Hospital Medical School, London SE1 7EH. (2) Dr J G G Ledingham, DM, FRCP, May reader in medicine, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford OX2 6HE. (3) Dr J H H MacRae, MB, CHB, general practitioner, London SW6 2LA. (4) Dr J Hampson, physician, Northallerton and Darlington Hospital Group, Yorks. (5) Dr J H Ross, MD, FRCP, consultant physician, Hereford HR1 IJE.
References Carone, S A, and Epstein, F H, American Journal of Medicine, 1960, 29, 539. Dorhout-Mees, E J, et al, Nephron, 1968, 5, 81. 3 Singer, I, and Rotenberg, D, Annals of Internal Medicine, 1973, 79, 679. Forest, J N, et al, New England Journal of Medicine, 1978, 298, 173. Zegers de Beyl, D, et al, British Medical Journal, 1978, 1, 760. 2
MATERIA NON MEDICA Sinking Lethe-wards I recently read a first edition of Nature, which was published in 1869. A wide range of subjects were covered in the articles and book reviews. Fertilisation of plants was discussed; there was an admonition to Huxley for overexciting the Australians by discussing the physical proteinaceous basis of life; ancient dolmens and the like were described, as were moths and the "pneumogastric nerve," which, we were told, slows the heart in animals. There was an article about the voice and another on the convolutions of the brain. All were fully comprehensible to the general reader. Today's journal, however, covers the same wide range of knowledge, but has titles like "Alfven waves generated by an inverted plasma energy distribution" and "Origin of olivine subgrain boundaries in mantle periodities." Throughout, the articles are laced with mathematics such as the "Ornstein-Uhlenbeck stochastic differential equation," somewhat above any mathematics that has crossed my path. To my mind, this reflects the exponential growth of scientific knowledge since Victorian times, and the impossibility of being a general "man of science" today. It all seemed sewn up a hundred years ago. According to Frazer, there had been a natural progression from magic through religion to science, the last being the logical culmination -a triumph of common sense. The universe was held together by atoms, and Newtonian laws prevailed; the odd flaws such as radioactivity and the travel of light through the "ether" would soon be cleared up. Then came Einstein and everything changed. No more absolutes, be it space, mass, time, or velocity. Even good old Euclidian geometry had its flaws; the fifth postulate could not be proved (this upset the young Bertrand Russell). Other geometries were constructed, and one by Riemann was found to be best suited to the new Einsteinian universe. Another mathematician, the famous Henri Poincare, who lived in Paris at the time of Toulouse Lautrec, had arrived at a similar non-Euclidian geometry. A flash of insight striking him as he boarded a bus led to his now famous "Theta-Fuchsian functions." The big bang, curved space, black holes, and quarks are the mysteries of today. In some ways we are back to magic, a magic understood by a gifted few among whom, alas, I am not. I can take only "shallow draughts," which, Pope warns us, "intoxicate the brain."-R E GOODMAN (general practitioner, Northenden, Manchester). A cricketer's lament
September has always been my saddest month of the year, for with the gathering gloom and misty evenings the fall of the cricket season arrives. For enthusiasts it means either a merciful release from further batting disasters or a sombre return to handiwork at home and Saturday afternoons spent fielding the wife's shopping around town.
April seems so far distant, when we could savour the expectation of a new season, linger over the pleasure of oiling a new bat, and enjoy the thought of putting all one's new theories, acquired during months of winter reading, into practice. Unfortunately, the summer months usually demonstrate all too frequently, and at great length, the folly of one's new technique. This may produce unreasonable depression each Monday morning after another "failure," leaving patients,
colleagues, and the wife wondering at my cyclothymic personality, for by Friday evening I will be buoyant once again in expectation of another weekend's cricket. The summer afternoons speed too quickly past, leaving memories of dropped catches, torrential rain, and fleeting moments of cricket. Then August brings with it the climax to all the major cricketing competitions, increasing the anticipation of each day's results. However, this serves only to heighten the enormous anticlimax when cricket descends from its zenith to its lowest ebb. The sightscreens are dismantled, the square fenced off, the dreaded footballers encroach on the sacred outfield, and despondency envelopes me as I put my kit away for the last time. Of the future all one can look forward to is those frosty mornings spent huddled up in bed with news from Australia crackling through the dawn. Huddled, alas, in the spare bed, for the cricket widow demands no cricket at 5 30 in the morning! Poor September, hurry sweet April, you are too far away.-R J GRIEVE (medical registrar, Birmingham). Plovdiv A guidebook described Plovdiv, where the congress was to be held, as "the Manchester of Bulgaria." We were therefore pleasantly surprised to find that all the industry, and those dreary high-rise blocks of flats that go with it, had been placed well outside the city, which was as charming an old town on its six hills as you would find anywhere and well deserves its ancient name of Philippopolis. Its pedestrian trafficfree area is proportionately larger than that of any other place I know. On the first morning's after-breakfast stroll we found a Roman theatre cleverly incorporated into the main street; a Roman amphitheatre still being excavated, with students poring over buckets of earth from the excavation; and no fewer than three other sites being actively explored. The archaeological museum had those splendid Thracian gold vessels (rhytons) recently on view at the British Museum, and the ethnographical museum was a treasure house of
interesting objects. The congress itself was disappointing. Eighty per cent of the papers were in Bulgarian or Russian without simultaneous translation, but the "off-duty" activities included a glass of peculiar brandy, taken with the Abbot of an eleventh-century monastery, at 9 30 in the morning. There was also a welcoming row of charming teenage girls in peasant costume with a bottle of red and a bottle of white wine in their hands, supported by great baskets of peaches and grapes, followed by dances in which everyone joined, including the president of the congress, Professor Pavlova, the great Pavlov's grandaughter. (I wrote to the Bulgarian Embassy in London to clarify the relationship, but received no reply. Doubtless they had other things on their mind at the time.) Indeed, my guess is that the Black Sea coast may take Spain's place as the mass touring Mecca for Western Europe in the 1980s, provided that many more and better-trained waiters and waitresses are employed so that every meal is not a source of frustration and irritation. Surely any experienced waiter knows that people will be content to wait longer for their meal if the drinks they have ordered are provided first. But neither bribery nor threats to leave could produce this result in Bulgaria.-NEVILLE GOODMAN (retired medical officer of health, Sandwich, Kent).
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18 NOVEMBER 1978
MEDICAL PRACTICE
Clinicopathological Conference Two
cases
of drug-induced disease
DEMONSTRATION AT THE ROYAL COLLEGE OF PHYSICIANS OF LONDON British
Medical_Journal, 1978, 2,
1405-1410
The quarterly clinicopathological conference held at the Royal College of Physicians of London on 27 April 1978 was introduced by Professor W I Cranston (1) who presented the first case. Case 1-Clinical summary PROFESSOR CRANSTON: The patient was a 27-year-old girl who worked for one of the nursing organisations. That fact significantly and wrongly coloured our attitude to the problem. She had had whooping cough in childhood and had developed bronchiectasis for which the lingula and left lower lobe had been removed in 1973. Since then she had had tetracycline during the winter months. Her father had died two months before the onset of her illness. On 23 November 1975 she was flying back from visiting- her mother in Ireland and suddenly became very thirsty. She drank about six bottles of Coca-Cola during the flight, and this severe polydipsia persisted with polyuria up to 12 times a day and twice at. night until her admission two weeks later. She had had influenza vaccine, two weeks before the onset but no other medication, and she had also then had a mild chest infection with some greenish sputum. Her general practitioner wrote that she was a level-headed young woman who was happy with her job and home. She was admitted on 2 December, when she had some crepitations in the lower left chest and an old lobectomy scar. She was producing seven or eight litres of urine a day with no chemical abnormality. The serum calcium and potassium concentrations were normal, as were the results of the liver function and glucose tolerance tests. The plasma urea concentration varied between 2-4 and 6-0 ,umol/l and the plasma creatinine concentration between 60 and 140 ,mol/l. We were left with a presumptive diagnosis of either diabetes insipidus or over-drinking.
After 13 hours of dehydration the urine osmolality was between 209 and 450 mmol (mosmol)/kg and the plasma osmolality between 304 and- 306 mmol/kg. Her weight loss was only 1-6 kg (starting weight 59 kg), although she said she had passed some unmeasured urine during the night. We, thought that she -was cheating us and was overdrinking. Another water deprivation test did, however, produce a maximum urine osmolality of 564 mmol/kg, which is certainly less than a person of this age should achieve. After vasopressin she achieved a urine osmolality of 562 mmol/kg and was able, after ammonium chloride loading, to acidify her urine to pH 4 9. After further discussion the penny dropped, and she was restored to normality. I am afraid that there is no disease, but I will now ask Dr Ledingham to give his views on the problem.
Diagnosis DR J G G LEDINGHAM (2): Thank you. In the absence of disease there is always room for argument. The problem then is why the sudden onset of thirst and polyuria in this girl. She was admitted nine days after her first symptom with 24-hour urine volumes of seven to eight litres. This does not really help us in deciding between Professor Cranston's possible diagnoses. Such urine volumes are compatible with various forms of nephrogenic diabetes insipidus, pituitary diabetes insipidus, or compulsive polydipsia. Perhaps I should begin with the history. Our patient had bronchiectasis and had undergone lobectomy, which suggests that the bronchiectasis was severe and of long standing. One might therefore consider, however reluctantly, that renal tubular amyloidosis was playing some part.- Another point in the history is that she was given tetracyclines in the winter, but we do not know if this was taken continually or only when her sputum was infected. This is a potentially important question. PROFESSOR CRANSTON: Continually for about six months each year.
BRITISH MEDICAL JOURNAL
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LEDINGHAM: I shall come back to these points, but the suggests. that in the first instance the doctors were considering compulsive drinking. The patient's father died recently; we do not know too much about her occupation; and her doctor's letter indicates uncertainty as to whether or not psychological factors were likely to be of importance in her case. In discussing the different'ial diagnosis in more detail I shall take the group of conditions associated with nephrogenic diabetes insipidus first, because the results of the water deprivation test are very much against there being a pituitary lesion. The investigations appear to rule out an acquired Fanconi syndrome, Sjogren's syndrome, and liver cirrhosis. Her renal function is too good for such disorders as nephrolithiasis, polycystic disease, or interstitial nephritis. Amyloidosis has been reported to cause nephrogenic diabetes insipidus,' 2 but this is rare. She did not have hypercalcaemia or hypokalaemia. Another form of nephrogenic diabetes insipidus is that associated with protein starvation, which results in a low urea concentration in the renal medulla. Medullary hyperosmolarity is lost with resultant reduction of maximal urinary concentration similar to that reported in this case. But we are not given any hint that our patient has anorexia nervosa nor any other form of protein malnutrition. Chronic sodium depletion may also lead to a form of nephrogenic diabetes insipidus in which we expect that the small amounts of sodium chloride eaten are reabsorbed avidly by the proximal renal tubules before delivery to the ascending limb of Henle's loop, where the chloride is actively reabsorbed and the work is done to make the medullary tissues hypertonic. In the absence of medullary hypertonicity, urine cannot be concentrated normally, even if antidiuretic hormone (ADH) is secreted and its action on the adenyl cyclase system of the collecting ducts is intact. Chronic water overload also causes a form of nephrogenic diabetes insipidus and is certainly a possible diagnosis on the information given. People who habitually drink seven or eight litres a day do have difficulty in concentrating their urine, probably because of washout of solute in the renal medulla. In summary thus far then, the fact that the patient could not concentrate her urine well and that there was no improvement DR
story
after'vasopressin'is compatible with chronic protein starvation, sodium depletion, or habitual water overload. To rule out these possibilities complete investigation requires, observation of the effects of several days of high protein feeding and adequate salt intake and water restriction. I take it that these tests were not considered'"tecessary ? PROFESSOR CRANSTON:
They
were not.
In considering- further the possibility of compulsive over-drinking it would be interesting to find out whether the plasma osmolarity fluctuated from day to day. In psychogenic polydipsia one would expect the plasma to be rather hypotonic with a lowish plasma sodium concentration, which is variable from day to day. In contrast, in pituitary or nephrogenic diabetes insipidus plasma osmolarity would be on the high side because here the hypertonicity is itself the stimulus' to drink. I am not sure if the plasma osmolarity of 304-306 mmol/kg was just when she was being deprived of water or was the figure at which she normally ran ? PROFESSOR CRANSTON: She ran at about 300 mmol/kg. DR LEDINGHAM: 'This is very muich- against psychogenic polydipsia, a condition in which one would expect a much lower figure; indeed such patients may continue to drink even when being given ADH, and .thereby run into trouble with hyponatraemia and water introxication. I wish to consider the drug-induced syndromes of inephrogenic diabetes insipidus later; but first what of possible central causes ? Compulsive drinking is a candidate here too, but there DR LEDINGHAM:
is nothing to suggest a hypothalamic lesion, or disease in the region of the third ventricle. Could she have pituitary diabetes insipidus? In favour of it is that the onset was particularly sudden, whereas the onset in psychogenic cases is generally rather vague. But unless you argue that the nephrogenic component shown by the concentration tests after vasopressin
18 NOVEMBER 1978
can be acquired in pituitary diabetes all the pituitary causes seem unlikely. Let us return then to nephrogenic diabetes insipidus. She might have renal amyloid-but I have traced only three case reports' 2 of renal tubular amyloid without uraemia. All patients presented with less severe polyuria than in this patient, and none were very convincing. Finally, what of drugs ? The agents that can interfere with urinary concentration are numerous-lithium carbonate, demethylchlortetracycline (Demeclocycline) (both used to treat the syndrome of inappropriate secretion of ADH), methoxyflurane anaesthesia, amphotericin B, propoxyphene, glibenclamide, and out-dated parenteral tetracycline. Methoxyfluorane anaesthesia, amphotericin B, and glybenclamide are not at all likely. I take it that she was not taking lithium carbonate. But she might have been taking demethylchlortetracycline for her bronchiectasis. This drug has had a lot of publicity recently, because at certain dose levels it is apt to produce a degree of nephrogenic diabetes insipidus.3 It has been used to treat the syndrome of inappropriate ADH secretion,4 and there is a recent report of its use in the treatment of congestive cardiac failure.5 Demethylchlortetracycline interferes with the action of ADH on the cells of the collecting duct, and the effect is dose dependent. The mechanism appears to be twofold. There is interference with the activation of adenyl cyclase in the tubular cells by circulating ADH, and the effects of cyclic 3'5' adenosine monophosphate on the renal tubular membranes are also inter-
fered with. If this patient's illness was due to demethylchlortetracycline she ought to have been taking a big dose (according to Singer's experiments3) or she may have been more susceptible because of reduced protein binding, altered hepatic handling, or renal excretion, or in association with prolonged treatment. In conclusion, the most likely diagnosis here is that the patient did have nephrogenic diabetes insipidus caused by demethylchlortetracycline given here chronically for her bronchiectasis. None of the other possibilities are very attractive. She ought to have been taking it in a dose of at least 600 mg a day for-at least a month and to have continued to take it after admission to St Thomas's Hospital; and she should have begun to improve about three weeks after it was stopped. It has a rather longer half-life than the commoner forms of tetracycline. Other less likely possibilities include renal amyloidosis, protein starvation, and compulsive polydipsia: but I will settle for demethylchlortetracycline. PROFESSOR CRANSTON: That is absolutely right. We went back and asked her what drugs she had been taking. In previous years she had been given tetracycline; this year, her treatment was changed to 600 mg/day of demethylchlortetracycline about a month before the onset of her illness. After stopping it she did get better, although it took about two months. Her most recent osmolality was 950 mmol/kg. What fooled us was the sudden onset. We have sent a yellow card to the Committee on Safety of Medicines. DR J H H MACRAE (3): Did you think of a cerebral abscess and whether she was taking frusemide or something similar, either mischievously or by dispenser's error ? PROFESSOR CRANSTON: We considered several factors of this sort but found no evidence. There were no signs of a neurological lesion. DR J HAMPSON (4): Would Dr Ledingham enlarge on the question of out-of-date tetracyclines ? DR LEDINGHAM: They have to be given parenterally and in high doses to produce a Fanconi lesion with glycosuria, phosphaturia, urate leak, and renal tubular acidosis rather than straight diabetes insipidus. That is why I did not consider them. DR J H ROSS (5): Have you any idea why it came on so dramnatically during air travel ? DR LEDINGHAM: No, I have not. I think it is quite uncharacteristic. PROFESSOR CRANSTON: I'd like to ask Dr Farebrother to present the second case.
-BRITISH MEDICAL JOURNAL
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18 NOVEMBER 1978
Case 2-Clinical summary DR M J B FAREBROTHER (6): The second patient is a white man aged 65 who used to be employed as a butcher, more recently as a messenger, and is now retired. Until August 1977 he had smoked 20 cigarettes a day but gave up when he became ill. He had had a myocardial infarct in 1967 but no subsequent angina or shortness of breath. In August 1977 he developed a painless lump in the neck on the left side below the mandible. It was biopsied and was reported as a lymph node showing diffiuse lymphoblastic lymphoma. He was referred to the radiotherapy department, where he has been treated by Dr Thelma Bates, to whom I am grateful for permission to present the case. In mid-September he was well but was found to have slow atrial fibrillation. He had an apical pansystolic murmur radiating to the axilla. The chest was clear. There were palpable lymph nodes in the left supraclavicular fossa, and also small ones in the axillae and inguinal regions. The liver was just palpable, but the spleen could not be felt. On the chest radiograph the heart was slightly enlarged but there was no other abnormality. His lymphoma was treated with oral chlorambucil, starting with 5 mg twice a day, and the dose being reduced to 5 mg daily a fortnight later. After a month on chlorambucil he was well, and his weight was steady but the nodes were unchanged. So the chlorambucil was stopped and prednisolone (10 mg three times a day), cyclophosphamide (100 mg daily), and vincristine (1 mg intravenously weekly) were started. After another month all the nodes except one in the supraclavicular fossa had disappeared. On 1 December he was admitt-ed as an emergency complaining of breathlessness. Although he said this had come on rather quickly four days previously, he was vague, and he may have been rather short of breath for ten days or more. He was anorexic and a little nauseated. He had a cough with white sputum but no haemotysis. He had stopped his prednisolone and cyclophosphamide four days before admission. He was unwell and short of breath even sitting in bed. His temperature varied between 36 2°C and 39 00C. He had no finger clubbing, but slight central cyanosis was noted. He was still in atrial fibrillation (80/min) and had moderate ankle oedema, but the jugular venous pressure was not raised. His blood pressure was 110/70 mm Hg. His pansystolic murmur was unchanged. The trachea was central, the lungs resonant, and the breath sounds normal with no added sounds. Only the supraclavicular node was palpable; the liver and spleen were not. Blood, urine, or sputum cultures were sterile. The white cell count was only 5 9 x 109/1, but 87% were neutrophils showing toxic granulation. The chest radiograph showed diffuse fine mottling, especially in the upper zones. On admission the prednisolone was restarted (10 mg twice daily). Five days later as all the specimens had been taken for culture and he still had a high intermittent fever he was started on a cocktail of gentamicin (60 mg intramuscularly every eight hours), amoxycillin (500 mg thrice daily by mouth), and flucloxacillin (500 mg thrice daily by mouth). He also had oral candidiasis so nystatin mouth washes were prescribed. On 9 December he was more breathless than on admission and was still feverish. He now had definite finger clubbing and fine crackling end-inspiratory crepitations could be heard in his chest on both sides. His liver was palpable three finger-breadths below the right costal margin but was not tender. The chest radiograph showed reticulonodular shadowing especially in the upper zones, more on the right (fig 1). He was too breathless for spirometry, but his blood gases showed quite a low Po2 (55 mm Hg, 7?3 kPa), the Pco2 (29 mm Hg, 3 9 kPa) was also low and the pH (7 53) rather high. Many investigations for infections were negative. The positive ones were a cytomegaloVirus complement fixation titre of 1/32 on 6 December, rising, to 1/256 on 12 December; the corresponding cytomegalovirus specific IgM antibody.titres were 1/8 and 1/32. Although herpes simplex was grown from throat swabs and he had a herpetic lesion orn his lip, the antibody titres on 6 Decembe'r and 12 December were both 1/20. As his fever was unaltered by the
.;.: . .
.
.:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.
FIG I-Chest radiograph showing reticulonodular shadowing upper zones, more on right.
especially in
FIG 2-Biopsy specimen being taken from right upper lobe using a fibreoptic bronchoscope.
antibiotic cocktail it was stopped on 12 December, and the temperature became normal within 48 hours. The electrocardiogram showed old inferior myocardial infarction. Echocardiography showed deep pansystolic prolapse of the posterior mitral valve leaflet but no vegetations. He was still ill, and.four transbronchial lung biopsy specimens were taken from the right upper lobe on 16 December using a fibreoptic bronchoscope
(fig 2).
PROFESSOR CRANSTON: Thank you. I am going to ask Dr P Davies to give his views on the nature of the problem.
Diagnosis DR PETER DAVIES (7): This is the classic chest physician's dilemma of the 1970s. The patient has a disease, in this case a
1408 lymphoma, which can cause these respiratory symptoms and radiographic signs. He has a disease and is having treatment which may cause immunosuppression, so he is a candidate for all types of opportunistic infections that might produce this clinical and radiological picture. Lastly, he has been taking drugs that can produce these symptoms, signs, and shadows on the radiographs. All experience teaches that in this situation one should not stand at the end of the bed and speculate but get to work and perform a lung biopsy. The sicker the patient the more he needs a biopsy. He may need blood transfusion or platelet transfusion to make it safe but it must be done, and it was done here. His doctors chose the fibreoptic technique with fluoroscopic control. This is probably the safest technique-there is a small risk of pneumothorax and a small risk of bleeding. The difficulty is that it produces very small bits of tissue on which many things may need to be done-microbiology, histology, and electronmicroscopy. Fibreoptic biopsies produce the answer in this type of diffuse disease in about 60% of 'cases. Percutaneous needle biopsy may raise this to 65% and drill biopsy to 76% But there is much more risk of pneumothorax-about 30% in our hands. Lastly, you may perform an open lung biopsy. This is a major procedure but you do obtain a satisfactory specimen and a positive answer in 85% of cases. This man has a lymphoma with a bad prognosis-it is diffuse and poorly differentiated. As he was 65 they began gentle 'reatment, with chlorambucil. After a month they changed to cyclophosphamide, prednisolone, and vincristine, and he improved. But three weeks later he was admitted urgently with respiratory symptoms and fever. The differential diagnosis is enormous-recurrence of lymphoma, opportunistic infections, and drug reactions. Statistically the best bet is infection; about 80% of patients with lymphomas die with infection, 45% with pneumonia. Non-Hodgkin's lymphoma may invade the lung, and unlike Hodgkin's disease, without radiological evidence of mediastinal and hilar lymph nodes being affected. But lymphosarcoma does not affect the lung in more than perhaps 25% of cases. Drug-induced lung disease is rare. Firstly, we might dismiss the heart as the source of the trouble. He has the mitral valve prolapse syndrome; probably his inferior myocardial infarction 10 years before has left him with an ischaemic papillary muscle. But we should just perhaps remind ourselves that the mitral valve prolapse syndrome may be responsible for chest pain, which can suggest atypical ischaemic pain and may also be responsible for ECG changes looking like inferior myocardial infarction. However that may be, there is nothing to suggest that this man was in cardiac failure and, therefore, we cannot invoke pulmonary oedema as the explanation for widespread pulmonary shadowing, nor is there anything to suggest bacterial endocarditis to account for his fever. The first possibility we have to consider is that we are dealing with a recurrence of lymphoma. The most' importit argument against this is that the superficial lymph nodes had regressed; while it is just possible for a lymphoma to regress at one site and advance at another simultaneously it does seem highly improbable. Another small point is that he developed finger clubbing. Although clubbing has been reported with Hodgkin's disease, I have not seen a patient with non-Hodgkin's lymphoma who developed it. Next we must try to decide whether he has an infection. The lymphoproliferative diseases themselves can cause hypogammaglobulinaemia and render the patient susceptible to bacterial infection, particularly pneumonic infections, and in addition he was being treated with immunosuppressive drugs. The toxic granulation suggested bacterial infection. He was treated withgentamicin, flucloxacillin, and amoxycillin, which would cover the Gramn-negative organisms and staphylococci. Perhaps we should think of the organism that causes legionnaire's disease as it has been reported in renal transplant patients and is
susceptible to erythromycin. I don't think we need seriously consider the possibility of herpes simplex. Interestingly, in the immunosuppressed patient
BRITISH MEDICAL
JOURNAL
18 NOVEMBER 1978
serological reactions often remain while the skin reactions are often lost. On the other hand, the titres of antibodies to cytomegalovirus are definite. Although we know that 80% of normal adults have some positive reaction, the increases here are significant, particularly in IgM, which is virtually diagnostic of a recent infection. Could cytomegalovirus produce this man's symptoms and signs ? Certainly in adults pneumonia is common, but the radiological picture does not really suggest cytomegalovirus pneumonia, in which there is usually indistinct nodulation, about 2-3 mm, mostly in the periphery of the lower zones. Again we come back to the finger' clubbing, and this to me excludes the possibility of cytomegalovirus as the sole cause of this man's symptoms and signs. It may explain his enlarged liver, which is otherwise difficult to account for. Cytomegalovirus infections in immunosuppressed patients are often associated with other infections. The results of tests for were negative-candida, cryptococcus, and aspergillus. We have to think of mycobacterial or atypical mycobacterial
fungi
disease, especially with lesions in the upper lobes, but I am put off tuberculosis because he presented with breathlessness and was grossly hypoxic, which would not be produced by a granulomatous process. The clubbing is also against it. Results of the sputum tests were negative. We must consider protozoal infestations-toxoplasmosis, for which there is no evidence, and Pneumocystis carinii. In the published series pneumocystis is a common cause of diffuse pulmonary disease'in immunosuppressed patients, and cytomegalovirus often goes with it. There are factors against pneumocystis, particularly the well marked signs-crepitations and finger clubbing. In pneumocystis the radiograph may show widespread shadowing, but there are usually few physical signs. The best test is the appearances on lung biopsy but the next best, the fluorescence antibody test, gave negative results, so I rule it out. That leaves us with the possibility that, apart from the cytomegalovirus infection, he had a drug-induced pulmonary reaction. I will start by asking Dr Farebrother about this' man's oxygen treatment because oxygen is probably the commonest cause of drug-induced disease-if you regard oxygen as a drug. DR FAREBROTHER: He was given oxygen on admission on 1 December, and it was continued intermittently until he improved. It was given through an MC mask so the concentration was not controlled, probably about 40-45%. DR DAVIES: We can dismiss that. He had been taking three drugs known to cause pulmonary disease and fibrosing alveolitis -chlorambucil, cyclophosphamide, and vincristine. I think I shall blame cyclophosphamide; it was the drug he was taking when he became ill and fibrosing alveolitis has been reported more often with it than with the others, though it is also probably used more. One criticism of this suggestion is that the disease continued to develop after the drug was stopped, but there are records of disease continuing and developing for months after cyclophosphamide was stopped. Another criticism may be that it developed and even worsened while he was on steroids, but fibrosing alveolitis does not always respond to withdrawal of the offending drug and the use of steroids. I am much influenced by a patient whom I looked after last year who had de.' -natomyositis and was having 80 mg of prednisolone a day. While on this dose fibrosing alveolitis appeared and progressed for over six months and ironically only responded when he was given cyclophosphamide with virtually compfete remission. So I don't think those two objections rule out the possibility of cyclophosphamide-induced alveolitis. Of the three-lymphoma, infection, and drugs-cyclophosphamide is far the most likely to have produced these symptoms and signs. So I suggest that the lung biopsy specimen will show diffuse alveolitis with changes in the alveolar and bronchiolar walls and in the lumen of the alveoli. With luck we may also see an eosinophilic inclusion of cytomegalovirus. PROFESSOR CRANSTON: Can I ask Dr Corrin to show us the pathological findings ?
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Pathological findings DR B CORRIN (8): Some of the more important findings in this biopsy specimen are negative ones. Firstly, there is no evidence of lymphoma. Secondly, there are no viral inclusions and no evidence of pneumocystis infection. Apart from an excess of bronchiolar goblet cells the only pathological finding is patchy interstitial pulmonary fibrosis (fig 3); the process is inactive with little interstitial pneumonia and no desquamation or intra-alveolar exudates. So this is an old and non-specific finding. Various causes have to be considered.
3-Transbronchial lung biopsy specimen showing moderately interstitial puionas- fibrosi with only -mild chronic interstitial pneumonia and- no intraluminal exudates (Haematoxylin and eosin x 75). FIG
severe
clinician go and look down the microscope and discuss the findings with the pathologist? Was the general practitioner involved in this case too, because if it had been a patient in a private or cottage hospital he would have discussed with the patient the pros and cons of starting treatment when he was asymptomatic ? PROFESSOR CRANSTON: I can't myself answer that. Dr Farebrother ? DR FAREBROTHER: The treatment was in the hands of the radiotherapy department, so I don't know if they did actually go and look at the sections. But in cases of this type -there is a close liaison between them and the pathology department. I don't know if the genieral practitioner was brought in, although he originally referred him with the lump in the neck and has been involved more recently. Just a few points before I bring you up to date. Left heart failure was considered and a single parenteral dose of frusemide produced no diuresis and no change in the pulmonary shadows. The echocardiogram appeared to rule out vegetations of infective endocarditis. The tuberculosis cultures were all eventually reported to be negative. We took the lung biopsy findings to mean" that the changes were due to damage by drugs. We took the advice of the virology department and ignored the cytomegalovirus titres. We favoured chlorambucil rather than cyclophosphamide as the damaging drug and, perhaps rashly, restarted him on cyclophosphamide because the nodes were getting bigger again after three weeks off it. But we covered it with larger doses of prednisolone, -60 mg a day, until 3 January and then reduced it to 40 mg a day. Certainly there was a dramatic improvement in his bre'athing. He lost his, cyanosis, and his finger clubbing went quickly. His blood gases became remarkably better, and by early January the Po, was 87 mm Hg, Pco2 36 mm Hg. This showed that the increased ventilatory drive had been removed. He was well enough to have full pulmonary function tests (see table). The
Respiratory function tests
There is nothing to suggest that the fibrosis has resulted from chronic interstitial oedema, and no asbestos bodies are seen. Neither are there any residual granulomas suggestive of causes such as sarcoidosis, eosinophilic granuloma, or extrinsic allergic alveolitis. The pathogenesis of pulmonary'fibrosis caused by cytotoxic drugs includes necrosis of the alveolar lining and organisation of mural exudates into the interstitium. There is then regeneration of alveolar lining cells, and the alveolar walls become progressively less cellular and more fibrotic. In our biopsy specimen we had an appearance compatible with this later stage, but nevertheless quite non-specific. If we are to assume that cytotoxic drugs have been responsible for the "pulmonary fibrosis'the process has evidently been going on for longer than the three weeks since the patient ceased taking cycddposphamide, and the earlier drug,' chloranbucil, appears 'to b6the more likply candidate. The pathological -diagnosis is interstitial fibrosis of uncertain cause. PROFESSOR CRANSTON:. I'd like to ask Dr Best to comment on
the virological titres. DR
JENNIFER BEST (9): We found rising
titres of complement-
fixing antibodies to cytomegalovirus and also of cytomegalovirusspecific IgM. These suggest an active infection by cytomegalovirus. But cytomegalovirus was not isolated from eight specimens of urine or from the lung biopsy specimen. Immunosuppressed patients commonly reactivate to viruses of the herpes group, such as cytomegalovirus. In one series of patients with renal transplants3 70-900h showed evidence of reactivation of cytomegalovirus, but in all cases it was subclinical. This was possibly the case here. PROFESSOR CRANSTON:
Are there any questions ?
;'DR MACRAE: On 12 September when treatment was started you say the man was well. Was treatment started on the strength of a piece of paper emanating from the laboratory or did a
Predicted ± 2 SD
.. FEV,(l,BTPS) .. .. FVC (1, BTPS) .. .. .. FEV,/FVC % VC (1,BTPS) .. .. .. .. RV (1,BTPS) TLC (1,BTPS) . .. TLCOSB (ml/min/mm Hg)
2-61-0 2-6±1-0 68-0 ±14-4 3-6±1-16 2-2±0-78 6-0±1-82 29-0±10-2
Actual 1-7 23 73-9 2-6 3-6
After salbutamol
18'
2-8 64-3
6-2
9-6
VC = Vital capacity; 1,BTPS = Litre, body temperature, pressure (prevailing atmospheric), and saturation (water vapour); RV = Residu5l volume; TLC = Total lung capacity; TLcoSB =Transfer factor for carbon monoxide (single breath method).
ratio of the forced expiratory volume in one second to the forced vital capacity (FEVj/FVG) appeared to get worse after salbutamol, but this was because the FVC responded better than the FEV1. The 'carbon monoxide transfer factor was much reduced. We thought that he probably also had some lower zone emphysema and that 'the restrictive defect that was getting better was superimposed on it. He went home, still taking cyclophosphamide and prednisolone, but was readmitted on 8 February with a left lower lobe pneumonia and effusion. Nothing was grown from the sputum, but this appeared to be a straightforward bacterial pneumonia that responded to ampicillin and flucloxacillin. The 'cyclophosphamide was stopped for two weeks during the pneumonia but was then restarted. It was finally stopped on 14 March. The nodes remained small in early March, but he became very confused and disorientated. Psychiatric advice was that this was probably due to the prednisolone, which wks by then down to 20 mg a day. So the cyclophosphamide and the prednisolone were stopped. His mental state has improved, and his lungs have remained good but the lymphoma is again advancing. PROFESSOR CRANSTON: So the connection between the cases is
1410
that both were drug-induced. This one also has been reported to the Committee on Safety of Medicines. Thank you. This conference was recorded and edited by Dr W F Whimster.
BRITISH MEDICAL JOURNAL
18 NOVEMBER 1978
(6) Dr M J B Farebrother, MD, MRCP, senior lecturer, Department of Medicine, St Thomas's Hospital Medical School, London SEI 7EH. (7) Dr Peter Davies, MD, FRCP, consultant chest physician, Whittington Hospital, London N19 5J G. (8) Dr B Corrin, MD, FRCPATH, reader in pathology, St Thomas's Hospital Medical School, London SE1 7EH. (9) Dr Jennifer Best, BSC, PHD, senior lecturer, Department of Virology, St Thomas's Hospital Medical School, London SEI 7EH.
APPOINTMENTS OF SPEAKERS
(1) Professor W I Cranston, MD, FRCP, professor of medicine, St Thomas's Hospital Medical School, London SE1 7EH. (2) Dr J G G Ledingham, DM, FRCP, May reader in medicine, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford OX2 6HE. (3) Dr J H H MacRae, MB, CHB, general practitioner, London SW6 2LA. (4) Dr J Hampson, physician, Northallerton and Darlington Hospital Group, Yorks. (5) Dr J H Ross, MD, FRCP, consultant physician, Hereford HR1 IJE.
References Carone, S A, and Epstein, F H, American Journal of Medicine, 1960, 29, 539. Dorhout-Mees, E J, et al, Nephron, 1968, 5, 81. 3 Singer, I, and Rotenberg, D, Annals of Internal Medicine, 1973, 79, 679. Forest, J N, et al, New England Journal of Medicine, 1978, 298, 173. Zegers de Beyl, D, et al, British Medical Journal, 1978, 1, 760. 2
MATERIA NON MEDICA Sinking Lethe-wards I recently read a first edition of Nature, which was published in 1869. A wide range of subjects were covered in the articles and book reviews. Fertilisation of plants was discussed; there was an admonition to Huxley for overexciting the Australians by discussing the physical proteinaceous basis of life; ancient dolmens and the like were described, as were moths and the "pneumogastric nerve," which, we were told, slows the heart in animals. There was an article about the voice and another on the convolutions of the brain. All were fully comprehensible to the general reader. Today's journal, however, covers the same wide range of knowledge, but has titles like "Alfven waves generated by an inverted plasma energy distribution" and "Origin of olivine subgrain boundaries in mantle periodities." Throughout, the articles are laced with mathematics such as the "Ornstein-Uhlenbeck stochastic differential equation," somewhat above any mathematics that has crossed my path. To my mind, this reflects the exponential growth of scientific knowledge since Victorian times, and the impossibility of being a general "man of science" today. It all seemed sewn up a hundred years ago. According to Frazer, there had been a natural progression from magic through religion to science, the last being the logical culmination -a triumph of common sense. The universe was held together by atoms, and Newtonian laws prevailed; the odd flaws such as radioactivity and the travel of light through the "ether" would soon be cleared up. Then came Einstein and everything changed. No more absolutes, be it space, mass, time, or velocity. Even good old Euclidian geometry had its flaws; the fifth postulate could not be proved (this upset the young Bertrand Russell). Other geometries were constructed, and one by Riemann was found to be best suited to the new Einsteinian universe. Another mathematician, the famous Henri Poincare, who lived in Paris at the time of Toulouse Lautrec, had arrived at a similar non-Euclidian geometry. A flash of insight striking him as he boarded a bus led to his now famous "Theta-Fuchsian functions." The big bang, curved space, black holes, and quarks are the mysteries of today. In some ways we are back to magic, a magic understood by a gifted few among whom, alas, I am not. I can take only "shallow draughts," which, Pope warns us, "intoxicate the brain."-R E GOODMAN (general practitioner, Northenden, Manchester). A cricketer's lament
September has always been my saddest month of the year, for with the gathering gloom and misty evenings the fall of the cricket season arrives. For enthusiasts it means either a merciful release from further batting disasters or a sombre return to handiwork at home and Saturday afternoons spent fielding the wife's shopping around town.
April seems so far distant, when we could savour the expectation of a new season, linger over the pleasure of oiling a new bat, and enjoy the thought of putting all one's new theories, acquired during months of winter reading, into practice. Unfortunately, the summer months usually demonstrate all too frequently, and at great length, the folly of one's new technique. This may produce unreasonable depression each Monday morning after another "failure," leaving patients,
colleagues, and the wife wondering at my cyclothymic personality, for by Friday evening I will be buoyant once again in expectation of another weekend's cricket. The summer afternoons speed too quickly past, leaving memories of dropped catches, torrential rain, and fleeting moments of cricket. Then August brings with it the climax to all the major cricketing competitions, increasing the anticipation of each day's results. However, this serves only to heighten the enormous anticlimax when cricket descends from its zenith to its lowest ebb. The sightscreens are dismantled, the square fenced off, the dreaded footballers encroach on the sacred outfield, and despondency envelopes me as I put my kit away for the last time. Of the future all one can look forward to is those frosty mornings spent huddled up in bed with news from Australia crackling through the dawn. Huddled, alas, in the spare bed, for the cricket widow demands no cricket at 5 30 in the morning! Poor September, hurry sweet April, you are too far away.-R J GRIEVE (medical registrar, Birmingham). Plovdiv A guidebook described Plovdiv, where the congress was to be held, as "the Manchester of Bulgaria." We were therefore pleasantly surprised to find that all the industry, and those dreary high-rise blocks of flats that go with it, had been placed well outside the city, which was as charming an old town on its six hills as you would find anywhere and well deserves its ancient name of Philippopolis. Its pedestrian trafficfree area is proportionately larger than that of any other place I know. On the first morning's after-breakfast stroll we found a Roman theatre cleverly incorporated into the main street; a Roman amphitheatre still being excavated, with students poring over buckets of earth from the excavation; and no fewer than three other sites being actively explored. The archaeological museum had those splendid Thracian gold vessels (rhytons) recently on view at the British Museum, and the ethnographical museum was a treasure house of
interesting objects. The congress itself was disappointing. Eighty per cent of the papers were in Bulgarian or Russian without simultaneous translation, but the "off-duty" activities included a glass of peculiar brandy, taken with the Abbot of an eleventh-century monastery, at 9 30 in the morning. There was also a welcoming row of charming teenage girls in peasant costume with a bottle of red and a bottle of white wine in their hands, supported by great baskets of peaches and grapes, followed by dances in which everyone joined, including the president of the congress, Professor Pavlova, the great Pavlov's grandaughter. (I wrote to the Bulgarian Embassy in London to clarify the relationship, but received no reply. Doubtless they had other things on their mind at the time.) Indeed, my guess is that the Black Sea coast may take Spain's place as the mass touring Mecca for Western Europe in the 1980s, provided that many more and better-trained waiters and waitresses are employed so that every meal is not a source of frustration and irritation. Surely any experienced waiter knows that people will be content to wait longer for their meal if the drinks they have ordered are provided first. But neither bribery nor threats to leave could produce this result in Bulgaria.-NEVILLE GOODMAN (retired medical officer of health, Sandwich, Kent).
