Clinical and diagnostic findings of an echovirus meningitis outbreak in the north west of England.

INTRODUCTION: An outbreak of echovirus meningitis occurred in the north west of England in 2001. This paper reviewed the clinical features and the role of different diagnostic methods. METHODS: This was a prospective study of adults admitted to a regional infectious disease unit with a probable diagnosis of meningitis, March to August 2001. RESULTS: Half the 40 cases were male; median age was 28 (range 16-51) years. Fifteen of 38 (39.5%) were smokers, and 20 of 24 (83.3%) had close contact with children. Median (range) duration of symptoms was 1.1 (0.25-7) days. Symptoms included headache (100%), photophobia (87.5%), and nausea (67.5%), and severity ranged from minimal signs to those consistent with a meningoencephalitis. The diagnosis was confirmed virologically in 29 of 40 (72%); echovirus 30 was isolated from six. Cerebrospinal fluid (CSF) enterovirus polymerase chain reaction (PCR) was positive in 26 of 32 (81%), and CSF virus culture in 3 of 16 (19%). Thirty one per cent of CSF samples had a neutrophil predominance, and 3 of 29 (10%) virologically confirmed cases had normal CSF microscopy and biochemistry. CONCLUSION: CSF microscopy may be normal or suggest bacterial meningitis in a substantial minority of cases of echovirus meningitis. CSF PCR for enterovirus seems to be more sensitive than virus culture of CSF, although PCR does not yield information on circulating virus type. Early and accurate diagnosis could reduce both use of parenteral antibiotics and length of hospital stay with both morbidity and cost implications. Close contact with children may be a risk factor, particularly if good hygiene measures are not practised.

'Disappearing diabetes'--resolution of apparent Type 1 diabetes in a patient with AIDS and cytomegalovirus (CMV) infection.

A 30-year-old African female with established acquired immunodeficiency syndrome (AIDS) and no history of diabetes, presented in severe diabetic ketoacidosis (DKA). Blood pH was 6.96, serum bicarbonate 5 mmol/l, plasma glucose (PG) 33.0 mmol/l, and urine heavily positive for ketones. She responded to standard treatment and was established on twice-daily subcutaneous insulin. Four months later her insulin was stopped because of hypoglycaemic attacks on small doses. A glucose tolerance test (GTT) at 6 months postdiagnosis was normal (fasting PG 4.4 mmol/l and 2 h PG 7.5 mmol/l), and at 12 months random PG was 4.1 mmol/l and HbA1c 4.3%. The onset of her apparent Type 1 diabetes coincided with an HIV-associated cytomegalovirus (CMV) infection, and a reversible 'CMV insulitis' may be an explanation. Alternatively, the patient may have had what has recently been described as 'atypical diabetes' in African or Afro-Caribbean diabetic patients. Here resolution of diabetes may occur after presentation, though complete return to normoglycaemia after true DKA is very unusual.

From trench fever to endocarditis.

The case of a 44 year old woman with infective endocarditis due to Bartonella quintana, an organism long recognised to cause a condition known as trench fever, is reported. This case illustrates the lengthy differential diagnosis of "culture negative" endocarditis. In addition the presence of serological cross reactivity of Bartonella spp and Chlamydia spp demonstrates the potential for misdiagnosis in these circumstances.

Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome.

OBJECTIVE: To assess the efficacy of an educational intervention explaining symptoms to encourage graded exercise in patients with chronic fatigue syndrome. DESIGN: Randomised controlled trial. SETTING: Chronic fatigue clinic and infectious diseases outpatient clinic. SUBJECTS: 148 consecutively referred patients fulfilling Oxford criteria for chronic fatigue syndrome. INTERVENTIONS: Patients randomised to the control group received standardised medical care. Patients randomised to intervention received two individual treatment sessions and two telephone follow up calls, supported by a comprehensive educational pack, describing the role of disrupted physiological regulation in fatigue symptoms and encouraging home based graded exercise. The minimum intervention group had no further treatment, but the telephone intervention group received an additional seven follow up calls and the maximum intervention group an additional seven face to face sessions over four months. MAIN OUTCOME MEASURE: A score of >/=25 or an increase of >/=10 on the SF-36 physical functioning subscale (range 10 to 30) 12 months after randomisation. RESULTS: 21 patients dropped out, mainly from the intervention groups. Intention to treat analysis showed 79 (69%) of patients in the intervention groups achieved a satisfactory outcome in physical functioning compared with two (6%) of controls, who received standardised medical care (P<0.0001). Similar improvements were observed in fatigue, sleep, disability, and mood. No significant differences were found between the three intervention groups. CONCLUSIONS: Treatment incorporating evidence based physiological explanations for symptoms was effective in encouraging self managed graded exercise. This resulted in substantial improvement compared with standardised medical care.

Update on vaccination guidelines.

Updated guidelines for the immunization of children and adults in the UK, incorporating a number of important changes, have recently been published. This article reviews the areas where recommendations have changed significantly and summarizes immunization guidelines in other problem areas.

Clinical audit of ciprofloxacin use in adults admitted to hospital with gastroenteritis.

We audited the use of ciprofloxacin, before and after the introduction of simple clinical guidelines, in adults admitted to a regional infectious diseases unit with presumed gastroenteritis. The case notes of 128 consecutive adult admissions over 6 months in 1993 were reviewed and a comparable group of 125 adults in 1994 were prospectively followed. The discharge diagnosis was infective gastroenteritis in 73% of the 1993 admissions and 75% of the 1994 admissions, of whom 42% and 51% had confirmed bacterial enteropathogens. The 1994 cohort appeared to be more ill, with longer duration of symptoms prior to admission, more patients with profuse diarrhoea prior to admission, and longer mean duration of hospital stay. The proportion of patients with a discharge diagnosis of gastroenteritis who received ciprofloxacin did not change (64% in 1993, 67% in 1994) but the proportion of these patients who were subsequently found to be culture-positive rose from 54% to 68%. The proportion of patients receiving intravenous ciprofloxacin fell from 20% to 10% and the total number of doses (intravenous and oral) fell from 1027 in 1993 to 768 in 1994, with cost savings of pound 1465 over 6 months. The benefits and drawbacks of empirical use of ciprofloxacin are discussed. Our audit suggests that simple clinical guidelines can assist in identifying suitable patients for empirical antimicrobial therapy, and result in substantial cost savings.

Zidovudine phosphorylation in HIV-infected patients and seronegative volunteers.

OBJECTIVES AND DESIGN: Measurement of phosphorylated zidovudine (ZDV) inside infected cells is more likely to provide satisfactory dose response relationships than serum concentrations. This study provides information on ZDV phosphorylation in HIV-seronegative volunteers (n = 5) and in patients with HIV infection (n = 12). METHODS: Intracellular ZDV phosphate metabolites were measured in peripheral blood mononuclear cells isolated from whole blood by density cushion centrifugation. Cells were washed and extracted overnight with 60% methanol prior to analysis by high performance liquid chromatography. Fractions eluted from the column corresponding to ZDV, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV triphosphate (ZDV-TP) were collected, hydrolysed by acid phosphatase and ZDV levels quantified by radioimmunoassay. RESULTS: The area under the plasma ZDV concentration-time curve (AUC0-6 h) was similar in seronegative volunteers and patients [mean +/- SD, 4.64 +/- 2.50 versus 5.56 +/- 2.67 mumoles/l h; 95% confidence interval (CI), -4.39-2.23; P = 0.646, Mann-Whitney U test]. However, ZDV phosphorylation was greater in patients, with the AUC0-6 h for total phosphate metabolites being 5.91 +/- 3.42 pmoles/10(6) cells h compared with seronegative volunteers (0.66 +/- 0.48 pmoles/10(6) cells h; 95% CI, -8.35 to -2.32; P = 0.0003). The concentration of ZDV-TP was similar in both groups, the increase in total phosphates in patients being due primarily to ZDV-MP. ZDV-MP AUC0-6 h and total ZDV phosphate AUC0-6 h were closely correlated (r2 = 0.94). The relationship between total ZDV phosphate AUC0-6 h and the CD4 count demonstrates that patients with a count < 100 x 10(6)/l have much higher ZDV phosphate levels, predominantly ZDV-MP. CONCLUSION: ZDV is phosphorylated to a greater extent in patients than in healthy volunteers. The increased ZDV-MP in patients with low CD4 counts may explain the well known occurrence of increased ZDV toxicity in patients with more advanced disease. The ability to measure ZDV phosphorylated metabolites (without the administration of radiolabelled nucleoside) represents a significant advance in our understanding of the clinical pharmacology of the drug.

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

1. Zidovudine (ZDV) has proved unsuccessful in controlling disease progression over extended periods of time in patients with AIDS. Combination of ZDV with another reverse transcriptase inhibitor, dideoxyinosine (ddI) may improve the duration of effectiveness of antiretroviral therapy. The aim of this study was to investigate the possibility of a pharmacokinetic drug interaction between ZDV and ddI. 2. The pharmacokinetics of ZDV and ddI were determined in eight patients with AIDS who were randomised to receive ZDV 250 mg orally, ddI 250 mg orally or a combination of ZDV 250 mg plus ddI 250 mg orally on 3 study days separated by 1 week. 3. The administration of ZDV did not significantly alter ddI pharmacokinetics. The mean AUC was 6.8 +/- 2.0 s.d. and 7.6 +/- 2.5 s.d. mumol l-1 h and oral clearance was 2766 +/- 686 and 2660 +/- 1297 ml min-1 in the presence and absence of ZDV, respectively. 4. In the presence of ddI the elimination half-life of ZDV was increased significantly by 18% from 1.1 +/- 0.3 to 1.3 +/- 0.3 h (P < 0.05) and the mean AUC increased significantly by 35% from 4.8 +/- 1.5 to 6.5 +/- 1.5 mumol l-1 h (P < 0.05). The clearance was decreased by 29% from 3518 +/- 1123 to 2505 +/- 575 ml min-1, but this difference was not significant. The renal clearance of ZDV was not altered by ddI. 5. Administration of ddI also resulted in a significant 22% increase in the AUC of GZDV, from 28.5 +/- 15.7 to 34.9 +/- 12.8 mumol l-1 h (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.

The effects of indomethacin and naproxen on zidovudine pharmacokinetics.

The effects of indomethacin and naproxen on zidovudine (ZDV) pharmacokinetics were studied in six patients with the acquired immunodeficiency syndrome (AIDS), AIDS related complex (ARC) or asymptomatic HIV disease using a placebo-controlled crossover design. Indomethacin 25 mg twice daily or naproxen 250 mg twice daily did not alter ZDV pharmacokinetics compared with placebo. The mean AUC value for the glucuronidated metabolite, GZDV, was reduced from 26.6 +/- 11.7 mumol l-1 h in the presence of placebo to 20.9 +/- 8.3 mumol l-1 h (95% C.I. of the difference 1.39-9.98; P < 0.05) following treatment with naproxen 250 mg twice daily for 3 days. The small decrease in plasma GZDV in the naproxen phase reflects an increase in clearance of ZDV to other metabolites and/or a decrease in the formation clearance to GZDV and/or an increase in the clearance of GZDV. A decrease in formation clearance to GZDV would be consistent with the results of in vitro studies reported previously. No significant increase in ZDV concentration in the presence of naproxen may reflect a lower sensitivity of parent drug measurements to selective inhibition of parallel pathways of metabolism. The clinical significance of these findings is unknown but toxicity may be increased if a decreased formation of GZDV is accompanied by shunting of metabolism to 3'-amino-3'-deoxythymidine which is alleged to be cytotoxic.