Background Survival analysis using time-updated CD4+ counts during antiretroviral therapy is frequently employed to determine risk of clinical events. The time-point when the CD4+ count is assumed to change potentially biases effect estimates but methods used to estimate this are infrequently reported. Methods This study examined the effect of three different estimation methods: assuming i) a constant CD4+ count from date of measurement until the date of next measurement, ii) a constant CD4+ count from the midpoint of the preceding interval until the midpoint of the subsequent interval and iii) a linear interpolation between consecutive CD4+ measurements to provide additional midpoint measurements. Person-time, tuberculosis rates and hazard ratios by CD4+ stratum were compared using all available CD4+ counts (measurement frequency 1–3 months) and 6 monthly measurements from a clinical cohort. Simulated data were used to compare the extent of bias introduced by these methods. Results The midpoint method gave the closest fit to person-time spent with low CD4+ counts and for hazard ratios for outcomes both in the clinical dataset and the simulated data. Conclusion The midpoint method presents a simple option to reduce bias in time-updated CD4+ analysis, particularly at low CD4 cell counts and rapidly increasing counts after ART initiation.
I thank Rafael Van den Bergh and colleagues for their thoughtful letter, in which they propose that antiretroviral-induced improvements in the function of macrophages rather than of T lymphocytes may principally underly the phenomenon of mycobacteriumassociated immune reconstitution disease (IRD) during highly active antiretroviral treatment (HAART). The host response to Mycobacterium tuberculosis involves the complex interplay of multiple cell types within which the interaction between macrophages and CD4 T lymphocytes is pivotal. The resulting granulomatous host response is responsible for either mycobacterial restriction or, if this fails, the immunopathology that characterises tuberculous disease. We have previously reviewed how, by diverse means, HIV infection disrupts this host response to M tuberculosis. 1 Although HIV-associated immunoparesis is most notably characterised by its devastating effects on both the quantity and function of CD4 T lymphocytes, deficits in various aspects of the functional responses of macrophages to a variety of microorganisms are also recognised. 1 Evidence suggests that these deficits may
We read with interest the recent paper by Lortholary et al. [1] describing cryptococcocal immune reconstitution disease (IRD) in France. This is an increasingly recognized complication of the initial weeks of antiretroviral treatment (ART) [1–5]. However, to our knowledge, the frequency of cryptococcocal IRD in low-income countries has not previously been reported. We run a community-based ART programme in Gugulethu, Cape Town, South Africa [6]. Between September 2002 and November 2004, 434 treatment-naive patients started triple-drug ART according to WHO 2002 treatment guidelines [7]. The patients' mean age was 34 years, their median blood CD4 cell count was 86 cells/μl [interquartile range (IQR) 46–146 cells/μl], and the median plasma HIV load was 76 337 copies/ml (IQR 32 723–192 772 copies/ml). A total of 137 patients (32%) had WHO stage 4 disease, and among these cryptococcal meningitis was the AIDS-defining illness in 18 (13%). These diagnoses were made a median of 7 months (range 2–24 months) before the initiation of ART. According to national guidelines, cryptococcal meningitis was treated with fluconazole 400 mg/day for 8 weeks followed by 200 mg/day as secondary prophylaxis. At data censorship in February 2005, the median follow-up was 46 weeks. During a total of 460 person-years of observation (PYO), nine patients developed either recurrent (n = 6) or new (n = 3) symptomatic cryptococcal disease of the central nervous system (Table 1). The median duration of ART at the onset of symptoms was 4 weeks. In the first, second and third months of ART, disease incidence based upon the time of symptom onset was 18.2 cases/100 PYO [95% confidence interval (CI) 8.2–40.6], 6.2 cases/100 PYO (95% CI 1.6–25.1) and 0 cases/100 PYO, respectively. Only one case of cryptococcal disease occurred after 12 weeks' ART. Six of the nine patients (66%) died and cryptococcal disease accounted for six out of 22 total deaths (27%) during the first 3 months of ART.Table 1: Features of nine cases of central nervous system cryptococcosis during the initial weeks of antiretroviral treatment.IRD results from the rapid restoration of immune function, leading to an exacerbation of partly treated opportunistic infections or unmasking of previously undiagnosed subclinical infections [8]. Several factors have suggested that IRD was the likely mechanism underlying the presentation of most or all of these cases of cryptococcosis: the very high incidence density rate within the initial weeks of ART, the sudden onset, the typically rapid evolution and fulminant clinical course. Of those with a previous history of cryptococcosis, one-third developed probable IRD. Although this proportion is comparable with other series [2,5], the mortality rate in our series is higher and represents a substantial problem that needs to be addressed to reduce the early mortality during ART among patients in resource-limited settings. Live organisms, dead organisms or their shed antigens may trigger IRD [8]. Among cases from whom viable organisms are cultured, symptoms may either be caused by IRD or simply represent new opportunistic disease. IRD case definitions that exclude clinically suspected cases with positive cultures increase the specificity of IRD diagnoses but may limit sensitivity. Of the nine patients described, seven had sterile cultures; although cultures from the remaining two cases were positive, a review of their clinical presentation suggested that IRD was potentially the underlying mechanism. Cryptococcocal IRD is likely to be increasingly frequently encountered in ART programmes in sub-Saharan Africa for several reasons. First, ART programmes in the region are currently inundated with large numbers of patients with very advanced immunodeficiency; such patients are at the greatest risk of developing IRD. Second, HIV-associated cryptococcal disease is common in the region. Third, the local standard of care for cryptococcal meningitis is treatment with oral fluconazole, which is supplied free of charge by the manufacturer. Fluconazole is a fungistatic drug, which is broadly effective as secondary prophylaxis, but has far less efficacy than amphotericin in clearing the organism during the initial treatment phase [9]. We suggest that the use of this agent for primary treatment may increase the risk of cryptococcal antigen persistence within the cerebrospinal fluid (CSF), possibly increasing the risk of IRD during ART. Among those with a previous history of cryptococcosis, an analysis of CSF before the initiation of ART might be used to identify those with a persistent antigen burden who might then be retreated to reduce the fungal burden before starting ART. However, this strategy may be impractical in view of the huge logistic challenges facing many ART programmes in low-income countries. However, the optimum interval between the treatment of cryptococcal meningitis and the initiation of ART needs to be defined, and clinicians should be made aware of cryptococcal IRD to promote early diagnosis and prompt treatment. Optimal management strategies for cryptococcal IRD need to be defined by future studies, including the choice of antifungal agents, the use of corticosteroids, and the role of the discontinuation of ART. Sponsorship: S.D.L. is funded by the Wellcome Trust, London.
Great progress has been made over the past few years in HIV testing in patients who have tuberculosis (TB) and in the scale-up of antiretroviral therapy. More than 3 million people in resource-limited settings were estimated to have started antiretroviral therapy by the end of 2007 and 2 million of these were in sub-Saharan Africa. However, little is known about what impact this massive public health intervention will have on the HIV-associated TB epidemic or how antiretroviral therapy might be used to best effect TB control. This article provides an in-depth review of these issues.
To the Editor: We thank Schmaltz et al1 for their interest in our article regarding the optimum time to initiate antiretroviral therapy (ART) in patients with tuberculosis (TB). Data from randomized controlled trials that definitively address this question are awaited, but in the interim, data from observational cohorts offer important insights. The issue of the optimum timing is complex, involving a number of variables including treatment tolerability, cotoxicity, pharmacokinetic drug interactions, and adherence. However, of overriding importance is mortality risk. The 2 key factors contributing to mortality seem to be the mortality risk associated with delays in ART initiation versus the mortality risk associated with immune reconstitution disease (IRD)2,3-the latter being strongly associated with early initiation of ART.4,5 The optimum timing of ART initiation is likely to be defined largely by the balance between these 2 opposing factors. However, both variables seem to vary between different patient populations and, in particular, may differ substantially when comparing treatment cohorts in high-income and low-resource settings. Mortality risk in the first year of treatment in ART programs in sub-Saharan Africa (8%-26%) greatly exceeds the risk in European and North American cohorts (approximately 2%-3%), with most deaths occurring during the initial months of treatment.6,7 The mortality cost of delays in ART initiation is therefore likely to be much higher in Africa than in high-income countries. As suggested by Schmaltz et al,1 an intermediate risk is likely to exist in Brazil. The reported incidence of TB-associated IRD varies between approximately 10% and 40% of patients with TB initiating ART.4,8 This wide range may reflect differences in cohort characteristics, timing of ART initiation, and methods of case ascertainment. Recent publication of consensus case definitions for TB-associated IRD applicable in both high-income and resource-limited settings may help provide standardization and comparability of data.9 Mortality risk in patients with TB-associated IRD has yet to be clearly defined. Although the proportion of patients reported to develop TB-associated IRD is generally higher in high-income countries than elsewhere,8 the associated mortality seems to be low in this setting4 as is also reported from Brazil.1,10 In contrast, deaths in patients with TB-associated IRD have been reported in South African and Thai cohorts.5,11 In South Africa, however, our experience is that severe TB-associated IRD tends to develop in patients who already have high mortality risk, specifically those with the lowest CD4 cell counts and those with disseminated TB. Thus, although 10.5% (2/19) of patients who developed TB-IRD in our cohort died, 9.9% (14/141) of patients with TB who did not develop IRD also died.5 Thus, development of IRD in this study was not associated with significant excess mortality risk. This observation, however, needs to be clarified in cohorts with larger numbers of cases of TB-associated IRD. Taking these observations together, we have suggested that the optimum time for ART initiation may differ between settings.3 We agree with Schmaltz et al1 that in lower income countries, the risk of mortality associated with delays in ART initiation is likely to substantially outweigh any excess mortality risk from TB-associated IRD. Thus, the optimum timing of ART initiation is likely to be earlier in the course of TB treatment for patients in resource-limited settings compared with those in high-income settings.2 We agree with current World Health Organization guidelines for low-resource settings that recommend that patients with TB/HIV with CD4 cell counts <200 cells per microliter receive ART within a 2- to 8-week time frame after starting TB treatment but that those with the most advanced immunodeficiency be started as soon as practicably possible.12 The policy described by Schmaltz et al1 of starting ART after 4 weeks of TB treatment in Brazil may require some refinement because optimal timing is likely to depend substantially on the patient's current CD4 cell count. We agree with the further important point made by Schmaltz et al that many patients with TB who require ART experience substantial delays between development of symptoms of TB, establishment of a TB diagnosis, initiation of TB treatment, and subsequent initiation of ART. Thus, although much interest has focussed on the issue of the optimum timing of ART in relation to TB treatment, the potentially more important issue of the overall delays in the care pathway in resource-limited settings have received much less attention. The tools routinely available for diagnosis of TB in HIV-infected patients in the countries with the highest burden of TB are extremely limited, and this contributes substantially to delays. New TB diagnostics with adequate sensitivity and rapidity for use in HIV-infected individuals are urgently required. In South Africa, HIV-infected patients with TB are often referred to ART services only after prolonged delay and yet the mortality associated with even short delays is unacceptably high.13,14 These health system delays are inherent within overstretched and fragmented primary care services. Well-organized and integrated systems of care for delivery of both TB treatment and ART are urgently needed to reduce these delays and optimize the chance of survival for these patients. ACKNOWLEDGMENTS S.D.L. is funded by the Wellcome Trust, London, United Kingdom. R.W. is funded in part by the National Institutes of Health, United States, grants A1058736-01A1 and 1U19AI53217-01. Stephen D. Lawn, MRCP, MD*† Robin Wood, FCP* *The Desmond Tutu HIV Centre Institute for Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town, South Africa †Clinical Research Unit Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London, United Kingdom
Journal Article Serum procalcitonin concentrations in patients with pulmonary tuberculosis Get access S.D. Lawn, S.D. Lawn 1Department of Medicine, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana2Division of Infectious Diseases, St George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Obeng, J. Obeng 1Department of Medicine, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana Search for other works by this author on: Oxford Academic PubMed Google Scholar J.W. Acheampong, J.W. Acheampong 1Department of Medicine, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana Search for other works by this author on: Oxford Academic PubMed Google Scholar G.E. Griffin G.E. Griffin 2Division of Infectious Diseases, St George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK author for correspondence: Professor G. E. Griffin, Division of Infectious Diseases, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK; phone +44 (0)181 725 5828, fax +44 (0)181 725 3487. Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 92, Issue 5, September-October 1998, Pages 540–541, https://doi.org/10.1016/S0035-9203(98)90906-3 Published: 01 September 1998 Article history Received: 30 April 1998 Revision received: 22 July 1998 Accepted: 28 July 1998 Published: 01 September 1998
Heavy reliance upon praziquantel for the treatment of schistosomiasis raises concerns over potential development of drug resistance. We describe a British traveller who acquired Schistosoma mansoni infection in East Africa and in whom repeated standard 40 mg/kg doses of praziquantel failed to clear the infection despite no opportunity for reinfection.
The diagnostic gold standard for active tuberculosis (TB) is the detection of Mycobacterium tuberculosis (MTB) by culture or molecular methods. However, despite its limited sensitivity, sputum smear microscopy is still the mainstay of TB diagnosis in resource-limited settings. Consequently, diagnosis of smear-negative pulmonary and extrapulmonary TB remains challenging in such settings. A number of novel or alternative techniques could provide adjunctive diagnostic use in the context of difficult-to-diagnose TB. These may be especially useful in certain patient groups such as persons infected with human immunodeficiency virus (HIV) and children, who are disproportionably affected by smear-negative and extrapulmonary disease and who are also most adversely affected by delays in TB diagnosis and treatment. We review a selection of these methods that are independent of nucleic acid amplification techniques and could largely be implemented in resource-limited settings in current or adapted versions. Specifically, we discuss the diagnostic use and potential of serologic tests based on detection of antibodies to MTB antigens; interferon gamma release assays using site-specific lymphocytes; detection of lipoarabinomannan, a glycolipid of MTB, in urine; the string test, a novel technique to retrieve lower respiratory tract samples; and fine needle aspiration biopsy of lymph nodes.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
'%3e%3cpath fill='%23001489' d='M0 0v6h9V0z'/%3e%3cpath fill='%23e03c31' d='M0 0v3h9V0z'/%3e%3cg stroke='%23fff' stroke-width='2'%3e%3cpath id='d' d='m0 0 4.5 3L0 6m4.5-3H9'/%3e%3cuse xlink:href='%23b' stroke='%23ffb81c' clip-path='url(%23c)'/%3e%3c/g%3e%3cuse xlink:href='%23d' fill='none' stroke='%23007749' stroke-width='1.2'/%3e%3c/g%3e%3c/svg%3e)
