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3.  Effects of upper respiratory tract infections in patients with cystic fibrosis. 
Thorax  1996;51(11):1115-1122.
BACKGROUND: The polymerase chain reaction has improved the detection of picornaviruses and rhinoviruses and our understanding of their role in reversible airways disease. The effects of colds on lower respiratory morbidity and bacterial colonisation in cystic fibrosis remain uncertain. METHODS: Children with cystic fibrosis were evaluated regularly in the clinic and the parents notified the investigators when their child developed a cold. Nasopharyngeal specimens were collected at the start of the infection for polymerase chain reaction, bacteriology was also undertaken and again three weeks later, and pulmonary function was measured in children aged > or = 6 years at four day intervals for three weeks. The effects of colds on rate of progression of cystic fibrosis were assessed by pulmonary function, Shwachman scores, and radiology. RESULTS: Thirty eight children suffered 147 colds over 17 months. Picornaviruses were detected in 51 (43%) of 119 nasopharyngeal specimens, and 21 of the 51 were further identified as rhinoviruses. Pulmonary dysfunction was similar following picornavirus and non-picornavirus infections; the mean change from baseline in forced expiratory volume in one second (FEV1) was -16.5% and -10.3% at 1-4 days and 21-24 days, respectively, after onset of a cold. Children who experienced more colds than average had evidence of disease progression with reduction in Shwachman score, increasing Chrispin-Norman score, and greater deterioration in FEV1 per annum. Ten of 12 new bacterial infections were associated with a cold. CONCLUSIONS: Picornavirus and non-picornavirus colds are associated with pulmonary function abnormalities and disease progression in patients with cystic fibrosis, and predispose to secondary bacterial infection and colonisation.
PMCID: PMC1090523  PMID: 8958895
4.  Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden. 
BMJ : British Medical Journal  1997;315(7115):1060-1064.
OBJECTIVE: To evaluate the disease burden of upper respiratory infections in elderly people living at home. DESIGN: Prospective surveillance of elderly people. INTERVENTION: None. SETTING: Leicestershire, England SUBJECTS: 533 subjects 60 to 90 years of age. MAIN OUTCOME MEASURES: Pathogens, symptoms, restriction of activity, duration of illness, medical consultations, interval between onset of illness and medical consultation, antibiotic use, admission to hospital, and death. RESULTS: 231 pathogens were identified for 211 (43%) of 497 episodes for which diagnostic specimens were available: 121 (52%) were rhinoviruses, 59 (26%) were coronaviruses, 22 (9.5%) were influenza A or B, 17 (7%) were respiratory syncytial virus, 7 (3%) were parainfluenza viruses, and 3 (1%) were Chlamydia species; an adenovirus and Mycoplasma pneumoniae caused one infection each. Infections occurred at a rate of 1.2 episodes per person per annum (95% confidence interval 1.0 to 1.7; range 0-10) and were clinically indistinguishable. Lower respiratory tract symptoms complicated 65% of upper respiratory infections and increased the medical consultation rate 2.4-fold (chi 2 test P < 0.001). The median interval between onset of illness and medical consultation was 3 days for influenza and 5 days for other infections. Rhinoviruses caused the greatest disease burden overall followed by episodes of unknown aetiology, coronaviruses, influenza A and B, and respiratory syncytial virus. CONCLUSIONS: Respiratory viruses cause substantial morbidity in elderly people. Although respiratory syncytial virus and influenza cause considerable individual morbidity, the burden of disease from rhinovirus infections and infections of unknown aetiology seems greater overall. The interval between onset of illness and consultation together with diagnostic difficulties raises concern regarding the role of antiviral drugs in treating influenza.
PMCID: PMC2127683  PMID: 9366736
5.  Impact of influenza and respiratory syncytial virus on mortality in England and Wales from January 1975 to December 1990. 
Epidemiology and Infection  1996;116(1):51-63.
The effects of influenza A and B and RSV on mortality in England and Wales were assessed by regression analysis for the period 1975-90. Morbidity data from sentinel practices were used to calculate 4-weekly rates of aggregated upper respiratory tract infections (URTI); PHLS laboratory reports were used as indices of infection, and 4-weekly death rates from all causes, excluding childbirths, were used to study relationships with mortality. Deaths correlated strongly with influenza A and B reports, temperature, and interactions between aggregated URTI and temperature, and RSV outbreaks and temperature. Estimates of 'seasonal' 4-weekly mortality associated with URTI were made by substituting into primary regression models the mean of annual trough consultation rates for aggregated URTI and baseline values for RSV and influenza. Peak 4-weekly mortality associated with URTIs was estimated at c. 24000 and c. 28000 during combined influenza and RSV epidemics of 1975-6 and 1989-90 respectively. Secondary regression analysis was carried out with the estimated 'seasonal' 4-weekly deaths associated with URTI as dependent variable and laboratory data as regressors. Estimated excess mortality associated with influenza was considerable even during years without major epidemics. Overall during the 15 winters the estimated mortality associated with RSV was 60-80% more than that associated with influenza. The modelling permits only a crude estimate of RSV associated mortality. None the less it suggests that RSV is an important cause of winter mortality.
PMCID: PMC2271234  PMID: 8626004
6.  Prophylactic intranasal alpha 2 interferon and viral exacerbations of chronic respiratory disease. 
Thorax  1991;46(10):706-711.
BACKGROUND As respiratory virus infections often lead to exacerbations of chronic bronchitis and asthma an effective antiviral drug may be helpful in such patients. Alpha 2 interferon has been shown to give protection against rhinovirus infections in field studies. METHODS Patients with chronic respiratory disease exposed to close contacts with symptoms of upper respiratory tract infection were randomly allocated to receive nasal sprays of recombinant alpha 2 interferon (3 x 10(6) IU) or placebo twice daily for five days. Of the 123 patients recruited into the study, 69 took 117 courses of medication; 11 courses were excluded from analysis. RESULTS No important side effects were recorded and the incidence of possible adverse effects was similar in the two groups. Interferon treatment did not reduce the number or severity of symptomatic episodes; 11 of 48 patients given interferon and 16 of 58 given placebo developed lower respiratory symptoms. There were no differences in mean symptom scores (51 interferon and 52 placebo), number of symptomatic days (3.3 interferon and 5.0 placebo), peak flow values, number of general practitioner consultations, or use of antibiotics. CONCLUSION Alpha 2 interferon 3 x 10(6) IU taken twice daily for five days does not protect patients with chronic respiratory disease from exacerbations after they have been in contact with an upper respiratory tract infection.
PMCID: PMC463387  PMID: 1750016
7.  Influenza immunization; vaccine offer, request and uptake in high-risk patients during the 1991/2 season. 
Epidemiology and Infection  1993;111(2):347-355.
Current levels of influenza vaccine uptake in patients considered to be at high risk have been determined by means of a questionnaire survey. During March-April 1992, information was sought from 624 patients in Leicestershire, UK with either chronic cardiovascular or respiratory disease, or diabetes; questions related to current health status and the request, offer and receipt of influenza vaccine in the current and three previous seasons. Ninety-eight percent of all offers of immunization were made in the primary care setting, and vaccine was well tolerated as judged by the fact that 86% of vaccinees between 1988/9-1990/1 returned for immunization in the following year. However in the 1991/2 season the overall level of vaccine uptake was only about 41% which is at variance with the stated policies and practices of general practitioners. Opportunities were missed, in both hospitals and general practices, to publicise and offer immunization to individuals with vaccine indications. Future attempts to improve vaccine uptake should focus on increasing the role of hospital staff in influenza prevention, in addition to promoting better vaccine delivery through primary care.
PMCID: PMC2271385  PMID: 8405161
8.  Impact of respiratory virus infection in patients with chronic chest disease. 
Epidemiology and Infection  1993;111(2):337-346.
This study investigated the morbidity associated with respiratory virus infections in patients with well-documented chest disease, and the risk of transmission between close contacts. Patients informed the study team if they were exposed to a family member or colleague with a cold. Patients and symptomatic index cases recorded respiratory symptoms during the study period. Acute nasopharyngeal swabs and paired sera were obtained for viral diagnosis. Twenty-five (43%) of 58 recorded exposures resulted in a symptomatic illness and 16 (28%) patients developed lower respiratory tract symptoms. Sixteen (64%) of the 25 symptomatic patients contacted their general practitioner, 14 (56%) received antibiotics and 4 (16%) were hospitalized. Mean duration of illness was 10.6 days in symptomatic patients and 5.7 days in their corresponding index cases (P < 0.005). Mean symptom scores were 100.6 in symptomatic patients and 62.2 in index cases (P < 0.01). Respiratory viruses were identified in 19 (33%) episodes. Rhinovirus, coronavirus and respiratory syncytial virus infections were all associated with lower respiratory tract exacerbations. Respiratory tract symptoms following exposure to a cold were comparatively severe in these patients with chronic chest disease. This group of patients might gain particular benefit from the introduction of effective vaccines or antiviral therapy.
PMCID: PMC2271374  PMID: 8405160
9.  Influenza deaths in Leicestershire during the 1989-90 epidemic: implications for prevention. 
Epidemiology and Infection  1992;108(3):537-545.
There is an association between excess winter mortality and epidemics of influenza and it has been suggested that annual influenza vaccination should be offered to all over 65 years old as in the United States. This paper identifies the number of people dying from influenza in Leicestershire UK during the 1989-90 epidemic and the factors associated with a fatal outcome. The findings show that deaths attributed to influenza occur predominantly in very elderly people with underlying ill-health. The risk of influenzal death is greater in residential patients and increases substantially with the number of underlying medical conditions. The estimated death rates in vaccinated and non-vaccinated groups were not significantly different, but there were trends towards protection in both residential and non-residential groups. Influenza vaccine is not reaching the principal target groups and improved methods of influenza control are required.
PMCID: PMC2272214  PMID: 1601083
11.  Acute upper respiratory tract viral illness and influenza immunization in homes for the elderly. 
Epidemiology and Infection  1990;105(3):609-618.
Occupants of 482 long-stay and 33 short-stay beds in 11 Leicester City Council homes for the elderly were studied during a 30-week period from September 1988 to March 1989 to determine the incidence, aetiology, morbidity, and mortality of acute upper respiratory tract viral infections and the use of influenza vaccine. Influenza immunization rates by home ranged from 15.4 to 90% (mean 45%). There were no differences in the distribution of medical conditions by home. The highest immunization rates were seen in people with chest disease (77%), heart disease (60%), diabetes (56%), and those with three medical conditions (75%). There was an average of 0.7 upper respiratory episodes per bed per annum with a mortality of 3.4% (6/179). Half of all episodes were seen by a general medical practitioner and 81 of 90 (90%) referrals were prescribed antibiotics costing approximately 7.50 pounds per patient. Lower respiratory tract complications developed during 45 (25%) of 179 episodes including 3 of 12 coronavirus infections, 3 of 9 respiratory syncytial virus infections, 2 of 4 adenovirus infections, 1 of 11 rhinovirus infections, but none of 5 influenza infections. Respiratory infections were caused mostly by pathogens other than influenza virus during the influenza period documented nationally. This highlights the role of coronaviruses, respiratory syncytial virus, and unidentified agents in the elderly, and questions the assumptions made in American estimates on the impact of influenza and the value of influenza vaccines.
PMCID: PMC2271825  PMID: 2249724
12.  Still's disease and myocarditis associated with recent mumps infection. 
Postgraduate Medical Journal  1988;64(755):693-695.
We describe a 16 year old patient who developed Still's disease with evidence of myocarditis. A rise in the mumps 'V' antigen indicated that the disease was associated with recent mumps infection.
PMCID: PMC2428969  PMID: 3251224
13.  Retinochoroiditis in acute Epstein-Barr virus infection. 
The British Journal of Ophthalmology  1989;73(12):1002-1003.
The case is reported of a 17-year-old male with secondary glaucoma and retinochoroiditis complicating acute clinical infectious mononucleosis. The diagnosis was confirmed by Epstein-Barr virus specific serology. Toxoplasmic infection was initially suspected. The differential diagnosis and relevant literature are discussed.
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PMCID: PMC1041954  PMID: 2611181
14.  Failure of interferon alfa and tribavirin in rabies encephalitis. 
BMJ : British Medical Journal  1989;299(6703):830-833.
OBJECTIVE--To test the effect of interferon alfa and tribavirin (ribavirin) in patients with rabies encephalitis. DESIGN--An open trial of chemotherapy and intensive care in patients with early rabies. SETTING--The intensive care unit of a Bangkok hospital. PATIENTS--Four conscious men with clinical rabies encephalitis. INTERVENTIONS--Rapid virological diagnosis of rabies. Treatment with intravenous and intraventricular injections of high doses of lymphoblastoid interferon alfa in three patients and tribavirin in one patient. Intensive care was given throughout. MAIN OUTCOME MEASURES--Rabies infection confirmed by antigen detection and virus isolation. Rabies neutralising antibody and specific IgM sought in serum and cerebrospinal fluid. Interferon concentrations monitored before and during treatment in three patients. RESULTS--Interferon alfa treatment produced high concentrations in serum and cerebrospinal fluid. All four patients died after 5 1/2 to 12 1/2 days of treatment with no evidence of virostatic or clinically beneficial effects from either treatment. CONCLUSION--Interferon alfa treatment is not effective in rabies encephalitis. The use of tribavirin warrants further study, possibly combined with new therapeutic methods.
PMCID: PMC1837695  PMID: 2510846
15.  Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre-exposure immunization. 
The Journal of Hygiene  1982;89(1):101-110.
The antibody responses of 194 volunteers were studied for up to 3 years after primary immunization with one, two or three doses of human diploid cell rabies vaccine, administered either in 0.1 ml volumes intradermally (i.d.) or as 1.0 ml intramuscularly (i.m.). Sero-conversion occurred in 95% of subjects after the first injection and in 100% after the second. The highest titres and most durable antibody responses were induced by three injections of vaccine. Booster doses were administered either by the subcutaneous (s.c.) or i.d. route, after 6, 12 or 24 months to randomly grouped volunteers; these induced responses greater than or equal to 5.0 i.u. per ml in 95% of subjects. The responses were rapid and were neither influenced by the primary regimen nor by the timing and route of the booster dose. Antibody titres after i.d. immunization were only two-fold lower than those induced by the larger volume of vaccine. The findings suggest that the i.d. route is both effective and economic.
PMCID: PMC2134158  PMID: 7096998
16.  Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May–September 2009) 
Thorax  2010;65(7):645-651.
Background
During the first wave of pandemic H1N1 influenza in 2009, most cases outside North America occurred in the UK. The clinical characteristics of UK patients hospitalised with pandemic H1N1 infection and risk factors for severe outcome are described.
Methods
A case note-based investigation was performed of patients admitted with confirmed pandemic H1N1 infection.
Results
From 27 April to 30 September 2009, 631 cases from 55 hospitals were investigated. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged ≥65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically-confirmed pneumonia and a raised C-reactive protein (CRP) level (≥100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people.
Conclusions
Pandemic H1N1 infection causes disease requiring hospitalisation of previously fit individuals as well as those with underlying conditions. An abnormal chest x-ray or a raised CRP level, especially in patients who are recorded as obese or who have pulmonary conditions other than asthma or COPD, indicate a potentially serious outcome. These findings support the use of pandemic vaccine in pregnant women, children <5 years of age and those with chronic lung disease.
doi:10.1136/thx.2010.135210
PMCID: PMC2921287  PMID: 20627925
Influenza; Human influenza A virus; H1N1 subtype; hospitalisation; mortality; critical care; clinical epidemiology; respiratory infection; viral infection
17.  Risk factors for lower respiratory complications of rhinovirus infections in elderly people living in the community: prospective cohort study. 
BMJ : British Medical Journal  1996;313(7065):1119-1123.
OBJECTIVE: To assess the role of rhinoviruses in elderly people living in the community. DESIGN: Prospective community based surveillance of elderly people, without intervention. Subjects were telephoned weekly to identify symptomatic upper respiratory tract infections. Symptoms and impact of illnesses were monitored, and specimens were collected for diagnostic serology and human rhinovirus polymerase chain reaction. SETTING: Leicestershire, England. SUBJECTS: 533 subjects aged 60 to 90. MAIN OUTCOME MEASURES: Symptoms, restriction of activity, medical consultations, and antibiotic use during 96 rhinovirus infections. Adjusted odds ratios for lower respiratory syndromes with respect to smoking and health status. RESULTS: A viral cause was established in 211 (43%) of 497 respiratory illnesses; rhinoviruses were identified in 121 (24%) and as single pathogens in 107. The median duration of the first or only rhinovirus infection in the 96 people with 107 rhinovirus infections was 16 days; 18 of the 96 patients were confined to bed and 25 were unable to cope with routine household activities. Overall, 60 patients with rhinovirus infections had lower respiratory tract syndromes; 41 patients consulted their doctor, 31 of them (76%) receiving antibiotics. One patient died. Logistic regression analysis showed that chronic medical conditions increased the estimated probability of lower respiratory rhinovirus illness by 40% (95% confidence interval 17% to 68%) and smoking by 47% (14% to 90%). There were almost six times as many symptomatic rhinovirus infections as influenza A and B infections. CONCLUSIONS: Rhinoviruses are an important cause of debility and lower respiratory illness among elderly people in the community. Chronic ill health and smoking increase the likelihood of lower respiratory complications from such infections. The overall burden of rhinovirus infections in elderly people may approach that of influenza.
PMCID: PMC2352467  PMID: 8916700
18.  Delays and diversity in the practice of local research ethics committees. 
Journal of Medical Ethics  1996;22(5):263-266.
OBJECTIVES: To compare the practices of local research ethics committees and the time they take to obtain ethical approval for a multi-centre study. DESIGN: A retrospective analysis of outcome of applications for a multi-centre study to local research ethics committees. SETTING: Thirty-six local research ethics committees covering 38 district health authorities in England. MAIN MEASURES: Response of chairmen and women, the time required to obtain approval, and questions asked in application forms. RESULTS: We received replies from all 36 chairmen contacted: four (11%) granted their approval, and 32 (89%) required our proposal to be considered by their local research ethics committee. Three committees asked us to attend their meetings. The application was approved by all 36 local research ethics committees but the time to obtain ethical approval varied between six to 208 days. One third of the committees did not approve the project within three months, and three took longer than six months. There was considerable variation in the issues raised by local research ethics committees and none conformed exactly to the Royal College of Physicians' guidelines. CONCLUSION: Obtaining ethical approval for a multi-centre study is time-consuming. There is much diversity in the practice of local research ethics committees. Our data support the recommendation for a central or regional review body of multi-centre studies which will be acceptable to all local research ethics committees.
PMCID: PMC1377056  PMID: 8910776
19.  Respiratory viruses and exacerbations of asthma in adults. 
BMJ : British Medical Journal  1993;307(6910):982-986.
OBJECTIVE--To study the role of respiratory viruses in exacerbations of asthma in adults. DESIGN--Longitudinal study of 138 adults with asthma. SETTING--Leicestershire Health Authority. SUBJECTS--48 men and 90 women 19-46 years of age with a mean duration of wheeze of 19.6 years. 75% received regular treatment with bronchodilators; 89% gave a history of eczema, hay fever, allergic rhinitis, nasal polyps, or allergies; 38% had been admitted to hospital with asthma. MAIN OUTCOME MEASURES--Symptomatic colds and asthma exacerbations; objective exacerbations of asthma with > or = 50 l/min reduction in mean peak expiratory flow rate when morning and night time readings on days 1-7 after onset of symptoms were compared with rates during an asymptomatic control period; laboratory confirmed respiratory tract infections. RESULTS--Colds were reported in 80% (223/280) of episodes with symptoms of wheeze, chest tightness, or breathlessness, and 89% (223/250) of colds were associated with asthma symptoms. 24% of 115 laboratory confirmed non-bacterial infections were associated with reductions in mean peak expiratory flow rate > or = 50 l/min through days 1-7 and 48% had mean decreases > or = 25 l/min. 44% of episodes with mean decreases in flow rate > or = 50 l/min were associated with laboratory confirmed infections. Infections with rhinoviruses, coronaviruses OC43 and 229E, influenza B, respiratory syncytial virus, parainfluenza virus, and chlamydia were all associated with objective evidence of an exacerbation of asthma. CONCLUSIONS--These findings show that asthma symptoms and reductions in peak flow are often associated with colds and respiratory viruses; respiratory virus infections commonly cause or are associated with exacerbations of asthma in adults.
PMCID: PMC1679193  PMID: 8241910
20.  Immunisation against influenza among people aged over 65 living at home in Leicestershire during winter 1991-2. 
BMJ : British Medical Journal  1993;306(6883):974-976.
OBJECTIVES--To assess the size of the elderly population for whom influenza vaccine is indicated and how many are vaccinated. DESIGN--Cohort questionnaire study. SETTING--Leicestershire general practices. SUBJECTS--800 elderly subjects selected a random from the Leicestershire family health services authority list who were not living in residential care, 565 of whom returned a questionnaire. MAIN OUTCOME MEASURES--Patient profile, vaccine offers, vaccination status, and reasons for not accepting vaccine. RESULTS--170 of 334 (51%) people aged 65-74 years and 106 of 205 (52%) aged > or = 75 years had one or more medical indications for influenza vaccine. 195 people were offered vaccine, 49 of whom had no risk factor. 152 offers were made opportunistically during visits to the practice and only six were made in writing or by telephone. Overall 113 of 266 patients with known medical indications were immunised. Vaccine was accepted by 148 of 189 (78%) offered it, and, as judged by acceptance in sequential years, influenza vaccine was well tolerated. The main reasons for not being vaccinated were misconception about risk status and inadequate advice from doctors. CONCLUSIONS--The prevalence of medical indications for vaccine is not large enough to justify a policy of universal immunisation. Most patients offered vaccine accept it and tolerate it well. Improved targeting and education is needed to increase immunisation of people at risk.
PMCID: PMC1677436  PMID: 8490478
22.  Genetic similarity and maintenance of Candida albicans strains from a group of AIDS patients, demonstrated by DNA fingerprinting. 
Journal of Clinical Microbiology  1992;30(4):935-941.
By using the computer-assisted Dendron system to analyze the patterns of Southern blots probed with the repetitive sequence Ca3, we have compared oral isolates of Candida spp. from a group of 11 nonhospitalized patients with AIDS suffering from recurrent episodes of oral thrush in Leicester, England, with oral isolates from a group of control individuals. Genetic diversity among the AIDS strains was significantly reduced compared with that of control strains. In addition, the same strains persisted through recurrent infections in patients with AIDS. Although AIDS strains were genetically less diverse than either control strains or oral commensal strains analyzed in previous studies, the majority did not form a genetically distinct group. The results of this study suggest that in the majority of patients with AIDS in this group from Leicester, original commensal strains were replaced, replacement occurred early in the manifestation of AIDS, and replacement occurred only once.
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PMCID: PMC265189  PMID: 1572980
23.  Amantadine for influenza A. 
BMJ : British Medical Journal  1991;302(6774):425-426.
PMCID: PMC1669349  PMID: 2004163
24.  Influenza vaccination and the elderly. 
BMJ : British Medical Journal  1990;301(6753):617-618.
PMCID: PMC1663881  PMID: 2224211
25.  Inflammation of the retinal pigment epithelium: a unique presentation of ocular schistosomiasis. 
We report the first case of inflammation of the retinal pigment epithelium (RPE) caused by Schistosoma mansoni and discuss its possible pathogenesis. This is of particular interest because the lesions resembled those found in acute multifocal placoid pigment epitheliopathy (AMPPE).
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PMCID: PMC1042159  PMID: 2116164

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