Acute adrenal insufficiency after discontinuation of inhaled corticosteroid therapy

1289

Serum aminotransferases and HHV-6 antibody titre.

antibody titres of her

serum, because serum antibody titres for viruses that induce liver dysfunction generally were negative. HHV-6 antibody rose from under 10 at admission to over 1280 after 4 days, and high titres were maintained for 3 months (> 1280) (figure). We suspected that her symptoms were caused by chronic HHV-6 infection and began daily intravenous injection of stronger neominophagen C (SNMC) containing glycyrrhizon and subcutaneous injections of recombinant G-CSF 25 ug (GRAN, Sankyo). SNMC therapy was ineffective. Her liver dysfunction worsened and granulocytopenia (segmentation 0%, band 0%) and anaemia (Hb 7-8 g/dl) continued. In May, she had mild jaundice (total bilirubin 1 4 mg/dl) and in June her aminotransferase values were increased (ALT 1949 and AST 1155 IU/1). To reduce virus activity, we administered interferon-ot (IFN-(x, Sumitomo) by daily subcutaneous injection, similar to the protocol for chronic hepatitis caused by hepatitis B or C viruses. We started at 20 000 U/kg per day and increased to 80 000 U/kg per day. Liver dysfunction improved (ALT 517 and AST 393 IU/1) 1 month later, and granulocytopenia and anaemia

slight degenerations were revealed by staining with haematoxylin and eosin. Thus first infection with or reactivation of HHV-6 during pregnancy may predispose to spontaneous abortion. Department of Obstetrics and Gynaecology, Nara Medical University, Kishihara, Nara, 634, Japan

YOSHIYA ANDO KAZUHIRO KAKIMOTO YUTAKA EKUNI MOTOHIKO ICHIJO

1. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988; ii: 1065-67. 2. Pietroboni GR, Harnett GB, Bucens MR, et al. Antibody to human herpesvirus 6 in saliva. Lancet 1988; i: 1059. 3. Asano Y, Yoshikawa T, Suga S, et al. Human herpesvirus-6 harbouring m kidney. Lancet 1989; ii: 1391. 4. Okukno T, Takahashi K, Balachandra K, et al. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 1989; 27: 651-53. 5. Levy JA, Ferro F, Greenspan D, et al. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990; 335: 1047-50. 6. Okuno T, Higashi K, Shiraki K, et al. Human herpesvirus 6 infection in renal transplantation. Transplantation 1990; 49: 519-22.

improved slowly. There have been

no

reports of

progressive liver dysfunction,

anaemia, and granulocytopenia associated with HHV-6 infection. All the symptoms in our case were suspected to have been caused by HHV-6 chronic active infection because of the clinical symptoms and the changes in HHV-6 antibody titre. We thank Dr K. Yamanishi for help with

measurement

of HHV-6

antibody titres. TAKAKO TAKIKAWA HIROSHI HAYASHIBARA YUICHIRO HARADA KAZUO SHIRAKI

Department of Pediatrics, Faculty of Medicine, Tottori University, Yonago 683, Japan

1 Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthema subitum. Lancet 1988; i: 1065-67. 2. Tajiri H, Nose O, Baba K, Okada S. Fatal fulminant hepatitis in an infant with human herpesvirus-6 infection. Lancet 1990; 335: 863. 3. Prezioso PJ, Cangiarella J, Lee M, et al. Fatal disseminated infection with human

herpesvirus-6. J Pediatr 1992; 120: 921-23.

HHV-6 infection

during

pregnancy and

spontaneous abortion SIR,-Human herpesvirus-6 (HHV-6) is the causative agent of exanthema subitum.1 We have examined the effect of HHV-6

infection in early pregnancy. Serum HHV-6 IgG and IgM antibodies2-5

were assayed in 30 patients with spontaneous abortion in weeks 6-12 of pregnancy. Villous tissue was collected in these patients to look for HHV-6 antigen with OHV-1," an HHV-6 monoclonal antibody (obtained, with thanks, from Professor Yamanishi at the Institute for

Microbiological Research, Osaka University). Mean serum HHV-6 IgG and IgM antibody titre in the patients was 160, which contrasts with a mean titre in normal pregnant women of 40.3 patients (10%) were positive for HHV-6 IgM antibody. HHV-6 antigen was detected in abortive villous tissue of 2 of the 3 IgM-positive patients. Changes such as swollen symplasts and

Acute adrenal insufficiency after discontinuation of inhaled corticosteroid

therapy SIR,-In asthmatic adults, inhaled steroids are recommended as safe and without serious side-effects.!,2 In children, growth velocity may be reduced by doses of inhaled steroids higher than 400 ug daily.3 A few cases of growth retardation and hypercortisolism in patients on long-term low-dose inhaled corticosteroid have been described.’ Suppression of the hypothalamic-pituitary-adrenal axis has been documented, but usually without clinical consequences.4-<; However, an adult on very high doses of inhaled steroids who developed acute adrenal insufficiency has been reported.7 We report a 7-year-old girl, who was referred to the paediatric intensive care unit because of varying consciousness, headache, extreme

fatigue, and vomiting without diarrhoea

or

fever. Blood

pressure was normal. She had been treated for asthma for 2 years up to 5 weeks before admission with inhaled budesonide 200 pg twice daily and budesonide nasal spray 50 g twice daily, via a metered inhaler and tube spacer. Growth retardation, weight gain in a

centripetal pattern, and a moon face became apparent. These signs interpreted as systemic side-effects of the steroid and the medication was reduced and stopped 7 days before admission. Admission erythrocyte sedimentation rate, haemoglobin, white were

were normal. Serum sodium 127 mmol/1, and glucose 58 mmol/l. Computed tomography of the brain revealed no abnormalities. Cerebrospinal fluid (CSF) showed normocytosis and normal values for glucose and protein. Bacterial and viral cultures of blood and CSF were negative. We postulated that the patient had acute adrenal insufficiency (Addisonian crisis) due to suppression of the hypothalamic-pituitary-adrenal axis caused by long-term use of inhaled steroids. Therefore hydrocortisone 45 mg/m2 intravenously was started immediately. Within hours, the patient was alert and symptom free.

cells, blood

potassium

urea, lactic

was

4-3

acid, and ammonia

mmol/l,

1290

Excretion

of

free

cortisol

in

urine

(collected before

hydrocortisone substitution started) was 218 nmol per 24 h. After 1 week, when stress was relieved and all steroids had been stopped, free cortisol excretion was under 10 nmol per 24 h. Morning blood cortisol (< 30 nmol/1) was low. Adrenocorticotropic hormone (ACTH) was low (45 ng/1) compared with cortisol. After ACTH stimulation (0-25 mg intravenously) cortisol increased to 85 nmol/l. These fmdings support our hypothesis of long-term suppressed ACTH secretion resulting in hypocortisolism. Treatment was changed to hydrocortisone 9 mg/m2 orally. Since then she has had no complaints, her symptoms have disappeared, and catch-up growth was observed. In this patient the substitution dose will be tapered and finally stopped. This case illustrates that suppression of the hypothalamicpituitary-adrenal axis may be a serious, although rare, complication in children treated for asthma with normal-dose long-term inhaled steroid. Perhaps deposition in the oropharynx was increased by use of a tube spacer instead of a large-volume spacer, which we would prefer at this age.

1007 MB Amsterdam, Netherlands

C. M. ZWAAN R. J. H. ODINK H. A. DELEMARRE-VAN DE WAAL J. E. DANKERT-ROELSE

Department of Paediatrics, Spaarne Hospital, Haarlem

J. A. BOKMA

Department of Paediatrics, Free University Hosptal,

1. Reed CE. Aerosol steroids

2. 3. 4. 5.

6.

7.

as primary treatment of mild asthma. N Engl JMed 1991; 325: 425-26. Bames JP. A new approach to the treatment of asthma. N Engl J Med 1989; 321: 1517-27. Wolthers OD, Pedersen S. Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids. Pediatrics 1992; 89: 839-42. Priftis K, Everard ML, Milner AD. Unexpected side-effects of inhaled steroids: a case report. Eur J Pediatr 1991; 150: 448-49. Philip M, Aviram M, Leiberman E, et al. Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids. Pediatr Pulmonul 1992; 12: 84-89. Brown PH, Blundell G, Greening AP, Crompton GK. Hypothalamo-pituitaryadrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respir Med 1991; 85: 501-10. Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaled steroids. BMJ 1992; 304: 1415.

Economic evaluation of peripheral blood stem cell transplantation for lymphoma SIR,-Autologous bone marrow transplantation (ABMT) is increasingly used in the treatment of leukaemia, lymphoma, and some solid tumours. New developments include the use of peripheral blood stem cells (PBSC) and recombinant haemopoietic growth factors. 6 months ago we started a programme of PBSC transplantation (PBSCT) in patients with lymphoma, based on evidence of more rapid neutrophil and platelet engraftinentll with the possibility of cost-savings compared with ABMT. We compared the average costs of 19 patients undergoing ABMT with the first 4 patients receiving PBSC combined with bone marrow. PBSC were mobilised with high-dose cyclophosphamide 4 g/m2 and filgrastim 300 Ilg subcutaneously daily, starting on day 5 post-cyclophosphamide and continuing until completion of stem cell harvests (9-10 days). No patient required admission during the mobilisation phase. PBSC were collected on 3 consecutive days with a Fenwall CS3000 Plus cell separator and (mean 45 x 10/kg mononuclear cells were collected). All patients received identical conditioning chemotherapy with BEAM (carmustine [BCNU], etoposide, cytarabine, melphalan)3 and antimicrobial prophylaxis with ciprofloxacin and fluconazole. No growth factors were given after transplantation. The major impact of PBSCT was on the post-transplantation inpatient stay, which was reduced from a median of 26 to 14 days. There was also a reduction in days on intravenous antibiotics, from 11to 6 days, because of fewer fertile days. Blood product support was

also decreased

(12

to

6 units of red cells and 65

to

15 units of

platelets). Pathology, radiology, and microbiology costs were also lower. No patient undergoing PBSCT has required parenteral nutrition.

Savings amounted to C5500 per patient. The mobilisation costs, including cell-separator consumables, came to 1700, resulting in

saving of c3800 per patient (25 % cheaper compared with ABMT). An alternative to PBSCT is to use ABMT followed by haemopoietic growth factor. However, studies of this approach have not consistently shown evidence for reduction of inpatient stay or antibiotic and blood product usage, although neutrophil recovery is an overall

3 accelerated. We believe PBSCT offers major advantages compared with ABMT in terms of shorter hospital stay, decreased morbidity, and potentially reduced mortality. To these benefits should be added a reduction in the cost of the procedure. Department of Haematology and Pharmacy Department, City Hospital, Nottingham NG5 7PB, UK

N. H. RUSSELL S. PACEY

AJ, Oscier D, Figes A, Hamblin T. Use of circulating stem cells to accelerate myeloid recovery after autologous bone marrow transplantation. Br J Haematol 1987; 67: 252-53. 2. Sheridan WP, Begley CG, Juttner CA, et al. Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy Lancet 1992; 339: 640-44. 3. Khwaja A, Linch D, Goldstone A, et al. Recombinant human granulocytemacrophage stimulating factor after autologous bone marrow transplantation for malignant lymphoma: a British National Lymphoma Investigation double-blind, placebo-controlled trial. Br J Haematol 1992; 82: 317-23. 1. Bell

Spurious outbreak of HCV in bone-marrow recipients treated with cytomegalovirus immunoglobulin SIR,-Since the introduction at the Hammersmith Hospital of routine testing of allogeneic bone-marrow transplant recipients for antibodies to hepatitis C virus (anti-HCV) with an Abbott second-generation recombinant enzyme immunoassay, we have uncovered a problem in patients who received intravenous therapy with cytomegalovirus (CMV) immunoglobulin (Venoglobulin) for CMV pneumonitis. 8 consecutive patients given this immunoglobulin seroconverted for HCV soon after. Positive antibody tests were validated by two other enzyme imrmmassays (Ortho and UBI) and a second-generation recombinant immunoblot assay (Ortho).1 Passive acquisition of antibody from blood or blood products seemed unlikely since all 8 patients were transplanted after the introduction in the UK in September, 1991, of routine screening of blood donors for anti-HCV and exclusion of those found to be positive. Once we realised that seroconversion coincided with immunoglobulin administration we tested one of the two batches of Venoglobulin and confirmed the presence of anti-HCV. Hence the patients had acquired passive antibody from this source; the other batch was not available for testing. This fmding surprised us because Venoglobulin is manufactured in the USA where, since October, 1991, the Food and Drug Administration (FDA) has recommended that plasma destined for fractionation should be tested for anti-HCV and seropositive units excluded2 because immunoglobulin pools show a high frequency of this antibody.3 The Venoglobulin used to treat our patients had been manufactured before the change in FDA policy, and the presence of anti-HCV was therefore predictable. The detection of anti-HCV in the blood of these 8 patients led to time-consuming and expensive laboratory investigations to establish the cause of the apparent outbreak. Many stored sera were tested to pinpoint the time of seroconversion and, in addition, some patients’ and donors’ sera were tested for HCV RNA with the polymerase chain reaction, but were negative. Even after it became clear that the antibody had most probably been passively acquired, the problems continued because anti-HCV that is synthesised in response to active infection with the virus cannot be distinguished from passive antibody. Thus the immunoglobulin may have contained not only anti-HCV but also infectious virus, so the patients might have become truly infected.33 Interpretation was further compounded because bone-marrow transplant patients often show abnormalities of liver function and sometimes overt jaundice due to graft-versus-host disease or virus infection (eg, adenovirus or CMV), and may have become truly infected with HCV at some time because of multiple blood