Retinal haemorrhage after thrombolytic therapy

1356

Desferrioxamine and HIV p

SIR,-Dr Tabor and colleagues recently reported (March 30, 795) the in-vitro inhibition of HIV-1 replication by

desferrioxamine (DFX) in the H-9 T-lymphocyte cell line. We have also tested DFX for antiviral activity and toxicity but used the MT-4 cell line instead and did not obtain as impressive results. The rationale for this work is to explain the low rate of symptomatic HIV-1 infection in multiply transfused thalassaemic patients who have been intensively chelated with DFX. MT4 cells (3 x 105 cells/ml) were infected with the IIIB strain of HIV-1 at ten times the median tissue culture infective dose per cell and maintained in culture for 6 days. Cells were exposed to either zidovudine (26 umol/1) or DFX (1-8-90 ).lffiol/l) for 1 h after viral adsorption. Controls received no drug. After 6 days, cells were evaluated by indirect immunofluorescence and the presence of viral p24 antigen, and culture fluids were tested for viral reverse

transcriptase activity: Reverse

Drug concentration

Compound

(wnolll)

Control Zidovudine DFX

987 525 23125 866100 732660 44779 26 246 21106

26 18

18 18 54 90

At 18

pmol/l,

transcriptase activity (cpm/ml)

DFX reduced

% cells fluorescent 80 0 564 55 37-1 no cells no

cells

transcriptase activity comparable with that seen for zidovudine. However, 37% of cells still expressed HIV-1 protein. At higher concentrations (54-90 umol/1) severe toxic effects were found, and no cells were available for study. These results confirm the potential for antiHIV-1 activity of DFX. However, DFX was also toxic against MT-4 cells at doses comparable with those known to cause clinical toxicity (10-20 (imol/1). DFX is an iron chelator with strong antioxidant properties. Antioxidants such as N-acetylcysteine, glutathione, glutathione ester,l and pentoxifylline2 can inhibit HIV-1gene expression, and substantially by

recent

an

reverse

amount

Antibiotic Reference Laboratory, Central Public Health Laboratory, London NW9 5HT, UK

N. WOODFORD R. C. GEORGE

Beaumont Hospital, Dublin, Ireland

E. MCNAMARA E. SMYTH

Altnagelvin Hospital, Londonderry

S. NAMNYAK

discussion has focused on the role of oxidative stress on HIV

expression. We believe that thalassaemic patients infected by HIV-1 who are not being treated with zidovudine and who receive DFX as an iron chelator should be studied for HIV-1 expression. Division of Haematology-Oncology, Montreal Children’s Hospital, McGill University, Montreal, Canada McGill AIDS Centre, Jewish General Hospital, McGill University

SYLVAIN BARUCHEL

QING GAO MARK A. WAINBERG

1. Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, Fauci AS Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci 1991;

88: 986-90. 2.

concentration > 1000 mg/1) were first reported in 1979,2 and rapidly became disseminated world wide.’ The resistance determinant can be transferred to strains of E faecium in vitro.3 So far HLGR E faecium have been isolated from a few clinical specimens in the USA’ but, as far as we are aware, not elsewhere. Since October, 1990, the Antibiotic Reference Laboratory has received eight isolates of HLGR Efaecium from three centres in the UK and Ireland. Six isolates were obtained from different patients in an intensive care unit in Dublin and single isolates have been received from two other hospitals in London and Londonderry. Several of these isolates have caused serious infections, including bacteraemia, in hospital patients. DNA hybridisation studies have confirmed that resistance in these isolates is due to the production of the aminoglycoside-modifying enzyme AAC(6’)APH(2").’ The mechanism of resistance is therefore identical to that reported in HLGR E faecium in the USA4 and in HLGR E faecalis world wide.’1 The resistance gene in these strains from the British Isles is located on plasmids of 10-60 MD and, in some cases, the plasmids are transferable in vitro to a recipient strain of E faecium. The presence of the resistance gene on transferable plasmids in E faecalis facilitated rapid dissemination of resistance within this species.’ Similar dissemination within E faecium is a worrying possibility. The AAC(6’)-APH(2") enzyme confers crossresistance to all other clinically important aminoglycosides, apart from streptomycin. HLGR Efaecium are therefore resistant to the synergistic effects of gentamicin in combination with a penicillin or vancomycin. Alternative treatments are very few. We believe that this is the first report of HLGR Efaeciurn outside the USA. Early recognition of such isolates is essential for successful patient management and to contain dissemination. Clinical microbiologists should therefore be aware that HLGR E faecium is now present in at least three centres outside the USA. This is probably indicative of a wider prevalence, and clinical microbiologists should initiate screening for these strains with either high-content (200 µg) gentamicin discs or a breakpoint method.’

Fazely F, Dezube BJ, Allen-Ryan J, Pardee AB, Ruprecht RM. Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 m human peripheral blood mononuclear cells and in cultured T cells. Blood 1991; 77:

1653-56. 3. Halliwell B, Gross CE. Reactive oxygen species, antioxidants, and acquired immunodeficiency syndrome: sense or speculation? Arch Intern Med 1991; 151: 29-31.

Enterococcus faecium with high-level resistance to gentamicin of increasing importance as nosocomial pathogens.1 Infections caused by E faecium are especially difficult to treat successfully because these organisms have intrinsic or acquired resistance to a very wide range of antimicrobials, including beta-lactams and most aminoglycosides.1 Strains of E faecium remain susceptible to gentamicin.For this reason the synergistic combination of a penicillin or vancomycin plus gentamicin is one of the few effective treatment regimens for serious E faecium infections. Isolates of E faecalis showing high-level gentamicin resistance (HLGR; minimum inhibitory

SIR, Enterococcus

spp

are

Dulwich Public Health London SE22

Laboratory, A. H. C. UTTLEY

1. Murray BE. The life and times of the enterococcus. Clin Microbiol Rev 1990; 3: 46-65. 2. Horodniceanu T, Bougueleret L, El-Solh N, Bieth G, Delbos F. High-level, plasmid-borne resistance to gentamicin in Streptococcus faecalis subsp zymogenes. Antimicrob Agents Chemother 1979; 16: 686-89 3 Chen HY, Williams JD. Transferable resistance and aminoglycoside-modifying enzymes in enterococci. J Med Microbiol 1985; 20: 187-96. 4. Eliopoulos GM, Wennersten C, Zighelboim-Daum S, Reiszner E, Goldmann D, Moellering RC Jr. High-level resistance to gentamicin in clinical isolates of Streptococcus (Enterococcus) faecium. Antimicrob Agents Chemother 1988, 32: 1528-32. 5. Bush LM, Calmon J, Chemey CL, et al. High-level penicillin resistance among isolates of enterococci. Ann Intern Med 1989; 110: 515-20 6. Ruoff KL, de la Maza L, Murtagh MJ, Spargo JD, Ferraro MJ. Species identities of enterococci isolated from clinical specimens. J Clin Microbiol 1990; 28: 435-37 7. Ferretti JJ, Gilmore KS, Courvalin P Nucleotide sequence analysis of the gene specifying the bifunctional 6’-aminoglycoside acetyltransferase 2"-aminoglycoside phosphotransferase enzyme in Streptococcus faecalis and identification and cloning of gene regions specifying the two activities. J Bacteriol 1986, 167: 631-38.

Retinal

haemorrhage after thrombolytic therapy

SIR,- Patients with diabetes mellitus and proliferative retinopathy are relatively contraindicated from receiving thrombolytic therapy for acute myocardial infarction (AMI) because of the risk of retinal haemorrhage and blindness- This complication has not been reported before, and we now describe, for the first time, a retinal haemorrhage after thrombolytic therapy. In December, 1990, a 46-year-old diabetic man was admitted with a 4-h history of chest pain. The patient showed signs of

1357

pulmonary congestion and poor peripheral perfusion. The electrocardiogram revealed an anterolateral MI. Proliferative retinopathy 1987 and he received argon laser panphotocoagulation both eyes. Twenty days before admission there were no signs of retinal haemorrhage at ophthalmoscopy. Streptokinase (1-5 million units) was given intravenously for 60 min. Previously raised ST segments fell and there was an early CK-MB peak (12 h after symptoms). On the next day, the patient noticed poor vision in his right eye. Ophthalmoscopy revealed a retinal and vitreous haemorrhage over the disc and temporal part of the retina. Visual function gradually improved over the subsequent three weeks, and the patient was was

diagnosed in

to

discharged. The proportion of eligible patients for thrombolytic therapy ranged from 14 to 35% in several studies,1,2 and there have been efforts to extend this treatment to patients with unstable angina, the elderly, and the relative contraindication group. Although the frequency of unsuspected proliferative retinopathy in diabetes is high, retinal haemorrhage after thrombolytic therapy has not previously been reported. Moreover, diabetic patients with AMI have a generally poor outlook and should be considered for thrombolytic treatment.3 Our patient gained a clear benefit from thrombolysis despite retinal haemorrhage.

Division of Clinical Medicine,

Coração Hospital, São Paulo, SP, Brazil 05403

BRUNO CARAMELLI BERNARDINO TRANCHESI JR OTAVIO CELSO E. GEBARA LUIS CARLOS FERREIRA DE SA FULVIO JOSE CARLOS PILEGGI

Thrombolytic intervention. In: Topol EJ, ed. Textbook of interventional cardiology. Philadelphia: WB Saunders, 1990. 2. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Gissi-2: a factorial randomised trial of altepase versus streptokinase and heparin versus no hepann among 12 490 patients with acute myocardial infarction. Lancet 1990; 336: 1. Topol EJ.

65-71. 3 Abbott RD, Donahue RP, Kannel WP, Wilson PWF. The impact of diabetes on survival following myocardial infarction in men vs women. JAMA 1988; 260: 3456-60.

Asthma

mortality in England and Wales, 1979-89

SIR,—There is a widespread belief, associated with an understandable concern, that deaths from asthma in children and young adults are increasing. This belief is based mainly on an analysis of the period 1974-841 but with publication of national data for 1989a it is now appropriate to review these trends. The earlier analysis faced three problems: (1) how to choose a suitable starting-point in relation to the end of the epidemic of deaths in the 1960s; (2) how to allow for the change in coding introduced with the 9th revision of the International Classification of Diseases (ICD) in 1979; and (3) the fact that data for ages 5-34 years were aggregated so that trends in mortality in childhood were not distinguished from changes among young adults, who contribute relatively more deaths in this age range. It is now possible to analyse trends, by age, over the eleven years 1979-89 entirely within the period of the ICD 9 (figure). Statistical significance of the trends shown has been tested by the Poisson regression techniqueTrends in the 0-14, 25-34, and 35-44 year There is however a age groups are not significant (p>0-1). significant (p<0’05) upward trend in the 15-24 year age group, averaging about 2% per year; this trend seems to be largely explained by a significant (p < 0-05) increase among females though their mortality in 1989 had fallen almost to the 1979 level. Within the 35-44 year age group there was a significant (p < 0-05) fall in mortality in females but a non-significant increase in males. Over this period the only factor that might have created artifactual changes was implementation in 1984 of the ICD coding rule 3. This provides for certain underlying causes of death, such as pneumonia, to be replaced by more likely primary causes recorded elsewhere in part 1 or 2 of the death certificate. However, this is unlikely to have materially increased death rates in younger asthmatics" a view confirmed by the absence of any step effect in 1984.

Asthma

mortality in children and young adults in England and

Wales, 1979-89.

We conclude that there is no evidence for an increase in asthma mortality in children over this period. This should be considered in the context of a possible increase in the prevalence of more severe forms of asthma and a rapidly increasing hospital admission rate, at least up to 1985.5-7 Mortality rates for young adults appear to have changed little, with the possible exception of a small upward trend among females aged 15-24. Nothing is known about trends in the prevalence of asthma in young adults but there has been a modest rise in hospital admissions.8 Further interpretation should be cautious. The findings could indicate that existing treatment, including hospital admission, is containing case-fatality in the face of a possible increase in the prevalence of severe disease. On the other hand, they are also compatible with the proposition that the underlying incidence of life-threatening asthma has changed little. Either way it is important to note that current levels of mortality are similar to those occurring not just one but three decades ago.s Department of Public Health Sciences, George’s Hospital Medical School,

St

London SW17 0RE, UK

H. R. ANDERSON D. P. STRACHAN

Bumey PG. Asthma mortality in England and Wales: evidence for a further increase, 1978-84. Lancet 1986; ii: 323-26. 2. Office of Population Censuses and Surveys. Mortality statistics, cause, England and Wales 1989 (series DH2 no 16). London: HM Stationery Office, 1991. 3. Payne CD, ed. The GLIM system manual: release 3.77. Oxford: Numerical Algorithms Group, 1985. 4. Office of Populations Censuses and Surveys. Mortality statistics, cause, England and Wales 1984 (series DH2 no 11). London: HM Stationery Office, 1985. 5. Anderson HR. Increase in hospital admissions for childhood asthma: trends in referral, severity and readmissions from 1970 to 1985 in a health region of the United Kingdom. Thorax 1989; 44: 614-19 6. Burr ML, Butland BK, King S, Vaughan-Williams E. Changes in asthma prevalence: 1.

7.

two surveys 15 years apart. Arch Dis Child 1989; 64: 1452-56. Bumey PG, Chinn S, Rona RJ Has the prevalence of asthma increased in children? Evidence from the national study of health and growth 1973-86. Br Med J 1990;

300: 1306-10. 8. Alderson MR. Trends in morbidity and mortality from asthma. 18-23.

Pop Trends 1987; 49:

Autistic and

developmental disorders after general anaesthetic delivery

SIR,-We have identified 49 children bom between 1975 and 1984 with developmental disorders who have a history of delivery under general anaesthesia. According to DSMIIIR, we have seen 23 cases of autistic disorder, 14 cases of specific developmental disorders, and 12 cases of mental retardation. Among the 23 cases of autistic disorder, 21 were born in the same hospital (hospital A) where 95% of children are born under general anaesthesia. The frequency of autistic disorder among children bom in hospital A