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ABSTRACT: Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development.
Pharmacogenomics 08/2012; 13(11):1285-306. · 3.97 Impact Factor
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ABSTRACT: The high diversity of HLA binding preferences has been driven by the sequence diversity of short segments of relevant pathogenic proteins presented by HLA molecules to the immune system. To identify possible commonalities in HLA binding preferences, we quantify these using a novel measure termed "targeting efficiency," which captures the correlation between HLA-peptide binding affinities and the conservation of the targeted proteomic regions. Analysis of targeting efficiencies for 95 HLA class I alleles over thousands of human proteins and 52 human viruses indicates that HLA molecules preferentially target conserved regions in these proteomes, although the arboviral Flaviviridae are a notable exception where nonconserved regions are preferentially targeted by most alleles. HLA-A alleles and several HLA-B alleles that have maintained close sequence identity with chimpanzee homologues target conserved human proteins and DNA viruses such as Herpesviridae and Adenoviridae most efficiently, while all HLA-B alleles studied efficiently target RNA viruses. These patterns of host and pathogen specialization are both consistent with coevolutionary selection and functionally relevant in specific cases; for example, preferential HLA targeting of conserved proteomic regions is associated with improved outcomes in HIV infection and with protection against dengue hemorrhagic fever. Efficiency analysis provides a novel perspective on the coevolutionary relationship between HLA class I molecular diversity, self-derived peptides that shape T-cell immunity through ontogeny, and the broad range of viruses that subsequently engage with the adaptive immune response.
Journal of Virology 11/2010; 85(3):1310-21. · 5.40 Impact Factor
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ABSTRACT: Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug. Early studies identified a strong association between the MHC class I allele HLA-B*5701 and AHS. These studies suggested that HLA-B*5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B*5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B*5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B*5701 screening can largely eliminate AHS. Furthermore, skin-patch testing was used in later-generation studies to separate those patients with true immunologically mediated AHS from those with false-positive clinical diagnoses. Currently, high-level evidence suggests that HLA-B*5701 has a negative predictive value of 100% for patch-test-confirmed AHS, which is generalizable across White and Black populations. Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B*5701 screening be incorporated into routine care for patients who may require abacavir. New laboratory techniques such as PCR and flow cytometric methods, as well as an international quality assurance program, have evolved to ensure the availability of cost-effective screening methods whose consistency and standard can be maintained over time. An elegant body of basic science has evolved, which supports and complements the clinical research in suggesting that AHS is specifically and exquisitely restricted by HLA-B*5701 and mediated by CD8+ lymphocytes. Abrogating factors explaining why 45% of those carrying HLA-B*5701 can tolerate abacavir remain to be defined. The research approach applied to AHS has led to a genetic screening test being successfully implemented globally in primary HIV clinical practice. The abacavir 'example' can be applied to other drugs to facilitate the development and operationalization of genetic tests that may be useful to predict and prevent otherwise unpredictable drug reactions.
Molecular diagnosis & therapy 02/2009; 13(1):1-9. · 1.71 Impact Factor
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Michael Saag,
Rukmini Balu, Elizabeth Phillips,
Philip Brachman,
Claudia Martorell,
William Burman,
Britt Stancil,
Michael Mosteller,
Cindy Brothers,
Paul Wannamaker,
Arlene Hughes,
Denise Sutherland-Phillips,
Simon Mallal,
Mark Shaefer
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ABSTRACT: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis.
White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants.
Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%.
Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.
Clinical Infectious Diseases 04/2008; 46(7):1111-8. · 9.15 Impact Factor
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Simon Mallal, Elizabeth Phillips,
Giampiero Carosi,
Jean-Michel Molina,
Cassy Workman,
Janez Tomazic,
Eva Jägel-Guedes,
Sorin Rugina,
Oleg Kozyrev,
Juan Flores Cid,
Phillip Hay,
David Nolan,
Sara Hughes,
Arlene Hughes,
Susanna Ryan,
Nicholas Fitch,
Daren Thorborn,
Alastair Benbow
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ABSTRACT: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir.
This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir.
The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001).
HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
New England Journal of Medicine 03/2008; 358(6):568-79. · 53.30 Impact Factor
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ABSTRACT: Abacavir hypersensitivity in genetically susceptible individuals implicates an abacavir-specific T-cell response to either the parent drug or a metabolite generated in vivo. We have analysed the cytokine profile in antigen-presenting cells and the T-lymphocytes that are involved in the pathological immune response to abacavir.
In this study, we compared abacavir-specific cytokine responses in cultured peripheral blood mononuclear cells (PBMCs) from HIV-infected abacavir hypersensitive, tolerant and naive individuals. Cells were cultured in the presence or absence of abacavir. Cytokine expression was determined by microarray analysis, enzyme-linked immunosorbent assays and flow cytometry.
We demonstrated using in vitro models of immune activation that the production of interferon-gamma was specifically induced by abacavir treatment in PBMCs obtained from hypersensitive patients carrying the HLA-B*5701 allele (median 123.86 compared with -30.83 for tolerant controls, P=0.001).
These results provide further insight into the immunological and metabolic basis of abacavir hypersensitivity syndrome. In vitro assays could assist in the identification of susceptible loci by providing a surrogate marker for the hypersensitivity reaction. Such a marker could be studied in unexposed individuals to shed further light on the immunopathogenesis of the abacavir hypersensitivity syndrome.
Antiviral therapy 01/2008; 13(2):281-8. · 3.16 Impact Factor
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ABSTRACT: We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting.
We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods.
From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment.
HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.
Antiviral therapy 01/2008; 13(8):1019-28. · 3.16 Impact Factor
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ABSTRACT: Drug hypersensitivity has been reported to occur 100 times more commonly in those living with HIV. In the first decade of HIV treatment, this mainly involved drugs used to treat HIV-related infections but now primarily includes drugs used to treat HIV. This review focuses on the current knowledge of the epidemiology, pathophysiology and clinical features of drug hypersensitivity reactions of drugs used in the management of the HIV-infected patient.
Our understanding of the immunogenetics and host predisposition to drug hypersensitivity has been advanced considerably by the antiretroviral drugs abacavir and nevirapine. The association of abacavir hypersensitivity reaction with HLA-B*5701 has been particularly important and provides a basis for genetic screening in the clinic setting.
The increased predisposition of drug hypersensitivity disease in HIV will continue to provide a fertile ground for study of the diverse and complex processes that drive its pathophysiology. Our knowledge of drug hypersensitivity will also increase as the expanding armentarium of antiretroviral therapy is applied to more diverse populations in the developing world. The potential for widespread implementation of HLA-B*5701 screening for abacavir hypersensitivity will set an important precedent for bringing individualized medicine to the clinic and the use of genetic testing to improve drug safety.
Current Opinion in Allergy and Clinical Immunology 09/2007; 7(4):324-30. · 4.11 Impact Factor
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ABSTRACT: A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity.
This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity.
In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001).
The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.
AIDS 07/2007; 21(10):1233-44. · 6.24 Impact Factor
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Emma Hammond,
Coral-Ann Almeida,
Cyril Mamotte,
David Nolan, Elizabeth Phillips,
Tineke Asma Schollaardt,
M John Gill,
Jonathan B Angel,
Doris Neurath,
Jianping Li, [......],
Betty Wong,
Marciano Reis,
Anita Rachlis,
David E Cole,
Choo Beng Chew,
Stefan Neifer,
Richard Lalonde,
Michel Roger,
Annie Jeanneau,
Simon Mallal
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ABSTRACT: HLA-B*5701 strongly predicts abacavir hypersensitivity (HSR), but implementation of effective routine screening into clinical practice requires testing be practical and accurate. We tested the proficiency of HLA-B*5701 typing among laboratories using sequence-specific primer PCR.
DNA panels (1 and 2) were distributed to seven laboratories (A to G) for blinded typing of the HLA-B*5701 allele. Panel 1 (n = 10 samples; n = 7 laboratories) included 3 positives and other closely related B17 subtypes (B*5702, B*5703, B*5704 and B*5801). Panel 2 (n = 96 samples; n = 4 laboratories) included 36 positives among a broad spectrum of other B alleles. Two laboratories (A and B) also submitted 96 routine samples, typed by the same methodology, to the reference centre for additional analysis by sequence-based typing.
All laboratories correctly typed panel 1 for HLA-B*5701 carriage. Laboratories A, B and C identified HLA-B*5701 alleles in panel 2 with 100% sensitivity and 100% specificity. Laboratory D reported one false negative, reportedly due to a sampling error. The results obtained for routine samples typed by laboratories A and B and those generated by the reference laboratory using sequencing were fully concordant.
Detection of HLA-B*5701 alleles among laboratories was 100% specific and 99.4% sensitive, indicating that participating HIV testing laboratories were currently offering effective primary screening to identify individuals at high risk of abacavir HSR. Accurate reporting of HLA-B*5701 status is critical for the safe administration of this drug and participation in quality assurance programmes by all sites who report HLA-B*5701 status should be promoted.
Antiviral therapy 02/2007; 12(7):1027-32. · 3.16 Impact Factor
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ABSTRACT: Eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage may reduce the risk of MRSA infection and prevent transmission of the organism to other patients.
To determine the efficacy of decolonization therapy, patients colonized with MRSA were randomized (3:1 allocation) to receive treatment (2% chlorhexidine gluconate washes and 2% mupirocin ointment intranasally, with oral rifampin and doxycycline for 7 days), or no treatment. Follow-up samples for MRSA culture were obtained from the nares, perineum, skin lesions, and catheter exit sites monthly for up to 8 months. The primary outcome measure was detection of MRSA at 3 months of follow-up. Univariate and multivariable analyses were performed to identify variables associated with treatment failure.
Of 146 patients enrolled in the study, 112 patients (87 treated; 25 not treated) were followed up for at least 3 months. At 3 months of follow-up, 64 (74%) of those treated had culture results negative for MRSA, compared with 8 (32%) of those not treated (P=.0001). This difference remained significant at 8 months of follow-up, at which time, 54% of those treated had culture results negative for MRSA (chi2=64.4; P<.0001, by log-rank test). The results of the multivariable analysis indicated that having a mupirocin-resistant isolate at baseline was associated with treatment failure (relative risk, 9.4; 95% confidence interval, 2.8-31.9; P=.0003), whereas decolonization therapy was protective (relative risk, 0.1; 95% confidence interval, 0.04-0.4; P=.0002). Mupirocin resistance emerged in only 5% of follow-up isolates.
Treatment with topical mupirocin, chlorhexidine gluconate washes, oral rifampin, and doxycycline for 7 days was safe and effective in eradicating MRSA colonization in hospitalized patients for at least 3 months.
Clinical Infectious Diseases 02/2007; 44(2):178-85. · 9.15 Impact Factor
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ABSTRACT: Abacavir hypersensitivity reaction (ABC HSR) is a potentially life-threatening adverse reaction that affects approximately 8% of patients that initiate this antiretroviral drug. Independent groups have shown a strong predictive association between ABC HSR and HLA-B*5701, indicating that exclusion of HLA-B*5701 positive individuals from abacavir treatment would largely prevent ABC HSR. However, the limited availability and relatively high cost of human leukocyte antigen (HLA) typing represent barriers to the widespread implementation of this pharmacogenetic approach to abacavir prescribing. To facilitate routine screening, we have developed a rapid flow cytometry method for HLA-B57 phenotyping using commercially available B17 monoclonal antibodies.
Whole blood samples from 84 human immunodeficiency virus (HIV) patients were examined by standard flow cytometry methods, using a two-colour B17-specific immunofluorescence assay in the CD45 lymphocyte population.
All eight HLA-B57 individuals examined tested positive, while HLA-B57/58 negative individuals (n=74) tested negative for this flow cytometry test. Two non-HLA-B57 individuals showed weak cross-reactivity.
In our predominantly Caucasian population, B17/CD45 dual staining was sufficient to identify individuals carrying B17 cell surface antigens. This approach, utilizing flow cytometry methods that are widely available in HIV laboratories, therefore offers a sensitive, rapid and cost-effective screening assay prior to abacavir prescription. Following risk stratification with this assay, it would be anticipated that identification of HLA-B*5701 using molecular HLA typing methods would be required in <10% of the screened population.
Pharmacogenetics and Genomics 05/2006; 16(5):353-7. · 3.48 Impact Factor
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Clinical Infectious Diseases 03/2006; 42(3):408-10. · 9.15 Impact Factor
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ABSTRACT: Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.
AIDS 02/2005; 19(1):97-9. · 6.24 Impact Factor
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ABSTRACT: The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host, as well as drug-drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized.
Pharmacogenomics 10/2004; 5(6):643-55. · 3.97 Impact Factor
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Annalise M Martin,
David Nolan,
Silvana Gaudieri,
Coral Ann Almeida,
Richard Nolan,
Ian James,
Filipa Carvalho, Elizabeth Phillips,
Frank T Christiansen,
Anthony W Purcell,
James McCluskey,
Simon Mallal
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ABSTRACT: Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.
Proceedings of the National Academy of Sciences 03/2004; 101(12):4180-5. · 9.68 Impact Factor
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Patrick Tang,
Marie Louie,
Susan E Richardson,
Marek Smieja,
Andrew E Simor,
Frances Jamieson,
Margaret Fearon,
Susan M Poutanen,
Tony Mazzulli,
Raymond Tellier, [......],
Lisa Fernando,
Timothy F Booth,
Bonnie Henry,
Anita R Rachlis,
Larissa M Matukas,
David B Rose,
Reena Lovinsky,
Sharon Walmsley,
Wayne L Gold,
Sigmund Krajden
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ABSTRACT: An outbreak of severe acute respiratory syndrome (SARS) began in Canada in February 2003. The initial diagnosis of SARS was based on clinical and epidemiological criteria. During the outbreak, molecular and serologic tests for the SARS-associated coronavirus (SARS-CoV) became available. However, without a "gold standard," it was impossible to determine the usefulness of these tests. We describe how these tests were used during the first phase of the SARS outbreak in Toronto and offer some recommendations that may be useful if SARS returns.
We examined the results of all diagnostic laboratory tests used in 117 patients admitted to hospitals in Toronto who met the Health Canada criteria for suspect or probable SARS. Focusing on tests for SARS-CoV, we attempted to determine the optimal specimen types and timing of specimen collection.
Diagnostic test results for SARS-CoV were available for 110 of the 117 patients. SARS-CoV was detected by means of reverse-transcriptase polymerase chain reaction (RT-PCR) in at least one specimen in 59 (54.1%) of 109 patients. Serologic test results of convalescent samples were positive in 50 (96.2%) of 52 patients for whom paired serum samples were collected during the acute and convalescent phases of the illness. Of the 110 patients, 78 (70.9%) had specimens that tested positive by means of RT-PCR, serologic testing or both methods. The proportion of RT-PCR test results that were positive was similar between patients who met the criteria for suspect SARS (50.8%, 95% confidence interval [CI] 38.4%-63.2%) and those who met the criteria for probable SARS (58.0%, 95% CI 44.2%-70.7%). SARS-CoV was detected in nasopharyngeal swabs in 33 (32.4%) of 102 patients, in stool specimens in 19 (63.3%) of 30 patients, and in specimens from the lower respiratory tract in 10 (58.8%) of 17 patients.
These findings suggest that the rapid diagnostic tests in use at the time of the initial outbreak lack sufficient sensitivity to be used clinically to rule out SARS. As tests for SARS-CoV continue to be optimized, evaluation of the clinical presentation and elucidation of a contact history must remain the cornerstone of SARS diagnosis. In patients with SARS, specimens taken from the lower respiratory tract and stool samples test positive by means of RT-PCR more often than do samples taken from other areas.
Canadian Medical Association Journal 02/2004; 170(1):47-54. · 8.22 Impact Factor
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Contact Dermatitis 04/2003; 48(3):169-70. · 3.51 Impact Factor
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ABSTRACT: This study was conducted to determine how frequently self-reported symptoms are captured as adverse drug events (ADEs) during chart abstraction.
We studied Ontario Cohort Study (OCS) participants attending the Toronto Hospital Immunodeficiency Clinic and compared OCS data on ADEs collected semi-annually through chart review and a self-administered questionnaire, completed on up to three occasions, which asked about the frequency, severity, and chronicity of symptoms including diarrhea, nausea, fatigue, and changes in body shape. Among 64 participants who completed the questionnaires, the median age was 42 years, the median time since HIV diagnosis was 9 years, 84% were male, 58% were men who had sex with men, 70% had viral load levels below 50 copies/mL, and the median CD4 was 422 cells/mm3. All patients were taking antiretroviral therapy.
The median (interquartile range) number of symptoms per participant reported on the questionnaire at the first visit was 3 (1-5). The most common symptoms reported by patients were diarrhea (58%), headache (59%), difficulty sleeping (52%), dry skin (53%), and changes in body shape (52%). The median number of ADEs during the study period per participant in OCS was 1 (0-2). Of 345 symptoms identified on the questionnaire, 16% were reported as ADEs in the OCS.
Although some symptoms were correctly not classified as ADEs as they were not related to antiretroviral medication, others may have been missed due to incomplete reporting to the physician, incomplete physician recording, or errors in chart extraction.
HIV Clinical Trials 8(5):311-9. · 1.64 Impact Factor
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Patrick Tang,
Scott Walsh,
Christian Murray,
Cecilia Alterman,
Monali Varia,
George Broukhanski,
Pamela Chedore,
Joel DeKoven,
Dalal Assaad,
Wayne L Gold,
Danny Ghazarian,
Michael Finkelstein,
Marjolyn Pritchard,
Barbara Yaffe,
Frances Jamieson,
Bonnie Henry, Elizabeth Phillips
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ABSTRACT: Cutaneous atypical mycobacterial infections have been increasingly described in association with cosmetic and alternative procedures.
We report an outbreak of acupuncture-associated mycobacteriosis. Between April and December 2002, 32 patients developed cutaneous mycobacteriosis after visiting an acupuncture practice in Toronto, Canada.
Of 23 patients whose lesions were biopsied, 6 (26.1%) had culture-confirmed infection with Mycobacterium abscessus. These isolates were genetically indistinguishable by amplified fragment length polymorphism. The median incubation period was 1 month. Of 24 patients for whom clinical information was available, 23 (95.8%) had resolution of their infection. All patients developed residual scarring or hyperpigmentation.
Nontuberculous mycobacteria should be recognized as an emerging, but preventable, cause of acupuncture-associated infections.
Journal of Cutaneous Maedicine and Surgery 10(4):166-9. · 0.98 Impact Factor
