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Cytotoxic drugs prevent cell division or cause cell death.1 They act predominantly on rapidly dividing cells such as T lymphocytes, and are therefore immunosuppressive and anti-inflammatory.1 When cytotoxic drugs were initially used in the treatment of cancer, it became apparent that they had profound effects on the immune system. This “unwanted” side effect has subsequently been exploited for the treatment of non-malignant disease where autoimmune mechanisms are considered important in the pathogenesis.2 More recently drugs such as cyclosporine, which act more specifically on the immune system via the inhibition of T lymphocyte function, are being used for the treatment of disease with immunologically mediated mechanisms. Generally speaking cytotoxic drugs (CDs) have anticancer activity as well as immunosuppressive properties, whereas immunosuppressive drugs (ISDs) show a more specific immunosuppressive effect, although this distinction is partly arbitrary. For the purposes of this review we have adopted the classification described in the British National Formulary defining cyclosporine as an ISD; cyclophosphamide, vincristine, chlorambucil, and methotrexate as CDs; and azathioprine (and its active metabolite 6-mercaptopurine) and mycophenolate mofetil as “cytotoxic immunosuppressants”. This review concentrates on the use of ISDs and CDs in the management of vasculitis and rheumatological disease, idiopathic nephrotic syndrome, and inflammatory bowel disease. For the majority of the disorders discussed treatment with ISDs and CDs will usually be initiated by clinicians with experience of the condition. Reference to efficacy and safety of ISDs and CDs in children will be made. Specifically, the use of ISDs and CDs in organ transplantation will not be addressed. CDs act primarily on rapidly dividing cells such as malignant cells, or those of the immune system, particularly T lymphocytes.1 Thus CDs have both anti-inflammatory and immunosuppressive effects. Azathioprine (and its metabolite 6-mercaptopurine) and mycophenolate mofetil inhibit biosynthesis of purines and act during the …

The prevalence of antineutrophil cytoplasmic antibodies (ANCA) was studied in 12 children with Wegener's granulomatosis. The serum samples were taken in the active phase of disease and were screened for ANCA by indirect immunofluorescence with normal neutrophils and enzyme linked immunosorbent assay (ELISA) using crude neutrophil extract, proteinase 3, myeloperoxidase, cathepsin G, lactoferrin, and elastase as antigens. Of these 12 patients, 10 were positive for ANCA in the active phase of their illness, and they showed a predominantly cytoplasmic ANCA staining pattern on indirect immunofluorescence. There were high titres of ANCA directed against crude neutrophil extract, proteinase 3, myeloperoxidase, and cathepsin G. IgM isotypes occurred as commonly as IgG isotypes. Therefore, screening for ANCA is usually but not invariably positive in children with Wegener's granulomatosis. Specific diagnosis still relies on clinical and pathological features, and the value of ANCA in the diagnosis of paediatric Wegener's granulomatosis requires further study.

Systemic vasculitis is a rare condition and diagnosis is often difficult. Any organ system can be affected and patients can present with an insidiously progressive illness, a remitting/relapsing pattern, or acute multisystem failure. The early institution of aggressive and potentially toxic immunosuppression may be necessary to minimise permanent organ damage, and, despite the difficulties, rapid and unambiguous diagnosis is sometimes of great importance. The development of assays for antineutrophil cytoplasm antibodies (ANCAs) over the past decade has provided clinicians with a laboratory test for vasculitis. Classification of the vasculitides is confusing and has been the subject of a recent international consensus conference.1The conditions most associated with the presence of ANCAs are small vessel necrotising vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and pauci-immune crescentic glomerulonephritis. ANCAs were first described in 1982 in eight Australians with segmental necrotising glomerulonephritis,2 and the association with vasculitis was soon recognised.3 In 1985 van der Woude et al reported that ANCAs were specific for Wegener’s granulomatosis, and that the titre was associated with the degree of disease activity.4 In 1988 ANCAs were first described in children, in three cases of necrotising glomerulonephritis.5 Subsequently ANCAs have been reported, in both adults and children, in numerous conditions characterised by vasculitis and inflammation.6 Recent work has also suggested that they may be pathogenic in vasculitis. ### INDIRECT IMMUNOFLUORESCENCE (IIF) IIF detects the binding of antibodies to antigens in the cytoplasm of whole ethanol fixed neutrophils. It is subjective, semiquantitative, and requires experience to interpret. However, it is a rapid and standard technique and is widely available.7 Two major staining patterns can be distinguished: granular cytoplasmic staining with central accentuation, known as C-ANCA, and perinuclear staining, known as P-ANCA. A C-ANCA pattern usually corresponds to antibodies against proteinase 3,8 and P-ANCA staining …

Four children (two boys and two girls) with hypoparathyroidism, renal insufficiency, and developmental delay are described. They were the products of consanguineous marriages in three related Asian families presenting over a six year period. All the children died within the first 15 months of life despite treatment. Postmortem examination on one child showed absent parathyroid glands. We believe these children represent a previously undescribed syndrome that appears to be inherited in an autosomal recessive manner.

We report 101 episodes of Kawasaki disease in 100 patients seen over a 12 year period. A total of 35 patients had cardiac involvement ranging from pericardial effusion to coronary artery aneurysms with ischaemic complications, which resulted in death in one patient. Laboratory investigations showed leucocytosis, thrombocytosis, and a raised erythrocyte sedimentation rate to be common features and the first two variables were significantly associated with cardiac involvement. Treatment regimens changed over the study period. Aspirin was used in most patients often in conjunction with dipyridamole and from 1986 intravenous immunoglobulin was given routinely to those patients seen early in the illness. Additional therapeutic measures in individual patients included prostacyclin, heparin, streptokinase, and plasma exchange/exchange transfusion. Attention is drawn to the uncertainity of the long term cardiovascular consequences in the light of adults reported with premature atherosclerotic lesions of similar appearance to those seen in Kawasaki disease.

Ninety-one patients with Kawasaki disease were examined by cross sectional echocardiography between 1980 and 1988. In the 75 patients evaluated during the acute phase of the illness (the first month), the first echocardiographic examination was carried out at a mean time of 16 days (range 5-30) and coronary arterial lesions were seen in 21 (28%). Two patients with medium sized aneurysms had myocardial infarctions, and one died. Coronary arterial lesions persisted in 17 (23%) patients, most often in younger children. The remaining 16 patients were examined from one month to four years after their acute illnesses, and this group did not have coronary arterial abnormalities. Seven patients with coronary artery lesions have reached school age and require regular echocardiographic examination and exercise electrocardiography. Selective coronary arteriography may be indicated in some patients to identify coronary artery stenosis, which the Japanese experience has shown may progress for several years after the acute illness.

To investigate the influence of a family history of essential hypertension on abnormalities of red cell membrane sodium transport, 28 hypertensive children and their families were studied. In 15 families one or both parents had either essential hypertension or a strong family history. In 13 families neither parent had essential hypertension or a positive family history. There were significant differences between the children with a positive family history of essential hypertension compared with those without. Values are expressed as mean (SD): intracellular sodium concentration (mmol/l cells) 8.19 (2.18) compared with 6.41 (0.98); sodium efflux rate constant 0.4873 (0.1379) compared with 0.5831 (0.1104); and numbers of sodium-potassium ATPase pump sites (BMax) (nmol/l cells) 7.96 (1.71) compared with 9.56 (1.7). Significant differences were also found when the index hypertensive children were excluded and the normotensive siblings with and without hypertensive family histories were compared. These data suggest that abnormal red cell membrane sodium transport has a familial component, and although it is not caused by the hypertension it may be the earliest pathophysiological step in its development, perhaps allowing the identification of children at risk of essential hypertension.

Since 1960 we have diagnosed phaeochromocytoma (paraganglioma) in 10 children. The cases include a 15 year old girl who over a three year period presented with multiple paragangliomata and an associated malignant carotid body tumour. All children were hypertensive, eight of 10 presenting with severe headaches. Diagnosis was based on finding a raised urinary vanillylmandelic acid excretion and plasma noradrenaline concentration. In addition six of eight children were hypercalcaemic with raised plasma calcitonin concentrations; plasma parathyroid hormone concentrations were high in two of seven and four out of eight children had raised plasma renin activities on presentation. No child, however, was found to have a multiple endocrine neoplasia syndrome. Despite the introduction of newer techniques for the detection of catecholamine producing tumours we found that selective arteriography and venous catecholamine sampling were superior for tumour localisation compared with ultrasound scanning, computed tomography, and metaiodo-benzyl-guanidine (MIBG) scanning.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enroll their suspected cases into this collaborative research project.

Two infants with a florid erythematous rash and generalised oedema, hypoalbuminaemia, and anaemia were found to have cystic fibrosis. This rare presentation is associated with false negative sweat tests, delays in diagnosis, and a considerable mortality. It is proposed that this presentation represents a manifestation of kwashiorkor secondary to malabsorption. The recognition that these infants have kwashiorkor provides some insight into the pathogenesis and management of their illness.

A child presented with ischaemic episodes of his left leg from the age of 2 months. He was found to have raised anticardiolipin antibodies so was started on low dose aspirin. At a three year follow up he was asymptomatic with a normal anticardiolipin antibody level while taking aspirin daily, probably for life.

Abnormalities of sodium-lithium countertransport have been extensively implicated in adult primary hypertension and a relationship between sodium-lithium countertransport and family history of hypertension in children has been previously found. More recently it has been suggested that increased sodium-lithium countertransport may play a part in the pathogenesis of nephropathy in insulin dependent diabetes mellitus (IDDM). Children and adolescents with IDDM and their family members were studied. In those with IDDM (n = 36, median age 14.6 years, range 9.5-19.2 years) there was no relationship between sodium-lithium countertransport (range 0.098-0.585 mmol/l red blood cells/hour) and age, blood pressure as expressed by systolic or diastolic SD scores, glycated haemoglobin, serum lipids, or intracellular sodium concentration. A positive relationship (rs = 0.44) was found between sodium-lithium countertransport and early morning urinary albumin to urinary creatinine ratio (UA/UC), expressed as the logarithm of the geometric mean of two consecutive samples, for each individual (range 0.4-22 mg/mmol). Sodium-lithium countertransport was increased in those with IDDM compared with their non-diabetic siblings, in a paired analysis (n = 26). There was no relationship between UA/UC in the children with diabetes and sodium-lithium countertransport in their parents. These studies in this population of diabetic children indicate that increased sodium-lithium countertransport may play a part in the early stages of the development of nephropathy in IDDM.

Between 1975 and 1985, 454 patients with hypertension were admitted to the Renal Unit of the Hospital for Sick Children. A total of 110 (24%) patients presented with severely raised blood pressures deemed to require emergency management. At presentation 84/110 had symptoms and signs of long standing hypertension with neurological involvement. Between 1975 and 1980 bolus intravenous injections of diazoxide and/or hydralazine were used with the aim of reducing the blood pressure to within the normal range for age in the first 12-24 hours after admission. Of 57 patients treated in this way 13 developed hypotensive complications and four, whose blood pressures returned to normal within 24 hours of admission, suffered irreversible neurological damage. Subsequently, the management changed to the use of intravenous infusions of labetalol (1-3 mg/kg/hour) and/or sodium nitroprusside (0.5-8 micrograms/kg/min) to enable a more gradual controlled reduction of blood pressure over the first 96 hours of admission. Between 1980 and 1985, 53 patients were treated using this regimen. In all cases blood pressure reduction was achieved in a more controlled manner without further neurological impairment or serious irreversible side effects. From our experience, the use of labetalol and sodium nitroprusside by incremental infusion in the critical early phase of management has resulted in improved control of accelerated hypertension without the sudden hypotensive episodes seen when bolus injections are used.

An infant presented with a non-metastatic renal spindle cell sarcoma and hypercalcaemia, which resolved after treatment with indomethacin. There was in vivo and in vitro evidence that hypercalcaemia was mediated by circulatory prostaglandins.

Seven cases of cystic fibrosis complicated by chronic salt depletion and failure to thrive were studied. After replacement of the salt deficit, the metabolic abnormalities resolved, and weight gain was rapid. This should be considered as a differential diagnosis in children who have been diagnosed as having cystic fibrosis, but who fail to thrive despite standard treatment.

Presenting features and clinical manifestations of six patients with toxic shock syndrome are reported. In four of the six cutaneous injury, sometimes trivial, occurred before the onset of symptoms and may have been a causal factor. All six children recovered. The need for early recognition and intensive management in this life threatening condition is discussed.

Increased activity of the renin/aldosterone system in the neonatal period is now well established in both animals and man but the control mechanisms are poorly understood. We have monitored the plasma renin activity (PRA) and plasma aldosterone concentration (PAldo) in 14 infants undergoing 21 exchange transfusions. PRA and PAldo were measured before and at 5, 10, 15, 30, 45, and 60 minutes after the injection, and 5, 10, 15, and 30 minutes after the withdrawal of 7 ml blood/kg birthweight immediately before exchange transfusions. PRA increased to a maximum of 53% and decreased to a maximum of 39% of the resting values after withdrawal or injection of blood respectively. PAldo values did not change significantly during the same period. Thus the renin-angiotensin system in the newborn infant is responsive to changes in blood volume.

Acute renal failure developed in 24 (5.3%) of 456 children undergoing cardiopulmonary bypass surgery during a 2-year period. It was more common in younger children, in those with complex cardiac lesions, and in those with long overall bypass times. Fourteen (58%) recovered renal function; renal failure was responsible for death in only two. Early vigorous peritoneal dialysis is advocated after cardiopulmonary bypass surgery if there is oliguria (less than or equal to 1.0 ml urine/kg per hour) resistant to volume repletion, dopamine infusion and diuretics, intractable fluid overload, or hyperkalaemia.

Twenty three children aged from 5 to 16 with mild to moderate hypertension were investigated using the orally active angiotensin converting enzyme inhibitor captopril. Falls in both systolic and diastolic blood pressure after a single dose of captopril were significantly correlated with initial plasma renin activity. In addition, some information about the aetiology of hypertension was deduced from the renin response to captopril. The blood pressure response to captopril is a useful screening test for renin dependent hypertension in childhood.

Twenty-one healthy newborn infants whose mothers had normal pregnancies and deliveries were studied. Plasma renin activity (PRA) and plasma aldosterone concentration (PAldo) were measured by semimicro methods in cord blood and on the 6th day of life. PRA and PAldo were increased in cord blood compared with values previously found in healthy infants between 1 month and 1 year of age. There was a twofold reduction in both values by the 6th day. PRA and PAldo were positively correlated when cord blood and 6th-day values were considered as a whole, but no significant correlations were found between either cord blood PRA or cord blood PAldo and their respective values on the 6th day. The PRA and PAldo findings were not related to birthweight, the infant's sex, weight change, 6th-day urinary sodium, or blood pressure measurements. The type of milk feed did not influence PRA but PAldo was slightly greater in bottle-fed babies on the 6 day. These observations confirmed that the inverse relationship between PRA, PAldo, and age extends into the neonatal period but they suggest that the balance of factors controlling these variables at birth is different to that operating at the age of 6 days.

Neurological symptoms in hypertensive subjects may be a reflection of intracranial vascular disease and not just a consequence of hypertension. Two hypertensive children with renovascular disease, neurological symptoms, and severe cerebral arterial disease were treated by extracranial-intracranial arterial bypass surgery with improvement of symptoms and easier control of blood pressure. Where revascularisation surgery is appropriate, this should be undertaken before neurological complications arise.

This paper describes 2 male infants who were born with sever micropenis and in whom testicular tissue could not be identified at surgery. HCG stimulation in one infant was not followed by a rise in plasma testosterone. It was decided that both cases would be best raised as females, despite their male chromosomal sex.

This paper describes an infant with gastroenteritis, who developed hypertension and oedema after administration of inaccurately prepared oral glucose salt solution. The renin aldosterone system was suppressed in this child and it was suggested that this may be a factor in the development of hypernatraemia when abnormal water losses occur in infants fed on hyperosmolar feeds. Unless salt can be given accurately in small amounts it may be safer to advise feeds of glucose only in infants with mild diarrhoea.

We report five children who presented with Raynaud's disease in whom we could find no clinical, haematological, or immunological evidence of a collagen disorder. Oral phenoxybenzamine proved useful for maintenance treatment in most, with infusions of prostacyclin, nitroprusside, and ketanserin during acute attacks.

A 5 month old boy died after fever, persistently raised blood pressure, and hypokalaemia. A disorder of cortisol metabolism caused by 11 beta-hydroxysteroid dehydrogenase deficiency was detected retrospectively.

10 infants are described with pseudohypoaldosteronism, 5 in detail and a further 5 briefly. They all presented with hyperkalaemia, urinary salt-wasting disease, and ostensibly normal renal and adrenocortical function. Diagnosis was established by demonstrating the greatly increased values of plasma renin activity and plasma aldosterone concentration, plus the increased excretion of aldosterone and its metabolites on gas chromatographic and mass spectrometric analyses of urine. The children were treated with sodium chloride supplements, up to 60 mmol/day, but by the time most of the infants were about a year old these could be stopped. Exogenous mineralocorticoids were without effect in those to whom they were administered. The precise aetiology of the condition remains conjectural; lack of renal tubular response to aldosterone seems probable. Pseudohypoaldosteronism may be more common than has been thought and new techniques for investigating salt-wasting disorders may show its true incidence.

Eight of 100 normotensive children who had pyelonephritic scarring secondary to urinary infection and vesicoureteric reflux were found in an earlier study to have increased plasma renin activity (PRA). Because the risk of these patients becoming hypertensive is between 10% and 20% and because renin activity may play a part in the pathogenesis of the hypertension, PRA and blood pressure were studied in 98 of the original group after five years of follow up. Two patients could not be traced, and other factors that might influence blood pressure or PRA led us to exclude 13 others, 10 of whom were girls taking oral hormonal contraceptives. Increased PRA was found in 11 of the remaining 85 patients but not in five of the eight patients with increased PRA in the first study. Of eight children identified as hypertensive in the follow up study, only three had had increased PRA five years previously. In normal children PRA decreases with age. In the initial study this tendency was less pronounced in children with renal scars, and in the follow up study it was reversed. This was also confirmed by PRA standard deviation scores, which showed a significant increase in PRA during the five years. PRA tends to rise in patients with pyelonephritic scars as they grow older. There was no direct correlation between blood pressure and PRA, plasma creatinine concentration, or degree of scarring. Analysis of blood pressure standard deviation scores, however, suggested an excessive rise in blood pressure during the five years.