register interest

Chris P Conlon FRCP

Research Area: Global Health
Scientific Themes: Immunology & Infectious Disease and Tropical Medicine & Global Health

I am responsible for a mixture of clinical, teaching, research and administrative duties, including covering the 18 bed Infectious Diseases Unit at the Churchill Hospital.  I collaborate with colleagues in HIV research and am currently on the trial steering committee of the RIVER study; a proof of principle trial of HDAC inhibitors and HIV vaccine use in an attempt to ‘cure’ HIV.  I also run the TB service in Oxford and collaborate with Professor Derrick Crook and others using whole genome sequencing to improve diagnoses.  I also have oversight of the Tropical Medicine Group and was recently invited to lecture at The First Beijing International Conference on Precision Medicine and Cancer Treatment Forum with a talk entitled “Medical Education in the 21st Century”

I am a Fellow and Tutor in Clinical Medicine at Oriel College, Oxford and regularly teach Oxford medical undergraduates in lectures and seminars, and at the bedside.  In addition, I am a Principal Examiner in Medicine in Oxford and Chair of the Royal College of Physicians Joint Specialty Committee for Infectious Diseases.

I was appointed Interim Head of Department for the Nuffield Department of Medicine in May 2016.  I have also been the Head NDM Experimental Medicine since 2014. 

Name Department Institution Country
Paul Klenerman Experimental Medicine Division Oxford University, Peter Medawar Building United Kingdom
Tim Peto Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Derrick Crook Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Sarah Rowland-Jones Target Discovery Institute Oxford University, NDM Research Building United Kingdom
Lucy Dorrell NDM Research Building Oxford University, NDM Research Building United Kingdom
Abd Hamid M, Colin-York H, Khalid-Alham N, Browne M, Cerundolo L, Chen J-L, Yao X, Rosendo-Machado S, Waugh C, Maldonado-Perez D et al. 2019. Self-maintaining CD103+ cancer-specific T cells are highly energetic with rapid cytotoxic and effector responses. Cancer Immunol Res, pp. canimm.0554.2019-canimm.0554.2019. | Show Abstract | Read more

Enrichment of CD103+ tumor-infiltrating T lymphocytes (TILs) is associated with improved outcomes in patients. However, the characteristics of human CD103+ cytotoxic CD8+ T cells (CTLs) and their role in tumor control remains unclear. We investigated the features and antitumor mechanisms of CD103+ CTLs by assessing T-cell receptor (TCR)-matched CD103+ and CD103- cancer-specific CTL immunity in vitro and its immunophenotype ex vivo. Interestingly, we found that differentiated CD103+ cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103+ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor co-expression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103+ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.

Li X, Wang R, Fan P, Yao X, Qin L, Peng Y, Ma M, Asley N, Chang X, Feng Y et al. 2019. A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer. Front Oncol, 9 (OCT), pp. 1066. | Show Abstract | Read more

Background: Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects. Method: This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort. Results: We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates "shared" subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4- and PD-1+TIGIT+2B4+Tim-3-KLRG-1-CTLA-4- from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27-CCR7-CD45RA-) among the "shared" subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4-) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients. Conclusions: To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.

Abd Hamid M, Wang R-Z, Yao X, Fan P, Li X, Chang X-M, Feng Y, Jones S, Maldonado-Perez D, Waugh C et al. 2019. Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses. Cancer Immunol Res, 7 (8), pp. 1293-1306. | Show Abstract | Read more

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor-specific T cells impairs IL2 receptor-dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.

Whitworth HS, Badhan A, Boakye AA, Takwoingi Y, Rees-Roberts M, Partlett C, Lambie H, Innes J, Cooke G, Lipman M et al. 2019. Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study. Lancet Infect Dis, 19 (2), pp. 193-202. | Show Abstract | Read more

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. FUNDING: National Institute for Health Research.

Gossez M, Martin GE, Pace M, Ramjee G, Premraj A, Kaleebu P, Rees H, Inshaw J, Stöhr W, Meyerowitz J et al. 2019. Virological remission after antiretroviral therapy interruption in female African HIV seroconverters. AIDS, 33 (2), pp. 185-197. | Show Abstract | Read more

INTRODUCTION: There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) in primary HIV infection (PHI). METHODS: We studied participants (n = 82) from South Africa and Uganda in Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion, the first trial of treatment interruption in African individuals with PHI randomized to deferred ART or 48 weeks of immediate ART. All were female and infected with non-B HIV subtypes, mainly C. We measured HIV DNA in CD4 T cells, CD4 cell count, plasma viral load (pVL), cell-associated HIV RNA and T-cell activation and exhaustion. We explored associations with clinical progression and time to pVL rebound after treatment interruption (n = 22). Data were compared with non-African Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion participants. RESULTS: Pretherapy pVL and integrated HIV DNA were lower in Africans compared with non-Africans (median 4.16 vs. 4.72 log10 copies/ml and 3.07 vs. 3.61 log10 copies/million CD4 T cells, respectively; P < 0.001). Pre-ART HIV DNA in Africans was associated with clinical progression (P = 0.001, HR per log10 copies/million CD4 T cells increase (95% CI) 5.38 (1.95-14.79)) and time to pVL rebound (P = 0.034, HR per log10 copies/ml increase 4.33 (1.12-16.84)). After treatment interruption, Africans experienced longer duration of viral remission than non-Africans (P < 0.001; HR 3.90 (1.75-8.71). Five of 22 African participants (22.7%) maintained VL less than 400 copies/ml over a median of 188 weeks following treatment interruption. CONCLUSION: We find evidence of greater probability of virological remission following treatment interruption among African participants, although we are unable to differentiate between sex, ethnicity and viral subtype. The finding warrants further investigation.

Evans C, Bateman E, Steven R, Ponsford M, Cullinane A, Shenton C, Duthie G, Conlon C, Jolles S, Huissoon AP et al. 2018. Measurement of Typhi Vi antibodies can be used to assess adaptive immunity in patients with immunodeficiency. Clin Exp Immunol, 192 (3), pp. 292-301. | Show Abstract | Read more

Vaccine-specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens, but interpretation may be complicated. Typhim Vi® , a polysaccharide vaccine for Salmonella typhoid fever, may be an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multi-centre study describing the analytical and clinical performance of a Typhi Vi immunoglobulin (Ig)G enzyme-linked immunosorbent assay (ELISA) calibrated to an affinity-purified Typhi Vi IgG preparation. Intra- and interassay imprecision was low and the assay was linear, between 7·4 and 574 U/ml (slope = 0·99-1·00; R2  > 0·99); 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations  > 7·4 U/ml, the concentration range was 7·7-167 U/ml. In antibody-deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were  < 25 U/ml. In vaccinated normal healthy volunteers, the median concentration post-vaccination was 107 U/ml (range 31-542 U/ml). Eight of eight patients (100%) had post-vaccination concentration increases of at least threefold and six of eight (75%) of at least 10-fold. In an antibody-deficient population (n = 23), only 30% had post-vaccination concentration increases of at least threefold and 10% of at least 10-fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies.

Walker TM, Crook DW, Peto TEA, Conlon CP. 2017. Whole-genome sequencing identifies nosocomial transmission of extra-pulmonary M. tuberculosis-response. QJM, 110 (9), pp. 613. | Read more

Alkhalil M, Conlon CP, Ashrafian H, Choudhury RP. 2017. Aggressive restenosis after percutaneous intervention in two coronary loci in a patient with human immunodeficiency virus infection. World J Clin Cases, 5 (2), pp. 40-45. | Show Abstract | Read more

A 54-year-old black African woman, 22 years human immunodeficiency virus (HIV)-positive, presented with an acute coronary syndrome. She was taking two nucleoside reverse transcriptase inhibitors and two protease inhibitors. Viral load and CD4 count were stable. Angiography revealed a right coronary artery lesion, which was treated with everolimus eluting stent. She also underwent balloon angioplasty to the first diagonal. She re-presented on three different occasions and technically successful coronary intervention was performed. The patient has reported satisfactory compliance with dual anti platelet therapy throughout. She was successfully treated with surgical revascularisation. The patient did not experience any clinical recurrence on follow up. This case demonstrates exceptionally aggressive multifocal and recurrent instent restenosis in a patient treated for HIV infection, raising the possibility of an association with HIV infection or potentially components of retro viral therapy.

Walker TM, Crook DW, Peto TEA, Conlon CP. 2016. Whole-genome sequencing identifies nosocomial transmission of extra-pulmonary M. tuberculosis. QJM, 109 (12), pp. 819-820. | Read more

Turtle L, Bali T, Buxton G, Chib S, Chan S, Soni M, Hussain M, Isenman H, Fadnis P, Venkataswamy MM et al. 2016. Human T cell responses to Japanese encephalitis virus in health and disease. J Exp Med, 213 (7), pp. 1331-1352. | Show Abstract | Read more

Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.

Hoehn KB, Gall A, Bashford-Rogers R, Fidler SJ, Kaye S, Weber JN, McClure MO, SPARTAC Trial Investigators, Kellam P, Pybus OG. 2015. Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals. Philos Trans R Soc Lond B Biol Sci, 370 (1676), pp. 20140241-20140241. | Show Abstract | Read more

Advances in immunoglobulin (Ig) sequencing technology are leading to new perspectives on immune system dynamics. Much research in this nascent field has focused on resolving immune responses to viral infection. However, the dynamics of B-cell diversity in early HIV infection, and in response to anti-retroviral therapy, are still poorly understood. Here, we investigate these dynamics through bulk Ig sequencing of samples collected over 2 years from a group of eight HIV-1 infected patients, five of whom received anti-retroviral therapy during the first half of the study period. We applied previously published methods for visualizing and quantifying B-cell sequence diversity, including the Gini index, and compared their efficacy to alternative measures. While we found significantly greater clonal structure in HIV-infected patients versus healthy controls, within HIV patients, we observed no significant relationships between statistics of B-cell clonal expansion and clinical variables such as viral load and CD4(+) count. Although there are many potential explanations for this, we suggest that important factors include poor sampling resolution and complex B-cell dynamics that are difficult to summarize using simple summary statistics. Importantly, we find a significant association between observed Gini indices and sequencing read depth, and we conclude that more robust analytical methods and a closer integration of experimental and theoretical work is needed to further our understanding of B-cell repertoire diversity during viral infection.

Sutherland RK, Russell KV, Trivedi PJ, Conlon CP, Smith RW. 2015. Elevation of the JVP in constrictive pericarditis. QJM, 108 (10), pp. 846. | Read more

Sutherland RK, Russell KV, Trivedi PJ, Warren B, Smith RW, Conlon CP. 2014. A constricting differential--a case of severe anaemia, weight loss and pericarditis due to Tropheryma whipplei infection. QJM, 107 (11), pp. 927-929. | Read more

Haj-Hassan T, McShane T, Mahmud I, Watkinson P, Conlon C, Hope T, Lloyd D, Maynard N. 2014. Israel-Gaza conflict. Lancet, 384 (9942), pp. 489. | Read more

Walker TM, Lalor MK, Broda A, Ortega LS, Morgan M, Parker L, Churchill S, Bennett K, Golubchik T, Giess AP et al. 2014. Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study. Lancet Respir Med, 2 (4), pp. 285-292. | Show Abstract | Read more

BACKGROUND: Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. METHODS: We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. FINDINGS: Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100,000 population per year in Oxfordshire, compared with 3·5 cases per 100,000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2-2·9]; p=0·009), social risk factors (4·4 [2·0-9·4]; p<0·0001), and be part of a local transmission cluster (4·8 [1·6-14·8]; p=0·006). INTERPRETATION: Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised. FUNDING: UK Clinical Research Collaboration (Wellcome Trust, Medical Research Council, National Institute for Health Research [NIHR]), and NIHR Oxford Biomedical Research Centre.

Haj-Hassan T, McShane T, Mahmud I, Watkinson P, Conlon C, Hope T, Lloyd D, Maynard N. 2014. Israel-Gaza conflict The Lancet, 384 (9942), pp. 489. | Read more

Ramagopalan SV, Goldacre R, Skingsley A, Conlon C, Goldacre MJ. 2013. Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies. BMC Med, 11 (1), pp. 97. | Show Abstract | Read more

BACKGROUND: Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB). METHODS: We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison's disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture's syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)). CONCLUSIONS: These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.

Thompson S, McPherson T, Price JD, Conlon C, Cooper S. 2013. Rash in an octogenarian. Intern Med J, 43 (1), pp. 103-104. | Read more

Eyre DW, Mankia KS, Sutherland RK, Turner GD, Conlon C. 2013. HIV-associated late seminal vesicle ‘BCGosis’ following intravesical bacille Calmette-Guérin therapy Journal of Clinical Urology, 6 (1), pp. 20-21. | Read more

Webb AJS, Conlon C, Briley D. 2012. Hypereosinophilia and acute bilateral facial palsy: an unusual presentation of a common disease. Pract Neurol, 12 (5), pp. 324-327. | Show Abstract | Read more

A 60-year-old man presented with an acute, pruritic, erythematous rash associated with marked hypereosinophilia (2.34×10(9)/l (0.04-0.40)). There was eosinophilic infiltration on hepatic, bone marrow and lymph node biopsies, with multiple lung nodules and mild splenomegaly. However, extensive investigation excluded parasitic or bacterial causes, specific allergens or the Fip1L1 mutation seen in myeloproliferative hypereosinophilia. Six months into the illness, he developed an acute, left, complete lower motor neurone facial palsy over hours, and an acute right lower motor neurone facial palsy 2&emsp14;weeks later, without recovery. Over the subsequent 3&emsp14;months, he developed complex partial seizures, a transient 72-h non-epileptic encephalopathy and episodic vertigo with ataxia. Further investigation showed bilateral enhancement of the VII nerves and labyrinthis on gadolinium-enhanced MR brain scan, cerebrospinal fluid lymphocytosis and neurophysiological evidence of polyradicolopathy. His eosinophil count fell with corticosteroids, hydroxycarbamide, imatinib and ultimately mepolezumab, but without symptomatic improvement. Repeat lymph node biopsy showed Kaposi's sarcoma, leading to a diagnosis of HIV-1 infection with a modestly reduced CD4 count of 413×10(6)/l (430-1690). Hypereosinophila and eosinophilic folliculitis are recognised features of advanced HIV infection, and transient bilateral facial palsy occasionally occurs at the time of seroconversion. This is the first report of a chronic bilateral facial palsy likely due to primary HIV infection, not occurring during seroconversion and in association with hypereosinophilia. This case emphasises the protean manifestations of HIV infection and the need for routine testing in atypical clinical presentations.

Minassian A, Jeffery K, Conlon C, Keshav S. 2011. DIAGNOSTIC DIFFICULTY IN THE GUT: A GRANULOMATOUS DILEMMACATEGORY: CLINICAL LESSON JOURNAL OF INFECTION, 63 (6), pp. E118-E119. | Read more

Ramasamy A, Patel C, Conlon C. 2011. Incomplete Stevens-Johnson syndrome secondary to atypical pneumonia BMJ Case Reports, | Show Abstract | Read more

Steven-Johnson syndrome is a common condition characterised by erythematous target lesions on the skin and involvement of the oral mucosa, genitals and conjunctivae. It has been documented as one of the extra-pulmonary manifestations of Mycoplasma pneumoniae infection. Recently, there has been several documentation of an incomplete presentation of this syndrome-without the typical rash but with mucosal, conjunctival and genital involvement. Our case illustrates that the incomplete Steven-Johnson syndrome may present with oral mucosal and conjunctival involvement alone without skin or genital involvement. This important clinical diagnosis should not be missed due to its atypical presentation. Treatment of Steven-Johnson syndrome remains supportive along with treating the underlying infection if recognised. Copyright 2011 BMJ Publishing Group. All rights reserved.

Ramasamy A, Patel C, Conlon C. 2011. Incomplete Stevens-Johnson syndrome secondary to atypical pneumonia. BMJ Case Rep, 2011 (oct03 1), pp. bcr0820114568-bcr0820114568. | Show Abstract | Read more

Steven-Johnson syndrome is a common condition characterised by erythematous target lesions on the skin and involvement of the oral mucosa, genitals and conjunctivae. It has been documented as one of the extra-pulmonary manifestations of Mycoplasma pneumoniae infection. Recently, there has been several documentation of an incomplete presentation of this syndrome - without the typical rash but with mucosal, conjunctival and genital involvement. Our case illustrates that the incomplete Steven-Johnson syndrome may present with oral mucosal and conjunctival involvement alone without skin or genital involvement. This important clinical diagnosis should not be missed due to its atypical presentation. Treatment of Steven-Johnson syndrome remains supportive along with treating the underlying infection if recognised.

Abid M, McCarthy N, Saldaña L, Langham T, McGown A, Conlon C, de Vena Franks P. 2011. Extensively drug-resistant tuberculosis case in the Thames Valley, UK and public health interventions. J Infect Public Health, 4 (4), pp. 207-210. | Show Abstract | Read more

This study describes the first case of extensively drug-resistant tuberculosis (XDR-TB) in the Thames Valley and South East Region and discuss the public health implications, highlighting the need to integrate current epidemiological knowledge with clinical expertise in order to diagnose drug-resistant tuberculosis (TB) early. The management of the XDR-TB patients is challenging with few treatment options, expensive therapy, side effects of drugs and a longer course of the treatment.

Goulding JMR, Pitcher A, Piris J, Conlon CP. 2010. Fevers, headache and abnormal liver function in a 68-year-old man. J R Soc Med, 103 (7), pp. 295-296. | Read more

Moran E, McGown A, Conlon C. 2010. Persistent Baltic cough. BMJ, 341 (aug31 3), pp. c3756. | Read more

Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D'Haens G, Domènech E, Eliakim R, Eser A, Frater J et al. 2009. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis, 3 (2), pp. 47-91. | Read more

Duda A, Lee-Turner L, Fox J, Robinson N, Dustan S, Kaye S, Fryer H, Carrington M, McClure M, McLean AR et al. 2009. HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection. J Virol, 83 (3), pp. 1228-1239. | Show Abstract | Read more

Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P = 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design.

Thananchai H, Makadzange T, Maenaka K, Kuroki K, Peng Y, Conlon C, Rowland-Jones S, Dong T. 2009. Reciprocal recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope by CD8+ T cells and NK cells. AIDS, 23 (2), pp. 189-193. | Show Abstract | Read more

OBJECTIVES: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCGGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. DESIGN AND METHOD: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. RESULT: : CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the 'escape' variant SL9 could bind to KIR2DL1 on NK cell lines with higher affinity than HLA-Cw4-SF9. The binding of KIR2DL1 to its ligand results in inhibition of NK cell function. Our results indicate that the HIV-1 gp120 variant peptide SL9 could potentially escape both from NK cell and CTL recognition by increasing its affinity for KIR2DL1 binding. CONCLUSION: These data suggest that HIV-1 can acquire mutations that are capable of escaping from both CTL and NK cell recognition, a phenomenon we have termed 'double escape'.

Thananchai H, Makadzange T, Maenaka K, Kuroki K, Peng Y, Conlon C, Rowland-Jones S, Dong T. 2009. Reciprocal recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope by CD8<sup>+</sup> T cells and NK cells AIDS, 23 (2), pp. 189-193. | Show Abstract | Read more

Objectives: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCCGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. Design and method: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. Result: CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the 'escape' variant SL9 could bind to KIR2DL1 on NK cell lines with higher affinity than HLA-Cw4-SF9. The binding of KIR2DL1 to its ligand results in inhibition of NK cell function. Our results indicate that the HIV-1 gp120 variant peptide SL9 could potentially escape both from NK cell and CTL recognition by increasing its affinity for KIR2DL1 binding. Conclusion: These data suggest that HIV-1 can acquire mutations that are capable of escaping from both CTL and NK cell recognition, a phenomenon we have termed double escapé © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Paranthaman K, Conlon CP, Parker C, McCarthy N. 2008. Resource allocation during an influenza pandemic - Reply EMERGING INFECTIOUS DISEASES, 14 (10), pp. 1676-1677. | Read more

Brent AJ, Hay D, Conlon CP. 2008. Souvenirs to make your skin crawl. Lancet Infect Dis, 8 (8), pp. 524. | Read more

Paranthaman K, Conlon CP, Parker C, McCarthy N. 2008. Resource allocation during an influenza pandemic. Emerg Infect Dis, 14 (3), pp. 520-522. | Read more

Paranthaman K, Conlon CP, Parker C, McCarthy N. 2008. In response Emerging Infectious Diseases, 14 (10), pp. 1676-1677. | Read more

Matthews PC, Conlon CP, Berendt AR, Kayley J, Jefferies L, Atkins BL, Byren I. 2007. Outpatient parenteral antimicrobial therapy (OPAT): is it safe for selected patients to self-administer at home? A retrospective analysis of a large cohort over 13 years. J Antimicrob Chemother, 60 (2), pp. 356-362. | Show Abstract | Read more

OBJECTIVES: Provision of outpatient parenteral antimicrobial therapy (OPAT) is an evolving field, facilitating discharge from hospital for selected patients with serious infections. We report on a large OPAT cohort focusing on the practice of supervised parenteral antibiotic administration in the community by patients and relatives, which we collectively term 'self-administration'. To distinguish between healthcare professional OPAT and self-administered OPAT, we have coined the terms H-OPAT and S-OPAT, respectively. PATIENTS AND METHODS: We analysed data on 2059 OPAT episodes collected prospectively over a 13 year time period from 1993 to 2005. RESULTS: Clinical diagnosis, microbiology and antibiotics in this OPAT series are comparable to those previously reported. We identified no excess complications or hospital re-admissions in the S-OPAT group compared with the H-OPAT group. CONCLUSIONS: Self-administration of intravenous antimicrobial therapy, in selected patients under the supervision of a specialist team, is a safe and feasible strategy.

Yang H, Dong T, Turnbull E, Ranasinghe S, Ondondo B, Goonetilleke N, Winstone N, di Gleria K, Bowness P, Conlon C et al. 2007. Broad TCR usage in functional HIV-1-specific CD8+ T cell expansions driven by vaccination during highly active antiretroviral therapy. J Immunol, 179 (1), pp. 597-606. | Show Abstract | Read more

During chronic HIV-1 infection, continuing viral replication is associated with impaired proliferative capacity of virus-specific CD8+ T cells and with the expansion and persistence of oligoclonal T cell populations. TCR usage may significantly influence CD8+ T cell-mediated control of AIDS viruses; however, the potential to modulate the repertoire of functional virus-specific T cells by immunotherapy has not been explored. To investigate this, we analyzed the TCR Vbeta usage of CD8+ T cells populations which were expanded following vaccination with modified vaccinia virus Ankara expressing a HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected patients receiving highly active antiretroviral therapy. Vaccinations induced the re-expansion of HIV-1-specific CD8+ T cells and these showed broad TCR Vbeta usage which was maintained for at least 1 year in some individuals. By contrast, virus-specific CD8+ T cell populations in the same donors which failed to expand after vaccination and in unvaccinated controls were oligoclonal. Simultaneously, we observed that CD8+ T cells recognizing vaccine-derived HIV-1 epitopes displayed enhanced capacity to proliferate and to inhibit HIV-1 replication in vitro, following MVA.HIVA immunizations. Taken together, these data indicate that an attenuated viral-vectored vaccine can modulate adaptive CD8+ T cell responses to HIV-1 and improve their antiviral functional capacity. The potential therapeutic benefit of this vaccination approach warrants further investigation.

Taylor N, Scarsbrook AF, Conlon CP, Anslow PA, Phillips RR. 2007. Imaging manifestations of neck masses in the immunocompromised host. Clin Radiol, 62 (7), pp. 615-625. | Show Abstract | Read more

Human immunodeficiency virus (HIV) infection, haematological malignancy, and immunosuppression for transplantation and autoimmune disorders have led to a large increase in immunocompromised patients. Neck masses are relatively common in this patient group and include both opportunistic and severe manifestations of common infections, benign hyperplasia, and primary or secondary malignancies. Although biopsy may be necessary for definitive diagnosis, features on cross-sectional imaging may suggest a specific diagnosis or limit the differential diagnosis and facilitate optimal patient management. This article will review critical aspects of neck anatomy, illustrate the spectrum of imaging features, and discuss the interpretative pearls and pitfalls when evaluating neck masses in immunocompromised patients.

Dorrell L, Williams P, Suttill A, Brown D, Roberts J, Conlon C, Hanke T, McMichael A. 2007. Safety and tolerability of recombinant modified vaccinia virus Ankara expressing an HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected persons receiving combination antiretroviral therapy. Vaccine, 25 (17), pp. 3277-3283. | Show Abstract | Read more

The safety of attenuated poxviruses in HIV-1-infected individuals is an important consideration in their application as vaccine vectors, first, because new HIV-1 infections may occur in vaccine trials involving persons at high risk of infection and secondly, therapeutic vaccinations are a potential means to enhance virus-specific immune responses once infection has occurred. We administered a candidate modified vaccinia virus Ankara-vectored HIV-1 vaccine, MVA.HIVA, by intradermal injection to 16 chronically infected adults during highly active antiretroviral therapy. Vaccinations were well tolerated and there were no serious adverse events. No breakthrough viraemia occurred after immunisations or throughout follow-up. These data confirm the safety of MVA.HIVA in HIV-1-infected individuals and provide support for further evaluation of MVA-vectored vaccines in prophylactic and therapeutic immunisation strategies.

Tonna I, Conlon CP, Davies RJO. 2007. A case of empyema necessitatis. Eur J Intern Med, 18 (5), pp. 441-442. | Show Abstract | Read more

We present a case of empyema necessitatis presenting with an inflammatory cellulitis of the chest wall. Most of the cases previously reported were due to tuberculosis, pneumococcus or actinomycosis, with only a few cases being due to Staphylococcus aureus, as in this case. Early treatment with antibiotics and surgical drainage can prevent further complications.

Ondondo BO, Yang H, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Rowland-Jones SL, Hanke T et al. 2006. Immunisation with recombinant modified vaccinia virus Ankara expressing HIV-1 gag in HIV-1-infected subjects stimulates broad functional CD4+ T cell responses. Eur J Immunol, 36 (10), pp. 2585-2594. | Show Abstract | Read more

Virus-specific CD4+ T cells with IL-2-secreting and/or proliferative capacity are detected readily in HIV-1-infected long-term nonprogressors and rarely in persons with untreated progressive infection. The contribution of these cells to viraemia control is uncertain, but this question might be addressed in clinical therapeutic vaccination studies. However, the quality of T helper responses induced by currently available HIV-1 vaccine candidates has not been explored in depth. We determined the effect of vaccination with modified vaccinia virus Ankara (MVA) expressing HIV-1 gag p24/p17 (MVA.HIVA) on HIV-1-specific CD4+ T cell responses in 16 chronically infected, highly active antiretroviral therapy (HAART)-treated subjects using CD8-depleted IFN-gamma ELISPOT assays, intracellular cytokine staining assays for IL-2 and IFN-gamma, and a CFSE-based proliferation assay. Gag-specific CD4+ T cell responses were significantly increased in magnitude and breadth after vaccination and targeted both known and new epitopes, several of which were also recognised by healthy HIV-uninfected volunteers immunised with the same vaccines. The frequencies of CD4+ T cells expressing IL-2 or IFN-gamma, alone or simultaneously, were also augmented. These findings indicate that functional virus-specific T helper cells can be boosted by vaccination in chronic HIV-1 infection. Further evaluation of their role in viraemia control is warranted.

Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P et al. 2006. Expansion and diversification of virus-specific T cells following immunization of human immunodeficiency virus type 1 (HIV-1)-infected individuals with a recombinant modified vaccinia virus Ankara/HIV-1 Gag vaccine. J Virol, 80 (10), pp. 4705-4716. | Show Abstract | Read more

Affordable therapeutic strategies that induce sustained control of human immunodeficiency virus type 1 (HIV-1) replication and are tailored to the developing world are urgently needed. Since CD8(+) and CD4(+) T cells are crucial to HIV-1 control, stimulation of potent cellular responses by therapeutic vaccination might be exploited to reduce antiretroviral drug exposure. However, therapeutic vaccines tested to date have shown modest immunogenicity. In this study, we performed a comprehensive analysis of the changes in virus-specific CD8(+) and CD4(+) T-cell responses occurring after vaccination of 16 HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara-vectored vaccine expressing the consensus HIV-1 clade A Gag p24/p17 sequences and multiple CD8(+) T-cell epitopes during highly active antiretroviral therapy. We observed significant amplification and broadening of CD8(+) and CD4(+) gamma interferon responses to vaccine-derived epitopes in the vaccinees, without rebound viremia, but not in two unvaccinated controls followed simultaneously. Vaccine-driven CD8(+) T-cell expansions were also detected by tetramer reactivity, predominantly in the CD45RA(-) CCR7(+) or CD45RA(-) CCR7(-) compartments, and persisted for at least 1 year. Expansion was associated with a marked but transient up-regulation of CD38 and perforin within days of vaccination. Gag-specific CD8(+) and CD4(+) T-cell proliferation also increased postvaccination. These data suggest that immunization with MVA.HIVA is a feasible strategy to enhance potentially protective T-cell responses in individuals with chronic HIV-1 infection.

Sutherland R, Yang H, Scriba TJ, Ondondo B, Robinson N, Conlon C, Suttill A, McShane H, Fidler S, McMichael A, Dorrell L. 2006. Impaired IFN-gamma-secreting capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long-term HAART. AIDS, 20 (6), pp. 821-829. | Show Abstract | Read more

OBJECTIVE: To determine whether long-term HAART in chronic HIV-1 infection restores fully functional Mycobacterium tuberculosis (MTB)-specific CD4 T-cell responses. DESIGN: A cross-sectional study of HIV-1-seropositive subjects on continuous HAART for over one year with CD4 cell counts greater than 300 cells/microl and undetectable viraemia, antiretroviral-naive individuals with primary HIV-1 infection (PHI), and healthy bacillus Calmette-Guérin-vaccinated low-risk controls. METHODS: Purified protein derivative (PPD)-specific cytokine-secreting CD4 T cells were quantified ex vivo by enzyme-linked immunospot assay and intracellular cytokine staining. Lymphoproliferation was detected by [3H]-thymidine incorporation. RESULTS: PPD-specific IFN-gamma-secreting CD4 T cells were markedly reduced in chronic HAART-treated HIV-1-positive and PHI subjects compared with healthy controls [medians 30, 155 and 582 spot-forming cells/million peripheral blood mononuclear cells (PBMC), respectively, P < 0.0001 and P < 0.002], but the frequency of these cells was, nonetheless, significantly greater in viraemic PHI subjects than in aviraemic chronic HIV-1-positive subjects (P < 0.01). In the latter, low frequencies of PPD-specific IL-2 and IL-4-secreting CD4 T cells were also observed. However, lymphoproliferation was evident after the in-vitro stimulation of PBMC with PPD, indicating that MTB-specific T cells were present. The defect in IFN-gamma secretion could be overcome by culture with IL-12. CONCLUSION: Despite an improvement in CD4 T-cell counts after HAART, MTB-specific CD4 T cells from chronically infected patients have impaired IFN-gamma-secreting capacity. The early initiation of HAART might preserve functional CD4 T-cell responses to MTB, and warrants evaluation in populations with a high risk of dual infection.

Cebere I, Dorrell L, McShane H, Simmons A, McCormack S, Schmidt C, Smith C, Brooks M, Roberts JE, Darwin SC et al. 2006. Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers. Vaccine, 24 (4), pp. 417-425. | Show Abstract | Read more

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9-14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911-9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.

Ondondo B, Yang H, Dong T, de Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P, Rowland-Jones SL et al. 2006. Detection of broad functional gag-specific CD4+T cell responses in HIV-1-infected subjects following therapeutic immunization with rMVA expressing an HIV-1 gag immunogen RETROVIROLOGY, 3

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Cebere I, Dorrell L, McShane H, Simmons A, McCormack S, Schmidt C, Smith C, Brooks M, Roberts JE, Darwin SC et al. 2006. Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers Vaccine, 24 (4), pp. 417-425. | Show Abstract | Read more

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9-14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911-9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies. © 2005 Elsevier Ltd. All rights reserved.

Dorrell L, Yang H, Iversen AK, Conlon C, Suttill A, Lancaster M, Dong T, Cebere I, Edwards A, Rowland-Jones S et al. 2005. Therapeutic immunization of highly active antiretroviral therapy-treated HIV-1-infected patients: safety and immunogenicity of an HIV-1 gag/poly-epitope DNA vaccine. AIDS, 19 (12), pp. 1321-1323. | Show Abstract | Read more

In view of the global emergency posed by lack of access to highly active antiretroviral therapy (HAART) and the limitations of current drug regimens, alternative therapeutic strategies are urgently needed. Cellular immune responses elicited by HIV-1 exert some control over virus replication, therefore the enhancement of HIV-1-specific responses by therapeutic vaccination might lead to viral containment without HAART. We evaluated the safety and immunogenicity, in HIV-1-infected individuals under HAART suppression, of a DNA vaccine, pTHr.HIVA.

Dong T, Stewart-Jones G, Chen N, Easterbrook P, Xu X, Papagno L, Appay V, Weekes M, Conlon C, Spina C et al. 2004. HIV-specific cytotoxic T cells from long-term survivors select a unique T cell receptor. J Exp Med, 200 (12), pp. 1547-1557. | Show Abstract | Read more

HIV-specific cytotoxic T lymphocytes (CTL) are important in controlling HIV replication, but the magnitude of the CTL response does not predict clinical outcome. In four donors with delayed disease progression we identified Vbeta13.2 T cell receptors (TCRs) with very similar and unusually long beta-chain complementarity determining region 3 (CDR3) regions in CTL specific for the immunodominant human histocompatibility leukocyte antigens (HLA)-B8-restricted human immunodeficiency virus-1 (HIV-1) nef epitope, FLKEKGGL (FL8). CTL expressing Vbeta13.2 TCRs tolerate naturally arising viral variants in the FL8 epitope that escape recognition by other CTL. In addition, they expand efficiently in vitro and are resistant to apoptosis, in contrast to FL8-specific CTL using other TCRs. Selection of Vbeta13.2 TCRs by some patients early in the FL8-specific CTL response may be linked with better clinical outcome.

Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, Beattie T, Chen Y-H, Dorrell L, McShane H et al. 2004. A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol, 85 (Pt 4), pp. 911-919. | Show Abstract | Read more

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime-boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime-MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

McMillan JR, Conlon C, Nuffield Council on Bioethics. 2004. The ethics of research related to health care in developing countries. J Med Ethics, 30 (2), pp. 204-206. | Show Abstract | Read more

The Ethics of Research Related to Health Care in Developing Countries by the Nuffield Council on Bioethics makes a number of innovative recommendations that depart from codes such as the Declaration of Helsinki. It recommends that standards of care might be relativised to the standard of that nation. It recommends that very good reasons need to be given for not giving post-trial access to medications but recognises that there may be justifiable instances of this. It is the view of the authors that these and other recommendations of the report are sensible pieces of advice given the complexities of the developing world.

Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, Dong T, Chesney G, Waters A, Easterbrook P et al. 2004. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol, 2 (2), pp. E20. | Show Abstract | Read more

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system.

Makris M, Conlon CP, Watson HG. 2003. Immunization of patients with bleeding disorders. Haemophilia, 9 (5), pp. 541-546. | Show Abstract | Read more

The immunization of patients with bleeding disorders differs from that of the normal population with respect to the risk of haematoma formation at the vaccination site and the unusual infective risks associated with the potential, and past, exposure to blood products. Most vaccinations can be given subcutaneously and this should be the preferred route. All routine childhood vaccinations should be given at the appropriate time. All patients with bleeding disorders should be vaccinated against hepatitis A and B. HIV positive patients should receive annual influenza vaccinations and should avoid the oral polio, oral typhoid, BCG and yellow fever vaccines.

Dawson D, Conlon C. 2003. Case study: metformin-associated lactic acidosis: could orlistat be relevant? Diabetes Care, 26 (8), pp. 2471-2472. | Read more

Barrett JP, Vardulaki KA, Conlon C, Cooke J, Daza-Ramirez P, Evans EGV, Hawkey PM, Herbrecht R, Marks DI, Moraleda JM et al. 2003. A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations. Clin Ther, 25 (5), pp. 1295-1320. | Show Abstract | Read more

OBJECTIVE: A systematic review was performed to compare the effectiveness and tolerability of lipid-based amphotericin B (AmB) formulations and conventional AmB in the treatment of systemic fungal infections. METHODS: The literature and unpublished studies were searched using MEDLINE, EMBASE, Biological Abstracts, AIDSLINE, CANCERLIT, CRD database, Cochrane Controlled Trials Register, and other databases. Search terms included: amphotericin, liposom*, lipid*, colloid*, antifungal agents, and mycoses. Studies were selected according to predetermined criteria. The outcome measures reviewed were efficacy, mortality, renal toxicity, and infusion-related reactions. Meta-analyses and number-needed-to-treat (NNT) analyses were performed. RESULTS: Seven studies (8 publications) met the entry criteria. Meta-analysis showed that lipid-based formulations significantly reduced all-cause mortality risk by an estimated 28% compared with conventional AmB (odds ratio [OR], 0.72; 95% CI, 0.54 to 0.97). There was no significant difference in efficacy between the lipid-based formulations and conventional AmB (OR, 1.21; 95% CI, 0.98 to 1.49). AmB lipid complex (ABLC) and liposomal AmB (L-AmB) significantly reduced the risk of doubling serum creatinine by an estimated 58% (OR, 0.42; 95% CI, 0.33 to 0.54). There was no significant reduction in risk of infusion-related reactions with lipid-based formulations, although this was difficult to interpret given the lack of consistent control of confounding factors. Comparing the lipid-based formulations with conventional AmB, the overall NNT to prevent 1 death was 31. The NNT to prevent a doubling of serum creatinine for both ABLC and L-AmB compared with conventional AmB was 6. CONCLUSIONS: This study demonstrates advantages with lipid-based formulations over conventional AmB in terms of reduced risk of mortality and renal toxicity. Future trials in patients with proven fungal infection should control for factors such as premedication, infusion rates, fluid preloading, sodium/potassium supplementation, and concomitant medication.

Angus BJ, Yates M, Conlon C, Byren I. 2001. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis, 33 (11), pp. E132-E134. | Show Abstract | Read more

A case of culture-positive primary cutaneous Mycobacterium tuberculosis infection of the penis was diagnosed in a male patient; 1 year later, endometrial tuberculosis was diagnosed in the patient's wife. These organisms were confirmed to be indistinguishable by use of molecular techniques.

Lalvani A, Pathan AA, McShane H, Wilkinson RJ, Latif M, Conlon CP, Pasvol G, Hill AV. 2001. Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Med, 163 (4), pp. 824-828. | Show Abstract | Read more

There is no reliable means of detecting latent M. tuberculosis infection, and even in patients with active tuberculosis, infection is often unconfirmed. We hypothesized that M. tuberculosis antigen-specific T cells might reliably indicate infection. We enumerated peripheral blood-derived interferon gamma (IFN-gamma)-secreting T cells responding to epitopes from ESAT-6, an antigen that is highly specific for M. tuberculosis complex but absent from BCG, in four groups of individuals. Forty-five of 47 patients with bacteriologically confirmed tuberculosis had ESAT-6-specific IFN-gamma-secreting T cells, compared with four of 47 patients with nontuberculous illnesses, indicating that these T cells are an accurate marker of M. tuberculosis infection. This assay thus has a sensitivity of 96% (95% confidence interval [CI] 92-100) for detecting M. tuberculosis infection in this patient population. By comparison, of the 26 patients with tuberculosis who had a diagnostic tuberculin skin test (TST), only 18 (69%) were positive (p = 0.003). In addition, 22 of 26 (85%) TST-positive exposed household contacts had ESAT-6-specific T cells, whereas zero of 26 unexposed BCG-vaccinated subjects responded. This approach enables rapid detection of M. tuberculosis infection in patients with active tuberculosis and in exposed asymptomatic individuals at high risk of latent infection; it also successfully distinguishes between M. tuberculosis infection and BCG vaccination. This capability may facilitate tuberculosis control in nonendemic regions.

Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P et al. 2001. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med, 193 (3), pp. 375-386. | Show Abstract | Read more

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

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Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P et al. 2001. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses JOURNAL OF EXPERIMENTAL MEDICINE, 193 (3), pp. 375-385. | Show Abstract | Read more

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KR WIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

Conlon C. 2000. Sepsis in immunocompromised hosts. J R Coll Physicians Lond, 34 (6), pp. 533-536.

Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA et al. 2000. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med, 192 (1), pp. 63-75. | Show Abstract | Read more

The use of peptide-human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8(+) T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8(+) T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, and perforin is analyzed by FACS((R)) within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8(+) T cells compared with cytomegalovirus (CMV)-specific CD8(+) T cells in HIV chronic infection. We show that the majority of circulating CD8(+) T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-gamma and MIP-1beta but not TNF-alpha. However, a striking finding is that HIV-specific CD8(+) T cells express significantly lower levels of perforin than CMV-specific CD8(+) T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8(+) T cells are impaired in cytolytic activity.

Conlon CP. 2000. Travel and the immunocompromised host. Hosp Med, 61 (3), pp. 167-170. | Show Abstract | Read more

Increasing opportunities for travel and advances in medicine mean that immunocompromised patients may venture to potentially risky parts of the world. This article examines the risks faced by such travellers. Some limitations of standard travel vaccines are discussed and suggestions are made as to how best to advise such travellers.

Cooke GS, Lalvani A, Gleeson FV, Conlon CP. 1999. Acute pulmonary schistosomiasis in travelers returning from Lake Malawi, sub-Saharan Africa. Clin Infect Dis, 29 (4), pp. 836-839. | Show Abstract | Read more

We describe four cases of acute schistosomiasis presenting to the Infectious Diseases Unit of John Radcliffe Hospital (Oxford, England) during a 2-month period in autumn 1997. All four patients had swum in Lake Malawi, a freshwater lake in sub-Saharan Africa that is associated with Schistosoma haematobium and, less commonly, Schistosoma mansoni infections. All four patients had a severe acute illness and had prominent pulmonary involvement, both clinically and radiologically. This represents a change in the recognized pattern of presentation and could possibly reflect a new parasite variant in the lake.

Armstrong PM, Ilyas I, Pandey R, Berendt AR, Conlon CP, Simpson AH. 1999. Pyoderma gangrenosum. A diagnosis not to be missed. J Bone Joint Surg Br, 81 (5), pp. 893-894. | Show Abstract | Read more

We describe a case of pyoderma gangrenosum which presented with severe wound breakdown after elective hip replacement. The patient was treated successfully with minimal wound debridement and steroids. This diagnosis should always be considered when confronted with an enlarging painful skin lesion which does not grow organisms when cultured and fails to respond to antibiotic therapy, especially if there are similar lesions in other sites. In patients who have a past history of pyoderma gangrenosum, prophylactic steroids may be indicated at the time of surgery or may be required early in the postoperative period.

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Armstrong PM, Ilyas I, Pandey R, Berendt AR, Conlon CP, Simpson AHRW. 1999. Pyoderma gangrenosum - A diagnosis not to be missed JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME, 81B (5), pp. 893-894. | Read more

Beck EJ, Griffith R, Fitzpatrick R, Mandalia S, Carrier J, Conlon C, Mandel B, Ong E, Pozniak A, Tang A et al. 1999. Patient satisfaction with HIV service provision in NPMS hospitals: the development of a standard satisfaction questionnaire. NPMS Steering Group. AIDS Care, 11 (3), pp. 331-343. | Show Abstract | Read more

A self-completion satisfaction questionnaire evaluating the standard of care of HIV outpatient services was developed as part of the National Prospective Monitoring System on the Use, Cost and Outcome of HIV Service Provision in English Hospitals (NPMS). The questionnaire was designed in conjunction with service users and health care professionals, and piloted in three London and three non-London HIV clinics. In addition to testing alternative methods of administering the questionnaire, the pilot provided satisfaction scores on a variety of aspects of service provision for participating clinics. The questionnaire was completed by 548 respondents and was most effectively collected using a sealed box in the clinic waiting area. Mean satisfaction scores for the attitude and skills of staff members was 4.7 (95% CI 4.6-4.7) but satisfaction scores were significantly lower for the clinic environment with a mean of 4.1 (95% CI 4.1-4.2). Satisfaction scores did not differ significantly by gender, age, sexual orientation, ethnic group, employment status or severity of symptoms. London respondents were more satisfied with the clinic environment and seeing preferred members of staff than their non-London counterparts, however there were no other differences between clinics. The questionnaire functioned well in practice and provided meaningful and useful information for individual clinics as well as at aggregate level.

Beck EJ, Pozniak A, Molesworth A, Power A, Griffin J, Easterbrook P, Fisher M, Innes J, Kinghorn G, Mandel B et al. 1999. Changing cost of English HIV service provision 1996-1997. NPMS Steering Group. National Prospective Monitoring System. Int J STD AIDS, 10 (6), pp. 357-362. | Show Abstract | Read more

The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were pound sterling 4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to pound sterling 128 million (95% CI pound sterling 109m to pound sterling 147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling 161m (95% CI pound sterling 141m to pound sterling 181m), while for triple therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2-3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decreased by 8-9%.

Tan R, Xu X, Ogg GS, Hansasuta P, Dong T, Rostron T, Luzzi G, Conlon CP, Screaton GR, McMichael AJ, Rowland-Jones S. 1999. Rapid death of adoptively transferred T cells in acquired immunodeficiency syndrome. Blood, 93 (5), pp. 1506-1510. | Show Abstract

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) probably play the major role in controlling HIV replication. However, the value of adoptive transfer of HIV-specific CTL expanded in vitro to HIV+ patients has been limited: this contrasts with the success of CTL therapy in treating or preventing Epstein-Barr virus and cytomegalovirus disease after bone marrow transplantation (BMT). We investigated the fate of expanded HIV-specific CTL clones in vivo following adoptive transfer to a patient with acquired immunodeficiency syndrome (AIDS). Two autologous CTL clones specific for HIV Gag and Pol were expanded to large numbers (>10(9)) in vitro and infused into an HIV-infected patient whose viral load was rising despite antiretroviral therapy. The fate of one clone was monitored by staining peripheral blood mononuclear cells (PBMCs) with T-cell receptor-specific tetrameric major histocompatibility complex (MHC)-peptide complexes. Although the CTL transfer was well tolerated, there were no significant changes in CD4 and CD8 lymphocyte counts and virus load. By tracking an infused clone using soluble MHC-peptide complexes, we show that cells bearing the Gag-specific T-cell receptors were rapidly eliminated within hours of infusion through apoptosis. Thus, the failure of adoptively transferred HIV-specific CTL to reduce virus load in AIDS may be due to rapid apoptosis of the infused cells, triggered by a number of potential mechanisms. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis.

Dorrell L, Dong T, Ogg GS, Lister S, McAdam S, Rostron T, Conlon C, McMichael AJ, Rowland-Jones SL. 1999. Distinct recognition of non-clade B human immunodeficiency virus type 1 epitopes by cytotoxic T lymphocytes generated from donors infected in Africa. J Virol, 73 (2), pp. 1708-1714. | Show Abstract

We present detailed studies of human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) responses to clade A or C HIV type 1 in three donors infected in East Africa. We define several novel non-clade B CTL epitopes, including some restricted by HLA alleles common in Africans. Although cross-clade CTL recognition of these epitopes does occur, recognition can also be highly clade specific.

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Tan R, Xu X, Ogg GS, Hansasuta P, Dong T, Rostron T, Luzzi G, Conlon CP, Screaton GR, McMichael AJ, Rowland-Jones S. 1999. Rapid death of adoptively transferred T cells in acquired immunodeficiency syndrome Blood, 93 (5), pp. 1506-1510. | Show Abstract

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) probably play the major role in controlling HIV replication. However, the value of adoptive transfer of HIV-specific CTL expanded in vitro to HIV+ patients has been limited: this contrasts with the success of CTL therapy in treating or preventing Epstein-Barr virus and cytomegalovirus disease after bone marrow transplantation (BMT). We investigated the fate of expanded HIV- specific CTL clones in vive following adoptive transfer to a patient with acquired immunodeficiency syndrome (AIDS). Two autologous CTL clones specific for HIV Gag and Pol were expanded to large numbers (>109) in vitro and infused into an HIV-infected patient whose viral lead was rising despite antiretroviral therapy. The fate of one clone was monitored by staining peripheral blood mononuclear cells (PBMCs) with T-cell receptor-specific tetrameric major histocompatibility complex (MHC)-peptide complexes. Although the CTL transfer was well tolerated, there were no significant changes in CD4 and CD8 lymphocyte counts and virus lead. By tracking an infused clone using soluble MHC-peptide complexes, we show that cells bearing the Gag-specific T- cell receptors were rapidly eliminated within hours of infusion through apoptosis. Thus, the failure of adoptively transferred HIV-specific CTL to reduce virus lead in AIDS may be due to rapid apoptosis of the infused cells, triggered by a number of potential mechanisms. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis.

McShane H, Tang CM, Conlon CP. 1998. Disseminated Penicillium marneffei infection presenting as a right upper lobe mass in an HIV positive patient. Thorax, 53 (10), pp. 905-906. | Show Abstract | Read more

A 35 year old HIV positive patient from Hong Kong presented with a fever, cough and a skin rash in association with a lung mass, all of which were due to disseminated Penicillium marneffei infection. He made a good response to antifungal therapy. The lung mass is a previously undescribed pulmonary manifestation of disseminated Penicillium marneffei infection. Infections with this fungus should be suspected in any patient with HIV and respiratory symptoms who has visited southeast Asia.

Atkins BL, Athanasou N, Deeks JJ, Crook DW, Simpson H, Peto TE, McLardy-Smith P, Berendt AR. 1998. Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group. J Clin Microbiol, 36 (10), pp. 2932-2939. | Show Abstract

A prospective study was performed to establish criteria for the microbiological diagnosis of prosthetic joint infection at elective revision arthroplasty. Patients were treated in a multidisciplinary unit dedicated to the management and study of musculoskeletal infection. Standard multiple samples of periprosthetic tissue were obtained at surgery, Gram stained, and cultured by direct and enrichment methods. With reference to histology as the criterion standard, sensitivities, specificities, and likelihood ratios (LRs) were calculated by using different cutoffs for the diagnosis of infection. We performed revisions on 334 patients over a 17-month period, of whom 297 were evaluable. The remaining 37 were excluded because histology results were unavailable or could not be interpreted due to underlying inflammatory joint disease. There were 41 infections, with only 65% of all samples sent from infected patients being culture positive, suggesting low numbers of bacteria in the samples taken. The isolation of an indistinguishable microorganism from three or more independent specimens was highly predictive of infection (sensitivity, 65%; specificity, 99.6%; LR, 168.6), while Gram staining was less useful (sensitivity, 12%; specificity, 98%; LR, 10). A simple mathematical model was developed to predict the performance of the diagnostic test. We recommend that five or six specimens be sent, that the cutoff for a definite diagnosis of infection be three or more operative specimens that yield an indistinguishable organism, and that because of its low level of sensitivity, Gram staining should be abandoned as a diagnostic tool at elective revision arthroplasty.

Ogg GS, Dong T, Hansasuta P, Dorrell L, Clarke J, Coker R, Luzzi G, Conlon C, McMichael AP, Rowland-Jones S. 1998. Four novel cytotoxic T-lymphocyte epitopes in the highly conserved major homology region of HIV-1 Gag, restricted through B*4402, B*1801, A*2601, B*70 (B*1509) AIDS, 12 (12), pp. 1561-1563. | Read more

Ogg GS, Dong T, Hansasuta P, Dorrell L, Clarke J, Coker R, Luzzi G, Conlon C, McMichael AP, Rowland-Jones S. 1998. Four novel cytotoxic T-lymphocyte epitopes in the highly conserved major homology region of HIV-1 Gag, restricted through B*4402, B*1801, A*2601, B*70 (B*1509) AIDS, 12 (12), pp. 1561-1563. | Read more

Yao QY, Croom-Carter DS, Tierney RJ, Habeshaw G, Wilde JT, Hill FG, Conlon C, Rickinson AB. 1998. Epidemiology of infection with Epstein-Barr virus types 1 and 2: lessons from the study of a T-cell-immunocompromised hemophilic cohort. J Virol, 72 (5), pp. 4352-4363. | Show Abstract

In apparent contrast to earlier work on Epstein-Barr virus (EBV) carriage in the general Caucasian population, in vitro virus isolations from human immunodeficiency virus (HIV)-positive male homosexual cohorts have shown frequent examples of multiple EBV infection and an overall prevalence of type 2 EBV strains exceeding 30%. Here we ask to what extent these findings might hold true in another T-cell-immunocompromised cohort, HIV-positive hemophilic patients. Resident EBV strains were rescued within lymphoblastoid cell lines derived from the blood and throat washings of 39 such individuals, using the same in vitro protocols of virus isolation as for the homosexual cohort. A mean of 19 independent cell lines was made per patient, and in each case the resident virus was characterized by PCR-based viral genomic analysis and by immunoblotting to reveal the viral "EBNAprint." By these criteria a significant proportion (14 of 39) of the hemophilic cohort carried more than one EBV strain, suggesting that T-cell impairment does indeed sensitize virus carriers to reinfection with new strains of exogenously transmitted virus. However, the overall incidence of type 2 EBV infection was 10%, which is close to that observed in the earlier work with healthy carriers and substantially lower than that seen in HIV-positive homosexuals. We infer that type 2 EBV is relatively rare in the general Caucasian population but has become endemic in the homosexual community.

Yao QY, Carter DC, Rickinson AB, Hill FGH, Conlon C, Wilde JT. 1998. Epidemiology of Epstein-Barr virus infection in HIV infected haemophilic patients. BRITISH JOURNAL OF HAEMATOLOGY, 101 pp. 83-83.

Conlon CP. 1998. Generalized infections. Curr Opin Infect Dis, 11 (2), pp. 169. | Read more

Tang CM, Conlon CP, Miller RF. 1997. Pyrexia of undetermined origin in advanced HIV disease. Genitourin Med, 73 (4), pp. 308-313. | Read more

Tang CM, Conlon CP, Miller RF. 1997. Pyrexia of undetermined origin in advanced HIV disease. Sexually Transmitted Infections, 73 (4), pp. 308-313. | Read more

Conlon CP, Kayley J, Lalloo DG, Berendt AR. 1997. Intravenous antibiotic treatment at home can provide higher quality care. BMJ, 314 (7093), pp. 1551. | Read more

Conlon CP. 1997. Generalized infections CURRENT OPINION IN INFECTIOUS DISEASES, 10 (2), pp. 133-133. | Read more

Lalvani A, Newton P, Conlon CP. 1997. Salmonella enteritidis and acute renal failure: Report of five cases and review INFECTIOUS DISEASES IN CLINICAL PRACTICE, 6 (3), pp. 193-195. | Read more

Conlon CP. 1996. Outpatient intravenous antibiotic therapy. J Antimicrob Chemother, 38 (4), pp. 557-559. | Read more

Goulder P, Conlon C, Mclntyre K, McMichael A. 1996. Identification of a novel human leukocyte antigen A26-restricted epitope in a conserved region of Gag. AIDS, 10 (12), pp. 1441-1443. | Read more

Farrant JM, Traill Z, Conlon C, Warren B, Mortensen N, Gleeson FV, Jewell DP. 1996. Pigbel-like syndrome in a vegetarian in Oxford. Gut, 39 (2), pp. 336-337. | Show Abstract | Read more

Enterocolitis necroticans or pigbel is a rare condition characteristically affecting chronically malnourished people who abruptly increase their intake of protein. The classic presentation of the disease as seen in the highlands of Papua New Guinea is that of a necrotising enterocolitis after the ritual ingestion of contaminated pork. In this context, the presentation of the same disease in a well nourished white vegetarian in Oxford was all the more intriguing.

Kayley J, Berendt AR, Snelling MJ, Moore H, Hamilton HC, Peto TE, Crook DW, Conlon CP. 1996. Safe intravenous antibiotic therapy at home: experience of a UK based programme. J Antimicrob Chemother, 37 (5), pp. 1023-1029. | Show Abstract | Read more

Outpatient i.v. antibiotic therapy is well developed in the United States, largely because of pressures from third-party payers to reduce costs of medical care. We have developed an outpatient i.v. antibiotic programme in Oxford, that has evolved from a desire to provide high quality i.v. therapy to AIDS patients with cytomegalovirus retinitis. We describe the rationale of the service and report on our first two years' experience. We treated 67 consecutive patients (eight with HIV infection) at home with i.v. antibiotics. This resulted in a saving of 2275 hospital days for those patients without HIV infection. HIV positive patients received 69 months of home i.v. therapy. Minor intravascular catheter complications occurred in only five patients (7.5%). The only serious complications were three episodes of catheter-related sepsis (4.5%), all occurring in AIDS patients who had lines in for more than six months. We have shown that home i.v. antibiotic therapy can be delivered safely to patients with a wide variety of infectious problems using the existing network of community nurses in the National Health Service. Essential components to the programme include a multidisciplinary team working between the hospital and community and a written shared care protocol. Such a programme can result in reduced lengths of hospital stay and patient, community nurse and physician satisfaction.

Conlon CP. 1996. Generalized infections CURRENT OPINION IN INFECTIOUS DISEASES, 9 (2), pp. 103-104. | Read more

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Kayley J, Berendt AR, Snelling MJM, Moore H, Hamilton HC, Peto TEA, Crook DWM, Conlon CP. 1996. Antimicrobial practice - Safe intravenous antibiotic therapy at home: Experience of a UK based programme Journal of Antimicrobial Chemotherapy, 37 (5), pp. 1023-1029. | Show Abstract | Read more

Outpatient iv antibiotic therapy is well developed in the United States, largely because of pressures from third-party payers to reduce costs of medical care. We have developed an outpatient iv antibiotic programme in Oxford, that has evolved from a desire to provide high quality iv therapy to AIDS patients with cytomegalovirus retinitis. We describe the rationale of the service and report on our first two years' experience. We treated 67 consecutive patients (eight with HIV infection) at home with iv antibiotics. This resulted in a saving of 2275 hospital days for those patients without HIV infection. HIV positive patients received 69 months of home iv therapy. Minor intravascular catheter complications occurred in only five patients (7.5%). The only serious complications were three episodes of catheter-related sepsis (4.5%), all occurring in AIDS patients who had lines in for more than six months. We have shown that home iv antibiotic therapy can be delivered safely to patients with a wide variety of infectious problems using the existing network of community nurses in the National Health Service. Essential components to the programme include a multidisciplinary team working between the hospital and community and a written shared care protocol. Such a programme can result in reduced lengths of hospital stay and patient, community nurse and physician satisfaction.

Newton P, Lalvani A, Conlon CP. 1996. Psittacosis associated with bilateral 4th cranial nerve palsies. J Infect, 32 (1), pp. 63-65. | Show Abstract | Read more

We report a 55-year-old man who presented with a moderately severe community acquired pneumonia due to Chlamydia psittaci, probably acquired from budgerigars. One of his presenting symptoms was diplopia, secondary to bilateral 4th cranial nerve palsies, which persisted for some months. The literature on neurological complications of pneumonia is reviewed.

Bakken JS, Conlon CP, Smerud KT, Vinen J, Wijlhuizen TG. 1996. Antibiotic administration options INFECTIOUS DISEASES IN CLINICAL PRACTICE, 5 (1), pp. 66-67. | Read more

Chiodini PL, Conlon CP, Hutchinson DB, Farquhar JA, Hall AP, Peto TE, Birley H, Warrell DA. 1995. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother, 36 (6), pp. 1073-1078. | Show Abstract | Read more

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.

Gordon A, Conlon C, Collin J, Peto T, Gray D, Hands L, Morris P. 1994. An eight year experience of conservative management for aortic graft sepsis. Eur J Vasc Surg, 8 (5), pp. 611-616. | Show Abstract | Read more

This paper describes the results of conservative management of 15 patients with aortic graft infection. The median time to presentation was 4 months. Six of eight grafts that were sent for culture grew organisms, of which the commonest were streptococci and coagulase negative staphylococci. Four patients did not receive intensive antibiotic treatment and all died of sepsis. Eleven patients received intensive intravenous and oral antibiotic therapy and appropriate surgical management; two of these died, one of a stroke and the other of an unknown cause. Two of the nine surviving patients had no surgery and the remainder had procedures to drain pus and unblock occluded grafts, including minimal graft excision in four patients, although two of these subsequently required total graft excision. The follow-up period for six of these nine patients is more than 4 years. For most patients with aortic graft infection aggressive antibiotic treatment supplemented by minimalist surgery is preferable to primary radical surgery.

Conlon CP, Klenerman P, Edwards A, Larder BA, Phillips RE. 1994. Heterosexual transmission of human immunodeficiency virus type 1 variants associated with zidovudine resistance. J Infect Dis, 169 (2), pp. 411-415. | Show Abstract | Read more

During zidovudine therapy, human immunodeficiency virus type 1 (HIV-1) acquires a distinctive set of mutations that diminish the sensitivity of the virus to this drug in vitro. An AIDS patient is described who, while being treated with zidovudine, transmitted HIV-1 bearing a drug resistance mutation to a young woman who had never received zidovudine treatment. DNA sequencing of HIV-1 proviruses confirmed that these 2 persons shared HIV genetic variants, including a mutation at codon 70 in the reverse transcriptase gene associated with reduced in vitro sensitivity to zidovudine. This mutation persisted in the woman > 1 year in the absence of antiretroviral therapy. HIV-1 with genetic markers of zidovudine resistance can be transmitted heterosexually, but it is uncertain whether dissemination of drug-resistant virus will substantially reduce the usefulness of this drug.

Conlon CP, Peto T. 1993. Post-tropical screening. Is of little value... BMJ, 307 (6910), pp. 1008. | Read more

A'Court CH, Garrard CS, Crook D, Bowler I, Conlon C, Peto T, Anderson E. 1993. Microbiological lung surveillance in mechanically ventilated patients, using non-directed bronchial lavage and quantitative culture. Q J Med, 86 (10), pp. 635-648. | Show Abstract | Read more

We surveyed bronchial microflora by alternate-day, non-directed bronchial lavage (NBL) in 150 patients requiring mechanical ventilation on an intensive care unit. This simple technique uses a 20 ml non-bronchoscopic lung lavage, then quantitative bacterial culture. NBL bacteriological findings were identical to those obtained by same-day bronchoscopic broncho-alveolar lavage on 16/20 occasions. Using serial NBLs, the bronchial bacterial population was characterized during 65 episodes of pneumonia defined by clinical and retrospective criteria. Mean bacterial colony counts increased significantly during the 2 days preceding the clinical onset of pneumonia, from < or = 10(3) cfu/ml to > or = 10(5) cfu/ml (p < 0.05). In 51 patients showing a clinical response to antibiotic treatment, mean colony counts fell significantly after antibiotic initiation (p < 0.05). By contrast, in 14 patients who showed progressive clinical deterioration or relapse, there was no significant fall in NBL counts, and serial NBLs revealed antibiotic resistance or superinfection. The surveillance data altered clinical management in 42% of patients. Positive NBLs guided the choice of antibiotics, whilst negative NBLs encouraged the withholding of antibiotics, or detection of alternative pathology. We propose routine bacteriological lung surveillance of mechanically ventilated patients using this simple, inexpensive and safe technique.

Conlon CP. 1993. The immunocompromised traveller. Br Med Bull, 49 (2), pp. 412-422. | Show Abstract | Read more

Increasing numbers of immunocompromised people are travelling abroad to areas where the risks of some infections are increased. HIV positive people respond reasonably well to most vaccines when asymptomatic but response is less predictable when symptomatic disease is present. Generally, live vaccines should be avoided in all stages of HIV disease. Patients with anatomic or functional asplenia are at particular risk of severe sepsis due to encapsulated bacteria and from malaria. They should be immunised against the pneumococcus, meningococcus, and haemophilus and should avoid travel to areas where the probability of malaria transmission is high. Patients receiving cancer chemotherapy or transplant recipients on long-term immunosuppression should avoid live virus vaccines but may benefit from bacterial polysaccharide vaccines such as the pneumococcal vaccine. All patients with potentially impaired immunity should be assessed on an individual basis in terms of the risks and benefits involved in travel and available prophylactic measures. Immunisations useful in their native regions can be reviewed at the same time. Such travellers should carry a physician's letter and contact address in case of medical problems encountered abroad.

Conlon CP, Peto TE. 1990. Infectious diarrhoea. Int J Colorectal Dis, 5 (4), pp. 236-240. | Show Abstract | Read more

The majority of people with infective diarrhoea, i.e. those with food poisoning or "traveller's diarrhoea", are relatively straightforward and will usually settle with rehydration and observation. The main problems in the field of infectious diarrhoea are with differential diagnosis, particularly from inflammatory bowel disease. Controversy surrounds the use of anti-diarrhoeal agents and the role of empiric antibiotics has yet to be defined. Finally, the place of the surgery in the management of these conditions can be very difficult but a conservative approach to surgical intervention is probably the best option. New pathogens as causative agents of diarrhoea are found every few years. The demand for mass-produced and quick-cook foods is increasing and the rules regarding the preparation and storage of food are often not followed. Also, travel is becoming easier and many more people are visiting developing countries. For these reasons and others it is likely that the problem of infective diarrhoea will continue to increase in the future. In addition to elucidating the pathogenesis of various forms of infective diarrhoea, future research will be directed towards prevention, earlier diagnosis and the development of better medical therapies for this problem. © 1990 Springer-Verlag.

Conlon C. 1990. Imported malaria. Practitioner, 234 (1494), pp. 841-843.

Conlon CP, Berendt AR, Dawson K, Peto TE. 1990. Runway malaria. Lancet, 335 (8687), pp. 472-473. | Read more

Clifford CP, Crook DW, Conlon CP, Fraise AP, Day DG, Peto TE. 1990. Impact of waterborne outbreak of cryptosporidiosis on AIDS and renal transplant patients. Lancet, 335 (8703), pp. 1455-1456. | Read more

Turtle L, Bali T, Buxton G, Chib S, Chan S, Soni M, Hussain M, Isenman H, Fadnis P, Venkataswamy MM et al. 2016. Human T cell responses to Japanese encephalitis virus in health and disease. J Exp Med, 213 (7), pp. 1331-1352. | Show Abstract | Read more

Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.

Sutherland RK, Russell KV, Trivedi PJ, Conlon CP, Smith RW. 2015. Elevation of the JVP in constrictive pericarditis. QJM, 108 (10), pp. 846. | Read more

Sutherland RK, Russell KV, Trivedi PJ, Warren B, Smith RW, Conlon CP. 2014. A constricting differential--a case of severe anaemia, weight loss and pericarditis due to Tropheryma whipplei infection. QJM, 107 (11), pp. 927-929. | Read more

Haj-Hassan T, McShane T, Mahmud I, Watkinson P, Conlon C, Hope T, Lloyd D, Maynard N. 2014. Israel-Gaza conflict. Lancet, 384 (9942), pp. 489. | Read more

Walker TM, Lalor MK, Broda A, Ortega LS, Morgan M, Parker L, Churchill S, Bennett K, Golubchik T, Giess AP et al. 2014. Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study. Lancet Respir Med, 2 (4), pp. 285-292. | Show Abstract | Read more

BACKGROUND: Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. METHODS: We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. FINDINGS: Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100,000 population per year in Oxfordshire, compared with 3·5 cases per 100,000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2-2·9]; p=0·009), social risk factors (4·4 [2·0-9·4]; p<0·0001), and be part of a local transmission cluster (4·8 [1·6-14·8]; p=0·006). INTERPRETATION: Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised. FUNDING: UK Clinical Research Collaboration (Wellcome Trust, Medical Research Council, National Institute for Health Research [NIHR]), and NIHR Oxford Biomedical Research Centre.

Ramagopalan SV, Goldacre R, Skingsley A, Conlon C, Goldacre MJ. 2013. Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies. BMC Med, 11 (1), pp. 97. | Show Abstract | Read more

BACKGROUND: Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB). METHODS: We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison's disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture's syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)). CONCLUSIONS: These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.

Thompson S, McPherson T, Price JD, Conlon C, Cooper S. 2013. Rash in an octogenarian. Intern Med J, 43 (1), pp. 103-104. | Read more

Eyre DW, Mankia KS, Sutherland RK, Turner GD, Conlon C. 2013. HIV-associated late seminal vesicle ‘BCGosis’ following intravesical bacille Calmette-Guérin therapy Journal of Clinical Urology, 6 (1), pp. 20-21. | Read more

Webb AJS, Conlon C, Briley D. 2012. Hypereosinophilia and acute bilateral facial palsy: an unusual presentation of a common disease. Pract Neurol, 12 (5), pp. 324-327. | Show Abstract | Read more

A 60-year-old man presented with an acute, pruritic, erythematous rash associated with marked hypereosinophilia (2.34×10(9)/l (0.04-0.40)). There was eosinophilic infiltration on hepatic, bone marrow and lymph node biopsies, with multiple lung nodules and mild splenomegaly. However, extensive investigation excluded parasitic or bacterial causes, specific allergens or the Fip1L1 mutation seen in myeloproliferative hypereosinophilia. Six months into the illness, he developed an acute, left, complete lower motor neurone facial palsy over hours, and an acute right lower motor neurone facial palsy 2&emsp14;weeks later, without recovery. Over the subsequent 3&emsp14;months, he developed complex partial seizures, a transient 72-h non-epileptic encephalopathy and episodic vertigo with ataxia. Further investigation showed bilateral enhancement of the VII nerves and labyrinthis on gadolinium-enhanced MR brain scan, cerebrospinal fluid lymphocytosis and neurophysiological evidence of polyradicolopathy. His eosinophil count fell with corticosteroids, hydroxycarbamide, imatinib and ultimately mepolezumab, but without symptomatic improvement. Repeat lymph node biopsy showed Kaposi's sarcoma, leading to a diagnosis of HIV-1 infection with a modestly reduced CD4 count of 413×10(6)/l (430-1690). Hypereosinophila and eosinophilic folliculitis are recognised features of advanced HIV infection, and transient bilateral facial palsy occasionally occurs at the time of seroconversion. This is the first report of a chronic bilateral facial palsy likely due to primary HIV infection, not occurring during seroconversion and in association with hypereosinophilia. This case emphasises the protean manifestations of HIV infection and the need for routine testing in atypical clinical presentations.

Minassian A, Jeffery K, Conlon C, Keshav S. 2011. DIAGNOSTIC DIFFICULTY IN THE GUT: A GRANULOMATOUS DILEMMACATEGORY: CLINICAL LESSON JOURNAL OF INFECTION, 63 (6), pp. E118-E119. | Read more

Ramasamy A, Patel C, Conlon C. 2011. Incomplete Stevens-Johnson syndrome secondary to atypical pneumonia. BMJ Case Rep, 2011 (oct03 1), pp. bcr0820114568-bcr0820114568. | Show Abstract | Read more

Steven-Johnson syndrome is a common condition characterised by erythematous target lesions on the skin and involvement of the oral mucosa, genitals and conjunctivae. It has been documented as one of the extra-pulmonary manifestations of Mycoplasma pneumoniae infection. Recently, there has been several documentation of an incomplete presentation of this syndrome - without the typical rash but with mucosal, conjunctival and genital involvement. Our case illustrates that the incomplete Steven-Johnson syndrome may present with oral mucosal and conjunctival involvement alone without skin or genital involvement. This important clinical diagnosis should not be missed due to its atypical presentation. Treatment of Steven-Johnson syndrome remains supportive along with treating the underlying infection if recognised.

Goulding JMR, Pitcher A, Piris J, Conlon CP. 2010. Fevers, headache and abnormal liver function in a 68-year-old man. J R Soc Med, 103 (7), pp. 295-296. | Read more

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