Mentorship is crucial for academic productivity and advancement for clinical and translational (CT) science faculty. However, little is known about the long-term effects of mentor training programs. The University of California, San Francisco (UCSF), Clinical and Translational Science Institute launched a Mentor Development Program (MDP) in 2007 for CT faculty. We report on an evaluation of the first three cohorts of graduates from the MDP. In 2010, all Mentors in Training (MITs) who completed the MDP from 2007 to 2009 (n=38) were asked to complete an evaluation of their mentoring skills and knowledge; all MITs (100%) completed the evaluation. Two-thirds of MDP graduates reported that they often apply knowledge, attitudes, or skills obtained in the MDP to their mentoring. Nearly all graduates (97%) considered being a mentor important to their career satisfaction. Graduates were also asked about the MDP’s impact on specific mentoring skills; 95% agreed that the MDP helped them to become a better mentor and to focus their mentoring goals. We also describe a number of new initiatives to support mentoring at UCSF that have evolved from the MDP. To our knowledge, this is the first evaluation of the long-term impact of a mentor training program for CT researchers.
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
Despite the increased frequency of recurrent pneumonia in HIV-infected patients and recent studies linking the airway bacterial community (microbiota) to acute and chronic respiratory infection, little is known of the oral and airway microbiota that exist in these individuals and their propensity to harbor pathogens despite antimicrobial treatment for acute pneumonia. This pilot study compared paired samples of the oral and airway microbiota from 15 hospitalized HIV-infected patients receiving antimicrobial treatment for acute pneumonia. Total DNA was extracted, bacterial burden was assessed by quantitative PCR, and amplified 16S rRNA was profiled for microbiome composition using a phylogenetic microarray (16S rRNA PhyloChip). Though the bacterial burden of the airway was significantly lower than that of the oral cavity, microbiota in both niches were comparably diverse. However, oral and airway microbiota exhibited niche specificity. Oral microbiota were characterized by significantly increased relative abundance of multiple species associated with the mouth, including members of the Bacteroides, Firmicutes, and TM7 phyla, while airway microbiota were primarily characterized by a relative expansion of the Proteobacteria. Twenty-two taxa were detected in both niches, including Streptococcus bovis and Chryseobacterium species, pathogens associated with HIV-infected populations. In addition, we compared the airway microbiota of five of these patients to those of five non-HIV-infected pneumonia patients from a previous study. Compared to the control population, HIV-infected patients exhibited relative increased abundance of a large number of phylogenetically distinct taxa, which included several known or suspected pathogenic organisms, suggesting that recurrent pneumonia in HIV-infected populations may be related to the presence of these species.
Pneumocystis jirovecii is an important opportunistic infection in HIV-infected patients. In the developed world, P. jirovecii epidemiology is marked by frequent colonization in immunosuppressed patients, but data on the prevalence of colonization is very limited in sub-Saharan Africa, where the majority of persons living with HIV reside. Our objective was to describe the epidemiology of P. jirovecii colonization among HIV-positive patients in a cross-sectional, hospital-based study of patients admitted with suspected pneumonia in Kampala, Uganda. P. jirovecii was detectable in bronchoalveolar lavage fluid from 7 of 124 (6%) consecutive patients with non-Pneumocystis pneumonia. Colonization was not associated with patient demographic or clinical information. This prevalence is substantially lower than in published studies in the developed world, and suggests that there is a limited reservoir of organisms for clinical infections in this Ugandan population. These findings may partially explain the low incidence of Pneumocystis pneumonia in Uganda and other sub-Saharan African countries.
Pneumocystis jirovecii; colonization; pneumonia; AIDS
Little is known about the serologic responses to Pneumocystis jirovecii major surface glycoprotein (Msg) antigen in African cohorts, or the IgM responses to Msg in HIV-positive and HIV-negative persons with respiratory symptoms.
We conducted a prospective study of 550 patients, both HIV-positive (n = 467) and HIV-negative (n = 83), hospitalized with cough ≥2 weeks in Kampala, Uganda, to evaluate the association between HIV status, CD4 cell count, and other clinical predictors and antibody responses to P. jirovecii. We utilized ELISA to measure the IgM and IgG serologic responses to three overlapping recombinant fragments that span the P. jirovecii major surface glycoprotein: MsgA (amino terminus), MsgB (middle portion) and MsgC1 (carboxyl terminus), and to three variations of MsgC1 (MsgC3, MsgC8 and MsgC9).
HIV-positive patients demonstrated significantly lower IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 compared to HIV-negative patients. We found the same pattern of low IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 among HIV-positive patients with a CD4 cell count <200 cells/µl compared to those with a CD4 cell count ≥200 cells/µl. HIV-positive patients on PCP prophylaxis had significantly lower IgM responses to MsgC3 and MsgC9, and lower IgG responses to MsgA, MsgC1, MsgC3, and MsgC8. In contrast, cigarette smoking was associated with increased IgM antibody responses to MsgC1 and MsgC3 but was not associated with IgG responses. We evaluated IgM and IgG as predictors of mortality. Lower IgM responses to MsgC3 and MsgC8 were both associated with increased in-hospital mortality.
HIV infection and degree of immunosuppression are associated with reduced IgM responses to Msg. In addition, low IgM responses to MsgC3 and MsgC8 are associated with increased mortality.
Pneumocystis jirovecii pneumonia (PCP) is an important opportunistic infection in patients infected with HIV, but its burden is incompletely characterized in those areas of sub-Saharan Africa where HIV is prevalent. We explored the prevalence of both PCP in HIV-infected adults admitted with pneumonia to a tertiary-care hospital in Uganda and of putative P. jirovecii drug resistance by mutations in fungal dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr). In 129 consecutive patients with sputum smears negative for mycobacteria, 5 (3.9%) were diagnosed with PCP by microscopic examination of Giemsa-stained bronchoalveolar lavage fluid. Concordance was 100% between Giemsa stain and PCR (dhps and dhfr). PCP was more prevalent in patients newly-diagnosed with HIV (11.4%) than in patients with known HIV (1.1%; p = 0.007). Mortality at 2 months after discharge was 29% overall: 28% among PCP-negative patients, and 60% (3 of 5) among PCP-positive patients. In these 5 fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation. No non-synonymous dhfr mutations were detected. PCP is an important cause of pneumonia in patients newly-diagnosed with HIV in Uganda, is associated with high mortality, and putative molecular evidence of drug resistance is prevalent. Given the reliability of field diagnosis in our cohort, future studies in sub-Saharan Africa can investigate the clinical impact of these genotypes.
Background. The diagnostic value of interferon-γ release assays (IGRAs) for active tuberculosis in low- and middle-income countries is unclear.
Methods. We searched multiple databases for studies published through May 2010 that evaluated the diagnostic performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB (T-SPOT) among adults with suspected active pulmonary tuberculosis or patients with confirmed cases in low- and middle-income countries. We summarized test performance characteristics with use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models.
Results. Our search identified 789 citations, of which 27 observational studies (17 QFT-GIT and 10 T-SPOT) evaluating 590 human immunodeficiency virus (HIV)–uninfected and 844 HIV-infected individuals met inclusion criteria. Among HIV-infected patients, HSROC/bivariate pooled sensitivity estimates (highest quality data) were 76% (95% confidence interval [CI], 45%–92%) for T-SPOT and 60% (95% CI, 34%–82%) for QFT-GIT. HSROC/bivariate pooled specificity estimates were low for both IGRA platforms among all participants (T-SPOT, 61% [95% CI, 40%–79%]; QFT-GIT, 52% [95% CI, 41%–62%]) and among HIV-infected persons (T-SPOT, 52% [95% CI, 40%–63%]; QFT-GIT, 50% [95% CI, 35%–65%]). There was no consistent evidence that either IGRA was more sensitive than the tuberculin skin test for active tuberculosis diagnosis.
Conclusions. In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection.
The clinical impact of Xpert MTB/RIF for tuberculosis (TB) diagnosis in high HIV-prevalence settings is unknown.
To determine the diagnostic accuracy and impact of Xpert MTB/RIF among high-risk TB suspects.
We prospectively enrolled consecutive, hospitalized, Ugandan TB suspects in two phases: baseline phase in which Xpert MTB/RIF results were not reported to clinicians and an implementation phase in which results were reported. We determined the diagnostic accuracy of Xpert MTB/RIF in reference to culture (solid and liquid) and compared patient outcomes by study phase.
477 patients were included (baseline phase 287, implementation phase 190). Xpert MTB/RIF had high sensitivity (187/237, 79%, 95% CI: 73–84%) and specificity (190/199, 96%, 95% CI: 92–98%) for culture-positive TB overall, but sensitivity was lower (34/81, 42%, 95% CI: 31–54%) among smear-negative TB cases. Xpert MTB/RIF reduced median days-to-TB detection for all TB cases (1 [IQR 0–26] vs. 0 [IQR 0–1], p<0.001), and for smear-negative TB (35 [IQR 22–55] vs. 22 [IQR 0–33], p = 0.001). However, median days-to-TB treatment was similar for all TB cases (1 [IQR 0–5] vs. 0 [IQR 0–2], p = 0.06) and for smear-negative TB (7 [IQR 3–53] vs. 6 [IQR 1–61], p = 0.78). Two-month mortality was also similar between study phases among 252 TB cases (17% vs. 14%, difference +3%, 95% CI: −21% to +27%, p = 0.80), and among 87 smear-negative TB cases (28% vs. 22%, difference +6%, 95% CI: −34 to +46%, p = 0.77).
Xpert MTB/RIF facilitated more accurate and earlier TB diagnosis, leading to a higher proportion of TB suspects with a confirmed TB diagnosis prior to hospital discharge in a high HIV/low MDR TB prevalence setting. However, our study did not detect a decrease in two-month mortality following implementation of Xpert MTB/RIF possibly because of insufficient powering, differences in empiric TB treatment rates, and disease severity between study phases.
Nucleic acid amplification tests (NAATs) have offered hope for rapid diagnosis of tuberculosis (TB). However, their efficiency with smear-negative samples has not been widely studied in low income settings. Here, we evaluated in-house PCR assay for diagnosis of smear-negative TB using Lowenstein-Jensen (LJ) culture as the baseline test. Two hundred and five pulmonary TB (PTB) suspects with smear-negative sputum samples, admitted on a short stay emergency ward at Mulago Hospital in Kampala, Uganda, were enrolled. Two smear-negative sputum samples were obtained from each PTB suspect and processed simultaneously for identification of MTBC using in-house PCR and LJ culture.
Seventy two PTB suspects (35%, 72/205) were LJ culture positive while 128 (62.4%, 128/205) were PCR-positive. The sensitivity and specificity of in-house PCR for diagnosis of smear-negative PTB were 75% (95% CI 62.6-85.0) and 35.9% (95% CI 27.2-45.3), respectively. The positive and negative predictive values were 39% (95% CI 30.4-48.2) and 72.4% (95% CI 59.1-83.3), respectively, while the positive and negative likelihood ratios were 1.17 (95% CI 0.96-1.42) and 0.70 (95% CI 0.43-1.14), respectively. One hundred and seventeen LJ culture-negative suspects (75 PCR-positive and 42 PCR-negative) were enrolled for follow-up at 2 months. Of the PCR-positive suspects, 45 (60%, 45/75) were still alive, of whom 29 (64.4%, 29/45) returned for the follow-up visit; 15 (20%, 15/75) suspects died while another 15 (20%, 15/75) were lost to follow-up. Of the 42 PCR-negative suspects, 22 (52.4%, 22/42) were still alive, of whom 16 (72.7%, 16/22) returned for follow-up; 11 (26.2%, 11/42) died while nine (21.4%, 9/42) were lost to follow-up. Overall, more PCR-positive suspects were diagnosed with PTB during follow-up visits but the difference was not statistically significant (27.6%, 8/29 vs. 25%, 4/16, p = 0.9239). Furthermore, mortality was higher for the PCR-negative suspects but the difference was also not statistically significant (26.2% vs. 20% p = 0.7094).
In-house PCR correlates poorly with LJ culture for diagnosis of smear-negative PTB. Therefore, in-house PCR may not be adopted as an alternative to LJ culture.
Pulmonary tuberculosis; Smear-negative TB; HIV-infected; HIV-TB co-infection; CD4 cell counts; Nucleic acid amplification tests; In-house PCR; Lowenstein-Jensen culture; Sensitivity; Specificity; Resource limited settings
Rationale: Tuberculosis case-detection rates are below internationally established targets in high-burden countries. Real-time monitoring and evaluation of adherence to widely endorsed standards of tuberculosis care might facilitate improved case finding.
Objectives: To monitor and evaluate the quality of tuberculosis case-detection and management services in a low-income country with a high incidence of tuberculosis.
Methods: We prospectively evaluated tuberculosis diagnostic services at five primary health-care facilities in Uganda for 1 year, after introducing a real-time, electronic performance-monitoring system. We collected data on every clinical encounter, and measured quality using indicators derived from the International Standards of Tuberculosis Care.
Measurements and Main Results: In 2009, there were 62,909 adult primary-care visits. During the first quarter of 2009, clinicians referred only 21% of patients with cough greater than or equal to 2 weeks for sputum smear microscopy and only 71% of patients with a positive sputum examination for tuberculosis treatment. These proportions increased to 53% and 84%, respectively, in the fourth quarter of 2009. The cumulative probability that a smear-positive patient with cough greater than or equal to 2 weeks would be appropriately evaluated and referred for treatment rose from 11% to 34% (P = 0.005). The quarterly number of tuberculosis cases identified and prescribed treatment also increased four-fold, from 5 to 21.
Conclusions: Poor adherence to internationally accepted standards of tuberculosis care improved after introduction of real-time performance monitoring and was associated with increased tuberculosis case detection. Real-time monitoring and evaluation can strengthen health systems in low-income countries and facilitate operational research on the effectiveness and sustainability of interventions to improve tuberculosis case detection.
tuberculosis; diagnosis; health care quality assurance; operations research; public health
Contamination by bacterial or fungal organisms reduces the effectiveness of mycobacterial culture for diagnosis of pulmonary tuberculosis (TB). We evaluated the effect of an anti-microbial and an anti-fungal oral rinse prior to expectoration on culture-contamination rates.
We enrolled a consecutive random sample of adults with cough for ≥2 weeks and suspected TB admitted to Mulago Hospital (Kampala, Uganda) between October 2008 and June 2009. We randomly assigned patients to oral rinse (60 seconds with chlorhexidine followed by 60 seconds with nystatin) vs. no oral rinse prior to initial sputum collection. Uganda National Tuberculosis Reference Laboratory technicians blinded to the method of sputum collection (with or without oral rinse) processed all sputum specimens for smear microscopy (direct Ziehl-Neelsen) and mycobacterial culture (Lowenstein-Jensen media).
Of 220 patients enrolled, 177 (80%) were HIV-seropositive (median CD4-count 37 cells/uL, IQR 13–171 cells/uL). Baseline characteristics were similar between patients in the oral-rinse (N = 110) and no oral-rinse (N = 110) groups. The proportion of contaminated cultures was significantly lower in the oral-rinse group compared to the no oral-rinse group (4% vs. 15%, risk difference −11%, 95% CI −18 to −3%, p = 0.005). Oral rinse significantly reduced the proportion of contaminated cultures among HIV-infected patients (3% vs. 18%, risk difference −14%, 95% CI −23 to −6%, p = 0.002) but not HIV-uninfected (6% vs. 4%, risk difference 2%, 95% CI −12 to +15%, p = 0.81) patients. However, the proportion of smear-positive specimens (25% vs. 35%, p = 0.10) and culture-positive specimens (48% vs. 56%, p = 0.24) were lower in the oral-rinse compared to the no oral-rinse group, although the differences were not statistically significant.
Oral rinse prior to sputum expectoration is a promising strategy to reduce mycobacterial culture contamination in areas with high HIV prevalence, if strategies can be devised to reduce the adverse impact of oral rinse on smear- and culture-positivity.
Background and objectives
The frequency, aetiologies, and outcomes of normal chest radiographs (CXRs) among HIV-seropositive patients with suspected pulmonary tuberculosis (TB) have been infrequently described.
Consecutive HIV-seropositive adults hospitalized for cough of ≥ 2 weeks duration at Mulago Hospital (Kampala, Uganda), between September 2007 and July 2008, were enrolled. Baseline CXRs were obtained on admission. Patients with sputum smears that were negative for acid-fast bacilli (AFB) were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii, and other fungi. Patients were followed for two months after enrolment.
Of the 334 patients, 54 (16%) had normal CXRs. These patients were younger (median age 30 vs. 34 years, P=0.002), had lower counts of CD4+ T lymphocytes (median 13 vs. 57 cells/μL, P<0.001), and were less likely to be smear positive for AFB (17% vs. 39%, P=0.002) than those with abnormal CXRs. Pulmonary TB was the most frequent diagnosis (44%) among those with normal CXRs, followed by unknown diagnoses, pulmonary aspergillosis, and pulmonary cryptococcosis. The frequency of normal CXRs was 12% among pulmonary TB patients. There was a trend towards increased two-month mortality among patients with normal CXRs compared to those with abnormal CXRs (40% vs. 29%, P=0.15).
Normal CXR findings were common among HIV-seropositive patients with suspected TB, especially those who were young, those with low CD4+ T cell counts, and those with sputum smears that were negative for AFB. Mortality was high among those with normal CXRs. Normal CXR findings should not preclude further diagnostic evaluation in this population.
clinical epidemiology; critical care medicine; immunodeficiency; radiology and other imaging; tuberculosis
To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from LTBI therapy.
Systematic review and meta-analysis.
We searched multiple databases through May2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-Gold In-tube [QFT-GIT] and T-SPOT. TB [TSPOT])in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in pre-specified sub-groups using forest plots, and where appropriate, calculated pooled estimates using random effects models.
The search identified 37 studies that included 5736 HIV-infected individuals. In3 longitudinal studies, the risk of active TB was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the 2 studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active TB(a surrogate reference standard for LTBI), pooled sensitivity estimates were heterogeneous, but higher for TSPOT (72%, 95% CI 62–81%) than for QFT-GIT (61%, 95% CI 41–75%). However, neither IGRA was consistently more sensitive than the tuberculin skin test (TST) in head-to-head comparisons. While TSPOT appeared to be less affected by immunosuppression than QFT-GIT and TST, overall, differences between the three tests were small or inconclusive.
Current evidence suggests that IGRAs perform similarly to the TST at identifying HIV-infected individuals with LTBI. Given that both tests have modest predictive value and sub-optimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistical considerations.
latent tuberculosis infection; systematic review; interferon-gamma release assay; HIV infection; tuberculin skin test
Peripheral blood interferon-gamma release assays (IGRAs) have sub-optimal sensitivity and specificity for diagnosis of active pulmonary tuberculosis (TB). However, assessment of local immune responses has been reported to improve the accuracy of TB diagnosis.
We enrolled HIV-infected adults with cough ≥2 weeks’ duration admitted to Mulago Hospital in Kampala, Uganda and referred for bronchoscopy following two negative sputum acid-fast bacillus smears. We performed an ELISPOT-based IGRA (T-SPOT.TB®, Oxford Immunotec, Oxford, UK) using peripheral blood and bronchoalveolar lavage (BAL) fluid mononuclear cells, and determined the accuracy of IGRAs using mycobacterial culture results as a reference standard.
94 HIV-infected patients with paired peripheral blood and BAL IGRA results were included. The study population was young (median age 34 years [IQR 28–40 years]) and had advanced HIV/AIDS (median CD4+ T-lymphocyte count 60 cells/µl [IQR 22–200 cells/µl]). The proportion of indeterminate IGRA results was higher in BAL fluid than in peripheral blood specimens (34% vs. 14%, difference 20%, 95% CI 7–33%, p = 0.002). BAL IGRA had moderate sensitivity (73%, 95% CI 50–89%) but poor specificity (48%, 95% CI 32–64%) for TB diagnosis. Sensitivity was similar (75%, 95% CI 57–89%) and specificity was higher (78%, 95% CI 63–88%) when IGRA was performed on peripheral blood.
BAL IGRA performed poorly for the diagnosis of smear-negative TB in a high HIV/TB burden setting. Further studies are needed to examine reasons for the large proportion of indeterminate results and low specificity of BAL IGRA for active TB in high HIV/TB burden settings.
The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study.
HIV/AIDS; pulmonary infections; pulmonary complications; smoking
During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV-associated Lung Infections and Complications (Lung HIV).
acquired immune deficiency syndrome; HIV; Pneumocystis; Pneumocystis pneumonia; dihydropteroate synthase
As HIV-infected persons on combination antiretroviral therapy (ART) are living longer and rates of opportunistic infections have declined, serious non–AIDS-related diseases account for an increasing proportion of deaths. Consistent with these changes, non–AIDS-related illnesses account for the majority of ICU admissions in more recent studies, in contrast to earlier eras of the AIDS epidemic. Although mortality after ICU admission has improved significantly since the earliest HIV era, it remains substantial. In this article, we discuss the current state of knowledge regarding the impact of ART on incidence, etiology, and outcomes of critical illness among HIV-infected patients. In addition, we consider issues related to administration of ART in the ICU and identify important areas of future research.
MeSH; intensive care unit; critical illness, human immunodeficiency virus; antiretroviral therapy; aging, quality of life
Infection with HIV increases the risk for lung diseases, including noninfectious pulmonary hypertension (PH). HIV-associated PH (HIV-PH) is an important lung disease in HIV-infected persons who live longer with antiretrovirals. The early stages of HIV-PH may be overlooked by healthcare providers due to nonspecific symptoms, including progressive dyspnea and nonproductive cough. HIV-PH may be detected via chest radiographs, CT scans, or electrocardiograms, but Doppler echocardiography is the most useful screening test to identify candidates for right heart catheterization. HIV-PH has a poor prognosis with high mortality; improved biomarkers to identify earlier stages of PH would benefit clinical care. The HIV-PH mechanism remains unknown, but HIV proteins such as Tat and Nef may play a role. HIV-1 Nef is a broad-spectrum adaptor protein that may affect HIV-infected and uninfected pulmonary vascular cells. Studies in macaques suggest that Nef is important in HIV-PH pathogenesis because monkeys infected with a chimeric simian immunodeficiency virus (SIV) expressing HIV-nef (SHIVnef) alleles, but not monkeys infected with the native SIV, develop pulmonary vascular remodeling. Four consistent amino acid mutations arose spontaneously in Nef passaged in the monkeys. To translate these findings to humans, one research endeavor of the Lung HIV Study focuses on the identification of HIV nef mutations in HIV-infected individuals with PH compared with HIV-infected normotensive patients. We present some of the preliminary evidence. Ongoing longitudinal studies will establish the connection between Nef mutations and the propensity for HIV-PH.
pulmonary hypertension; HIV proteins; HIV-1 Nef; pathogenesis; Lung HIV study
Smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are of particular concern in the HIV-infected population. Smoking rates are high in this population, and long-term exposure to cigarette smoke in the setting of HIV infection may increase the number of complications seen. Before the era of combination antiretroviral therapy, HIV-infected persons were noted to have an accelerated form of COPD, with significant emphysematous disease seen in individuals less than 40 years old. Unlike many of the AIDS-defining opportunistic infections, HIV-associated COPD may be more common in the current era of HIV because it is frequently reported in patients without a history of AIDS-related pulmonary complications and because many aging HIV-infected individuals have had a longer exposure to smoking and HIV. In this review, we document the epidemiology of HIV-associated COPD before and after the institution of combination antiretroviral therapy, review data suggesting that COPD is accelerated in those with HIV, and discuss possible mechanisms of HIV-associated COPD, including an increased susceptibility to chronic, latent infections; an aberrant inflammatory response; altered oxidant-antioxidant balance; increased apoptosis associated with HIV; and the effects of antiretroviral therapy.
HIV; chronic obstructive pulmonary disease; emphysema; immune reconstitution
Rationale: Smear-positive tuberculosis (TB) case detection rates are far below targets in most low-income countries. The standard approach to smear microscopy involves sputum collection over multiple days and examination of sputum smears by light microscopy (LM), an insensitive and time-consuming technique.
Objective: To determine whether two alternative approaches can increase smear-positive case detection by increasing the efficiency (single-specimen microscopy) or sensitivity (light-emitting diode [LED] fluorescence microscopy [FM]) of TB suspect evaluation.
Methods: We enrolled patients with cough of 2 weeks or more admitted to Mulago Hospital in Kampala, Uganda and collected spot and early morning sputum specimens. We compared the diagnostic accuracy of four prespecified strategies based on the number of sputum specimens collected (one specimen versus two specimens) and the type of microscopy (LM versus LED FM) using mycobacterial culture as a reference standard.
Measurements and Main Results: Two hundred thirty-three of 464 (50%) patients had culture-positive TB. There was no difference in sensitivity between single-specimen and two-specimen strategies when smears were examined with LM (55 vs. 56%; difference, −1%; 95% confidence interval [CI], −5 to +2%) or LED FM (61 vs. 64%; difference, −3%; 95% CI, −7 to +1%). LED FM was more sensitive than LM with both the single-specimen (61 vs. 55%; difference, 6%; 95% CI, 2–10%) and two-specimen strategies (64 vs. 56%; difference, 8%; 95% CI, 3–12%). Findings were similar among the HIV-infected patient subset (n = 321 patients).
Conclusions: In low-income, high TB burden settings, single-specimen microscopy and LED FM, either alone or in combination, could considerably increase identification of smear-positive TB cases.
tuberculosis; diagnosis; smear-positive case detection
Rationale: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era.
Objectives: To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons.
Methods: We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%).
Measurements and Main Results: Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline.
Conclusions: Pulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non–AIDS-defining and chronic conditions, many of which are associated with aging.
HIV; respiratory tract diseases; lung diseases, obstructive; pneumonia; pneumonia, bacterial
Respiratory infections are a leading cause of death in Africa, especially among HIV-infected patients. Data on the etiology of fatal respiratory diseases are largely based on autopsy studies. We evaluated causes of pneumonia associated with early mortality among hospitalized HIV-infected patients in Kampala, Uganda.
Prospective cohort study of HIV-infected patients admitted to Mulago Hospital, Kampala, with at least 2 weeks of cough. Consecutively enrolled patients with negative Ziehl Neelsen sputum smears for acid-fast bacilli underwent bronchoscopy with bronchoalveolar lavage and examination for mycobacteria (smear, solid culture), Pneumocystis jirovecii (Giemsa stain), and fungi (KOH mount, India ink stain, Sabouraud culture). Early mortality was defined as death before the 2-month follow-up visit.
Follow-up data were available for 353 (87%) of 407 patients enrolled. Of participants with follow-up data, 112 (32%) died within 2 months. Among patients with early mortality, a diagnosis was confirmed in 74 (66%), including tuberculosis (TB) (56%), cryptococcal pneumonia (1%), Pneumocystis pneumonia (3%), pulmonary Kaposi sarcoma (4%), and pneumonia caused by 2 or more disease processes (3%).
Mortality in HIV-infected TB suspects is high, with TB associated with the largest proportion of deaths. A significant proportion of patients die without a confirmed diagnosis.
HIV; tuberculosis; mortality; hospital admission; Africa
To determine the need for routine speciation of positive Lowenstein-Jensen mycobacterial cultures in HIV-infected patients suspected of having pulmonary tuberculosis at Mulago Hospital in Kampala, Uganda.
Sputum and bronchoalveolar lavage Lowenstein-Jensen mycobacterial culture isolates from consecutive, HIV-infected patients admitted to Mulago Hospital with 2 weeks or more of cough were subjected to IS6110 PCR and rpoB genetic analysis to determine the presence of Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM).
Eighty (100%) mycobacterial cultures from 65 patients were confirmed to be members of MTBC. Subsequent analysis of the cultures from 54 patients by PCR and sequence analyses to identify co-infection with NTM confirmed the presence of MTBC as well as the presence of Micrococcus luteus (n = 4), Janibacter spp. (n = 1) and six cultures had organisms that could not be identified.
Presumptive diagnosis of tuberculosis on the basis of a positive Lowenstein-Jensen culture is sufficient in HIV-infected Ugandans suspected of having tuberculosis. Routine molecular confirmation of positive Lowenstein-Jensen cultures is unnecessary in this low resource setting.
The prevalence and clinical course of pulmonary cryptococcosis in Sub-Saharan Africa are not well-described.
Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between September 2007 and July 2008 with cough ≥ 2 weeks were enrolled. Patients with negative sputum smears for acid-fast bacilli were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii, and fungi. Patients were followed two and six months after hospital discharge.
Of 407 patients enrolled, 132 (32%) underwent bronchoscopy. Of 132 BAL fungal cultures, 15 (11%) grew Cryptococcus neoformans. None of the patients were suspected to have pulmonary cryptococcosis on admission. The median CD4 count among those with pulmonary cryptococcosis was 23 cells/µL (IQR 7–51). Of 13 patients who completed six-month follow-up, four died and nine were improved, including five who had started antiretroviral therapy (ART) but had not received antifungal medication.
Pulmonary cryptococcosis is common in HIV-infected TB suspects in Uganda. Early initiation of ART in those with isolated pulmonary infection may improve outcomes, even without anti-fungal therapy. This finding suggests that some HIV-infected patients with C. neoformans isolated from respiratory samples may have colonization or localized infection.
Pulmonary Cryptococcosis; HIV/AIDS; Bronchoscopy